Anti-Cancer Drugs

Antitumor activity of triptolide in SKOV3 cells and SKOV3/DDP in vivo and in vitro

This study was designed to investigate the antitumor activity of triptolide in ovarian cancer inoculated with SKOV3 and SKOV3/cisplatin (DDP) cells, and to assess the mechanisms. In-vivo and in-vitro experiments were designed to evaluate the effects of triptolide on the tumor growth of SKOV3 and SKOV3/DDP cells. The experiments were divided into four groups: a SKOV3 group, a SKOV3 + TP treatment group, a SKOV3/DDP group and a SKOV3/DDP + TP treatment group. The expression of Sorcin, vascular endothelial growth factor and matrix metalloproteinase-2 were detected by western blotting and immunohistochemistry. Tumor cell apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling. In-vitro experiments showed that compared with SKOV3 control group, the level of colony-stimulating factor 1 and expression of Sorcin in SKOV3/DDP was significantly higher. Interestingly, triptolide treatment could reduce colony-stimulating factor 1 level and expression of Sorcin in both SKOV3 and SKOV3/DDP cell lines. In-vivo experiments showed that tissue necrosis area in SKOV3 + TP and SKOV3/DDP + TP was larger than SKOV3 and SKOV3/DDP group, respectively. Triptolide treatment induced apoptosis in both SKOV3 and SKOV3/DDP cells. Compared with SKOV3 group, the size of tumors was large, and the expression of MMP-2, Sorcin and vascular endothelial growth factor was higher in SKOV3/DDP group. Triptolide treatment reduced the size of tumors, and the expression of MMP-2, Sorcin and vascular endothelial growth factor in SKOV3/DDP as well as in SKOV3 tumors. In conclusion, triptolide has antitumor activity in both SKOV3 and SKOV3/DDP cells likely through inducing apoptosis and regulating MMP-2, Sorcin and vascular endothelial growth factor expression.

SMAC mimetic BV6 acts in synergy with mTOR inhibitor to increase cisplatin sensitivity in ovarian cancer

The objective of this study is to observe the antitumor efficacy of the second mitochondria-derived activator of caspases (SMAC) mimetic bivalent smac mimetic (BV6) in combination with target of rapamycin (mTOR) inhibitor on DDP (cisplatin) sensitivity. Ovarian cancer cells were exposed to cisplatin, BV6, DDP + BV6, and DDP + BV6 + mTOR inhibitor Rapamycin. Using proteomics and bioinformatics, protein expression profiles in ovarian cancer were determined. Bagg Albino color nude mice were treated with DDP or BV6 alone or in combination, or BV6 + DDP + Rapamycin. The effects of different treatments on ovarian cancer cells and tumor growth were evaluated in vivo and in vitro. Proteomics and bioinformatics analysis revealed significant changes of protein kinase (AKT)/mTOR pathway. Consistently, western blot data indicated that AKT/mTOR axis was gradually activated in BV6-treated ovarian cancer cells and attenuated the cytotoxic effect of BV6. Functional assays showed that DDP or BV6 treatment alone significantly enhanced the sensitivity and inhibited the migration of ovarian cancer cells, but without any synergistic effects. In addition, combination with BV6 and mTOR inhibitor Rapamycin significantly decreased cell viability and inhibited migration of ovarian cancer cells exposed to DDP. Consistently, the xenograft model showed that co-treatment with Rapamycin with BV6 had significantly suppressed tumor growth and metastasis. Our study demonstrated that SMAC analogue BV6 exhibits a strong anticancer effect on ovarian cancer in vitro and in vivo. Combination with Rapamycin overcomes the activation of mTOR pathway by BV6 and increases the chemosensitivity to DDP. These data suggest a potential application of triple combination with DDP + BV6 + Rapamycin in clinical management of ovarian cancer.

Mutational profile in circulating tumor DNA in a patient affected by low-risk endometrial cancer: predictable tool of relapse?

Endometrial cancer is the commonest gynecological cancer, the majority is endometrioid type, diagnosed at an early stage with 69–88% 5-year survival. Low-grade endometrial cancers have low recurrence rates and often do not receive adjuvant therapy; however, a subset of these patients will have poor outcomes and would benefit from adjuvant treatment has been challenging. We evaluate the circulating cell-free DNA (ccfDNA) in a patient with low-risk endometrial cancer in order to identify the presence of molecular markers associated with risk of recurrence. The evaluation of mutation profile was performed by next-generation sequencing (NGS) in primary tumor formalin-fixed paraffin-embedded (FFPE) tissue and in circulating tumor DNA (ctDNA). We identified a specific mutational profile in ctDNA, different from primary tumor tissue suggesting that the clone involved in the relapse may be different in comparison to the most represented in the primary tumor. These findings open new prospective and new wonderings. The molecular characterization of tissue may be useful for setting new target personalized therapy even in the treatment of endometrial cancer, moreover, endometrial cancer at low risk should be not underestimated for the incidence of relapse, and for this evaluation the molecular characterization may be useful. Moreover, these results suggest that the single analysis of primary tumors may be not sufficient for setting a specific personalized therapy targeted to avoid the relapse but may be necessary to join the molecular characterization of liquid biopsy to primary tissue.

Incidence of squamous cell carcinomas of the head and neck following prolonged pegylated liposomal doxorubicin

Despite numerous case reports, the incidence of a secondary diagnosis of head and neck squamous cell carcinoma (HNC) following pegylated liposomal doxorubicin (PLD) treatment is unknown. Computerized pharmacy records were searched at a large, multi-center healthcare system for patients who received PLD. Electronic medical records were searched to identify the patient’s age at treatment initiation of PLD, diagnosis for which they were treated with PLD, number of courses and total cumulative dose of PLD (TCDPLD) and secondary malignancies. Published PLD associated HNC was utilized to determine the lowest and median TCDPLD doses associated with HNC. One thousand two hundred ninety eligible patients who had been treated with PLD were identified. The lowest TCDPLD associated HNC in the literature is 405 mg/m2. In our healthcare system, 275 patients received more than 400 mg/m2 yielding a risk of 0.004%. One hundred fifty-one patients received the lowest TCDPLD associated with HNC cancer in our series which was 640 mg/m2 yielding a risk of 0.007%. Four of 30 patients (13.3%) developed HNC who received the median TCDPLD associated with HNC in the literature of 1440 mg/m2. Five of 20 patients (25%) receiving 1650 mg/m2 developed HNC in our healthcare system. Prolonged therapy with PLD is associated with an increased risk of HNC. This risk appears to be related to the cumulative dose varying from 0.004 to 13.3% at the lowest and median TCDPLD of reported cases in the literature, respectively. Oncologists need to be aware of this risk and to screen patients appropriately.

Precision design of an HLA-I-targeted multiepitope vaccine against human papillomavirus 16 oncoproteins E6/E7: integrated immunoinformatic and immunogenicity profiling

Viral oncogenes E6 and E7 are ideal targets for therapeutic vaccines against human papillomavirus (HPV)-associated cervical cancer (CC). T cell-mediated immunity plays a crucial role in the clearance of HPV infection and regression of intraepithelial neoplasia. Current strategies for therapeutic vaccine development predominantly depend on immunoinformatic predictions of human leukocyte antigen (HLA)-restricted cytotoxic T lymphocyte (CTL) epitopes. Three T-cell epitope prediction programs were used to identify HPV16 E6 and E7 epitopes restricted to HLA-A*02:01. Subsequently, in silico evaluations were performed using five bioinformatic databases and computational servers. The binding affinities of these peptides to HLA-A2 molecules were experimentally validated using a T2 cell-binding assay. The effectiveness of the vaccine developed by combining peptides and CpG-containing oligonucleotide (CpG-ODN) was validated by inducing the generation of CTLs ex vivo, and its immunogenicity was verified in HLA-A*02:01/H-2D d (AAD) transgenic mice. Eight HLA-A*02:01-restricted candidate peptides were preliminarily identified, and all candidate peptides demonstrated binding capabilities to HLA-A2 molecules. Using the integrated approach, four high-affinity peptides were successfully identified. Notably, these peptides also exhibited the potential to induce dendritic cell maturation, enhance the activation and proliferation of CD8 + T cells, and elicit potent antigen-specific CTL responses against tumor cells. These findings support the potential application of the selected peptides in CTL-based immunotherapy for HPV-driven malignancies. Furthermore, the described peptide-screening platform proved to be an effective strategy for the rational design of candidate antigens for HPV therapeutic vaccines.

CDKN2A inhibited ferroptosis through activating JAK2/STAT3 pathway to modulate cisplatin resistance in cervical squamous cell carcinoma

Cervical squamous cell carcinoma (CESC) is a significant threat to women’s health. Resistance to cisplatin (DDP), a common treatment, hinders the therapeutic efficacy. Understanding the molecular basis of DDP resistance in CESC is imperative. Cyclin-dependent kinase inhibitor 2A (CDKN2A) expression was evaluated through quantitative real-time-PCR and western blot in clinical samples from 30 CESC patients and human cervical epithelial cells and CESC cell lines (SiHa, C33A, and Caski). It was also evaluated through bioinformatics analysis in Timer, Ualcan, and GEPIA database. Cell viability was detected by CCK-8. Apoptosis was detected by Calcein AM/PI assay. Lipid reactive oxygen species (ROS), malondialdehyde, glutathione, Fe2+, and iron level were detected by kits. Protein level of JAK2, STAT3, p-JAK2, p-STAT3, ACSL4, GPX4, SLC7A11, and FTL were detected by western blot. In CESC, elevated CDKN2A expression was observed. Cisplatin exhibited a dual effect, inhibiting cell proliferation and inducing ferroptosis in CESC. CDKN2A knockdown in a cisplatin-resistant cell line suppressed proliferation and induced ferroptosis. Moreover, CDKN2A was identified as an inhibitor of erastin-induced ferroptosis. Additionally, targeting the JAK2/STAT3 pathway enhanced ferroptosis in cisplatin-resistant cells. CDKN2A could inhibit ferroptosis in CESC through activating JAK2/STAT3 pathway to modulate cisplatin resistance.

Regulation of cervical cancer via G15-mediated inhibition of G protein-coupled estrogen receptor

Cervical cancer is among the most common gynecological malignancies. G protein-coupled estrogen receptor (GPER) is involved in the development of various tumors; however, its role in cervical cancer remains unclear. We investigated whether G15, an inhibitor of GPER, can regulate its expression and affect cervical cancer progression. We examined the biological behaviors of G15-treated SiHa and HeLa cells using Cell Counting Kit-8, monoclonal proliferation, plate scratching, and Transwell invasion experiments. Western blotting was used to detect the expression of GPER, E-cadherin, N-cadherin, vimentin, Bcl-2, Bax, phosphatidylinositol-3-kinase (PI3K)/AKT, and programmed death ligand 1 (PD-L1). The expression of GPER, E-cadherin, vimentin, and PD-L1 in cervical cancer and adjacent tissues was detected using immunohistochemistry. The correlation between GPER expression and clinicopathological characteristics was analyzed. The expression of GPER in cervical cancer tissues was significantly higher than that in paracancerous tissues, and it was detected in the membrane and cytoplasm of SiHa and HeLa cells. The proliferation, migration, and invasion abilities of SiHa and HeLa cells were reduced after G15 treatment. The G15-treated groups exhibited higher expression of E-cadherin and Bax and lower expression of N-cadherin, vimentin, Bcl-2, GPER, p-PI3K, p-AKT, and PD-L1 than the control group. The expression of E-cadherin was lower and that of vimentin was higher in cancer tissues than in paracancerous tissues; PD-L1 was highly expressed in tumor and stromal cells in cancer tissues but not in paracancerous tissues. G15 functions by regulating the GPER/PI3K/AKT/PD-L1 signaling pathway and may serve as a new immunotherapy for treating patients with cervical cancer.

Efficacy of nimotuzumab in combination with immunotherapy for a young recurrent cervical cancer patient: a case report and literature review

Cervical cancer is one of the most common malignant tumors in women, and more than one-third of the patients have already developed to a locally advanced stage at initial diagnosis. After standard concurrent chemoradiotherapy, recurrence still occurs in 29–38% of patients with locally advanced cervical cancer (LACC), and the 5-year survival rate of patients with recurrence is only 3.8–13.0%, resulting in a poor prognosis and limited therapeutic choices. Currently, the recommended first-line systemic treatment for recurrent metastatic cervical cancer involves cisplatin or carboplatin in combination with paclitaxel-based chemotherapy, supplemented with the antivascular agent bevacizumab and the immune checkpoint inhibitor pembrolizumab. The use of these drugs, however, is limited due to side effects such as myelosuppression, gastrointestinal perforation, and bleeding, so new treatment modalities need to be explored. Anti-EGFR (epithelial growth factor receptor, anti-surface growth factor receptor antibody) targeted drugs have been demonstrated to have a significant radiosensitizing effect on synchronous chemoradiotherapy in LACC and are now considered to have potential for the treatment of recurrent cervical cancer. We represented a LACC patient who relapsed 6 months after concurrent chemoradiotherapy. The patient received six cycles of nimotuzumab combined with camrelizumab, and the efficacy was evaluated to be partial remission after two or four cycles of treatment, with progression-free survival up to 9 months, without significant side effects. Until March 2024, the patient was still undergoing treatment. Promising efficacy and tolerable side effects of nimotuzumab in combination with camrelizumab were observed in this case.

EZH2-mediated lncRNA ABHD11-AS1 promoter regulates the progression of ovarian cancer by targeting miR-133a-3p

Long-chain noncoding RNAs (lncRNAs) are involved in a wide range of biological and pathological processes in ovarian cancer. The purpose of this study was to investigate the effects of EZH2-mediated ABHD11-AS1 promoter on the pathogenesis of ovarian cancer. The expression levels of EZH2, ABHD11-AS1 and miR-133a-3p were examined in ovarian cancer tissues using reverse transcription-quantitative PCR. Cell proliferation was evaluated using cell counting kit 8 assay, and cell invasion/migration was determined using a Transwell assay. Cell apoptosis was evaluated using flow cytometry. Dual luciferase assay was performed to confirm the interaction between ABHD11-AS1 and miR-133a-3p. The binding site of H3K27me3 on ABHD11-AS1 promoter was confirmed by ChIP. The expression of ABHD11-AS1 was significantly upregulated in ovarian cancer samples, and its levels were closely associated with lymph node metastasis, tumor stage and 3-year survival rate. Furthermore, interference of ABHD11-AS1 suppressed the proliferation, migration and invasion of ovarian cancer cells, while cell apoptosis was promoted. Additionally, miR-133a-3p could be a novel target of ABHD11-AS1, and EZH2-mediated H3K27me3 protein might bind to ABHD11-AS1 promoter directly. Moreover, rescue experiments indicated that the effects caused by ABHD11-AS1 knockdown on the malignant characteristics of ovarian cancer cells were notably enhanced by miR-133a-3p mimics, whereas the influences on cell growth and metastasis induced by overexpressed ABHD11-AS1 were abrogated by the restoration of miR-133a-3p expression. In summary, EZH2-mediated enrichment of H3K27me3 on ABHD11-AS1 promoter could regulate the progression of ovarian cancer via miR-133a-3p. Therefore, EZH2/ABHD11-AS1/miR-133a-3p axis might be a putative candidate for targeted treatment of ovarian cancer.

The mechanism of circ-PIP5K1A/miR-942-5p/NFIB axis in cisplatin resistance in ovarian cancer based on imaging and molecular diagnosis

Cisplatin (DDP)-based chemotherapy is the main chemotherapeutic agent for ovarian cancer (OC) treatment. Circular RNA PIP5K1A (circ-PIP5K1A) was found to promote OC tumorigenesis. However, whether circ-PIP5K1A was involved in DDP resistance in OC remains unclear. Levels of circ-PIP5K1A, microRNA (miR)-942-5p, and nuclear factor I B (NFIB) were detected using quantitative real-time PCR and Western blot assays. In-vitro experiments were conducted by using cell counting kit-8, cell colony formation, 5-ethynyl-2′-deoxyuridine, flow cytometry, and transwell assays, respectively. In-vivo assay was performed using murine xenograft model. The binding interaction between miR-942-5p and circ-PIP5K1A or NFIB was confirmed using dual-luciferase reporter assay. Exosomes were obtained from culture media by the use of commercial kits and qualified by transmission electron microscopy and Western blot. Circ-PIP5K1A was highly expressed in DDP-resistant OC tissues and cells. Circ-PIP5K1A knockdown could constrain the proliferation, migration, and invasion, as well as increase apoptosis and sensitivity to DDP in DDP-resistant OC cells. Mechanistically, circ-PIP5K1A acted as a sponge for miR-942-5p to positively regulate NFIB expression. Moreover, rescue experiments demonstrated that the anticancer and DDP sensitization effects caused by circ-PIP5K1A silencing in DDP-resistant OC cells were achieved through the miR-942-5p/NFIB axis. Importantly, circ-PIP5K1A silencing enhanced DDP efficacy and impeded tumor growth in OC in vivo. Additionally, we also found that circ-PIP5K1A was packaged into exosomes and could be internalized by surrounding cells. Circ-PIP5K1A knockdown reduced the resistance to DDP in OC via regulating miR-942-5p/NFIB axis. Besides that, circ-PIP5K1A was packaged into exosomes and exosomal circ-SKA3 could mediate intercellular communication between OC cells. These findings provided a promising therapeutic target for OC.

CircBNC2 affects epithelial ovarian cancer progression through the miR-223-3p/LARP4 axis

Epithelial ovarian cancer (EOC) is one of the most serious cancer. Circular RNA BNC2 (circBNC2) expression was decreased in EOC tissues. However, the molecular mechanism of circBNC2 remains unknown. The expression of circBNC2, microRNA-223-3p (miR-223-3p), and La-related proteins 4 (LARP4) were detected by quantitative real-time fluorescence PCR (qRT-PCR). A series of in-vitro experiments were designed to explore the function of circBNC2 in EOC cells and the regulatory mechanism between circBNC2 and miR-223-3p and LARP4 in EOC cells. Western blot examined the protein levels of Snail1, Slug, and LARP4. The relationship between miR-223-3p and circBNC2 or LARP4 was verified by Dual-luciferase reporter assays. The xenotransplantation model was established to study the role of circBNC2 in vivo. The expression of circBNC2 and LARP4 was decreased in EOC tissues, while the expression of miR-223-3p was increased. CircBNC2 can sponge miR-223-3p, and LARP4 is the target of miR-223-3p. In-vitro complement experiments showed that overexpression of circBNC2 significantly decreased the malignant behavior of EOC, while co-transfection of miR-223-3p mimics partially upregulated this change. In addition, LARP4 knockdown increased the proliferation, migration, and invasion of EOC cells inhibited by miR-223-3p inhibitor. Mechanically, circBNC2 regulates LARP4 expression in EOC cells by spongy miR-223-3p. In addition, in-vivo studies have shown that overexpression of circBNC2 inhibits tumor growth. Overexpression of circBNC2 decreased proliferation, migration, and invasion of EOC cells by regulating the miR-223-3p/LARP4 axis, suggesting that circBNC2/miR-223-3p/LARP4 axis may be a potential regulatory mechanism for the treatment of EOC.

CircSETDB1 contributes to paclitaxel resistance of ovarian cancer cells by sponging miR-508-3p and regulating ABCC1 expression

Ovarian cancer is a gynecological tumor with a poor prognosis. The chemotherapy failure and recurrence induced by paclitaxel (Ptx) resistance are the main reason for the failure of ovarian cancer treatment. In this study, we aimed to explore the role of circular RNA (circRNA) in the regulation of Ptx resistance in ovarian cancer. Quantitative reverse transcription PCR was performed to detect the expression of circRNA SET domain bifurcated histone lysine methyltransferase 1 (circSETDB1), microRNA (miR)-508-3p and ATP-binding cassette subfamily C member 1 (ABCC1) mRNA. The effects of circSETDB1 on Ptx resistance were explored by cell counting kit-8, 5-ethynyl-2′-deoxyuridine, and flow cytometry experiments in vitro. The protein level was assessed by western blot. Dual-luciferase reporter and RNA pull-down assays were carried out to confirm the interactions among circSETDB1, miR-508-3p, and ABCC1. Xenograft tumor experiment was performed to investigate the effect of circSETDB1 on Ptx resistance in vivo. CircSETDB1 was highly expressed in Ptx-resistant ovarian cancer. CircSETDB1 knockdown inhibited cell proliferation viability, half maximal inhibitory concentration value of Ptx, cell cycle progression, and induced cell apoptosis in Ptx-resistant ovarian cancer cells. miR-508-3p was a target of circSETDB1, and inhibition of miR-508-3p overturned the effects of circSETDB1 knockdown on the Ptx resistance of ovarian cancer cells. miR-508-5p could bind to ABCC1. Overexpression of ABCC1 reversed the effects of circSETDB1 knockdown on the Ptx resistance of ovarian cancer cells. CircSETDB1 knockdown also enhanced Ptx sensitivity in vivo. In conclusion, circSETDB1 regulated Ptx resistance of ovarian cancer by targeting miR-508-3p/ABCC1 axis.

Phase II study of gemcitabine, cisplatin, and bevacizumab for first recurrent and refractory ovarian clear cell carcinoma Kansai Clinical Oncology Group-G1601

Patients with advanced ovarian clear cell carcinoma (CCC) have a poor prognosis in the absence of an effective standard treatment. Combination therapy with gemcitabine, cisplatin, and bevacizumab (GPBev) is promising for ovarian CCC. Thus, we conducted a multi-institutional, phase II trial in Japan to examine the efficacy and safety of GPBev for CCC. This is the first study on the use of GPBev for CCC. Eighteen patients (median age, 56.5 years) with pathologically confirmed first recurrent or refractory CCC and having evaluable regions, as assessed using RECIST, were recruited between January 2017 and May 2019. Gemcitabine (1000 mg/m2), cisplatin (40 mg/m2), and bevacizumab (10 mg/kg) were administered intravenously on days 1 and 15, every 28 days, for 6–10 cycles, until disease progression or intolerable toxicity. The primary endpoint was overall response rate (ORR). The secondary endpoints included disease control rate (DCR) and adverse events (AEs). Fifteen patients (83.3%) completed 6–10 cycles of treatment; three patients (two with AEs and one with progressive disease) did not. The ORR was 61.1% [complete response (CR) 3 and partial response (PR) 8] and DCR was 88.9% (CR 3, PR 8, and stable disease 5). Grade 3 and 4 hematological AEs were observed in 16.7 and 5.6% of the patients, respectively. Nonhematological AEs of grades 3 and 4 were observed in 27.8 and 5.6% of the patients, respectively. GPBev is a promising therapy for CCC owing to the high ORR and acceptable toxicity for the first recurrence and refractory CCC.

Circ_0026123 promotes cisplatin resistance and progression of ovarian cancer by upregulating RAB1A through sequestering miR-543

Background Circular RNAs can act as critical regulators in the tumorigenesis and chemoresistance of ovarian cancer (OC). Herein, this work aimed to probe the function and mechanism of circ_0026123 in the cisplatin (DDP) resistance and progression of OC and its potential value in the clinic. Methods The quantitative real-time PCR and western blotting were used to detect the levels of RNAs and proteins. In vitro experiments were conducted using CCK-8, EdU, transwell, tube formation assays and flow cytometry. Mouse subcutaneous xenograft model was used for in vivo experiments. The interaction between circ_0026123 or RAB1A (Ras-related protein Rab-1A) and miR-543 was confirmed using dual-luciferase reporter and RNA immunoprecipitation assays. Results Circ_0026123 expression was higher in DDP-resistant OC tissues and cells. Silencing of circ_0026123 dramatically boosted the sensitivity of DDP-resistant OC cells to DDP, as well as inhibited cell growth, angiogenesis, invasion and migration abilities in vitro. Circ_0026123 functionally targeted miR-543, and knockdown of miR-543 reversed the impacts of circ_0026123 deficiency on DDP sensitivity and the malignant behaviors of DDP-resistant OC cells. RAB1A was a target of miR-543, RAB1A overexpression attenuated the inhibitory functions of miR-543 on DDP resistance and the malignant phenotypes of DDP-resistant OC cells. Preclinically, lentivirus-mediated circ_0026123 downregulation also suppressed OC growth and enhanced DDP cytotoxicity in vivo. Conclusion Our study demonstrated that circ_0026123 acted as a sponge for miR-543 to elevate RAB1A expression, thus promoting cisplatin resistance and tumorigenesis in ovarian cancer.

Circular RNA circ_0000212 accelerates cervical cancer progression by acting as a miR-625-5p sponge to upregulate PTP4A1

Cervical cancer is one of the most common malignant tumors in women. Circular RNA (circRNA) has been shown to play a crucial role in cervical cancer. Here, the aim of this study was to explore the functions and a novel miRNA/mRNA network underlying circ_0000212 in cervical cancer regulation. The expression of circ_000212, miR-625-5p and Protein Tyrosine Phosphatase 4A1 (PTP4A1) mRNA was measured by quantitative real-time PCR (qRT-PCR). 5-ethynyl-2’-deoxyuridine assay was conducted to detect the proliferation of cervical cancer cells. Wound healing and transwell assays were employed to assess cell migration and invasion. The angiogenesis abilities of cervical cancer cells were evaluated by tube formation assay. Flow cytometry was performed for analyzing cell apoptosis. The expression of PTP4A1 protein and apoptosis-relative protein were detected via western blot. The dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were employed to clarify the interaction between circ_0000212 or PTP4A1 and miR-625-5p. The impact of circ_0000212 on cervical cancer growth in vivo was detected by xenograft assay. Circ_0000212 and PTP4A1 were highly expressed and miR-625-5p expression level was decreased in cervical cancer. Circ_0000212 silencing suppressed cervical cancer cell proliferation, migration, invasion and angiogenesis while promoting apoptosis. MiR-625-5p was targeted by circ_0000212, and miR-625-5p inhibition reversed the effects of circ_0000212 knockdown. MiR-625-5p directly targeted PTP4A1, and the inhibitory effect of miR-625-5p on the malignant progression of cervical cancer was reversed after PTP4A1 overexpression. In-vivo assays validated that circ_0000212 promoted cervical cancer tumor growth in vivo. circ_0000212 acted as an oncogene in cervical cancer progression, and knockdown of circ_0000212 repressed cervical cancer development by increasing miR-625-5p and decreasing PTP4A1.

Extensive vitiligo associated to response to c-kit inhibitor in metastatic mucosal melanoma

Mucosal melanoma is rare and accounts for 1.3–1.4% of all melanomas. Kit mutations are found in approximately 15–20% of mucosal melanomas. Immunotherapy with anti cytotoxic T-lymphocyte associated protein 4 and antiprogrammed cell death protein 1 have reported low clinical efficacy in this melanoma subtype. Studies with Kit inhibitor Imatinib showed response rates ranging from 20 to 30%. We present the case of a patient with a c-kit mutated metastatic melanoma who developed autoimmune vitiligo during treatment with oral tyrosine kinase inhibitor Masitinib.

PARP inhibitors decrease response to subsequent platinum-based chemotherapy in patients with BRCA mutated ovarian cancer

To determine the effect of poly-adenosine ribose phosphatase inhibitors (PARPi) on the response to subsequent platinum-based chemotherapy (PBC) in patients with recurrent, platinum-sensitive BRCA-mutated epithelial ovarian, peritoneal, or fallopian cancer (BRCAm EOC). This is a retrospective, single-institution cohort study of patients with BRCAm EOC who received retreatment with PBC. The PFS of patients with BRCAm EOC to 2nd or 3rd PBC with and without a prior PARPi was determined. Additionally, we compared the PFS to subsequent PBC following a prior PARPi for BRCAm and non-BRCAm. One hundred and fifteen patients with BRCAm EOC received a 2nd PBC and 55 received a 3rd PBC. The median PFS was 2.3 and 2.4 times longer, respectively for patients who did not receive a PARPi, (2nd P = 0.005, 3rd P < 0.001). Among 20 PARPi exposed patients with BRCAm EOC the PFS to a 2nd or 3rd PBC was worse at 8.0 months vs. 19.1 months HR 4.01 [2.25,7.16], P < 0.001. Following PARPi exposure the PFS for patients with BRCAm EOC was similar for patients with platinum-free intervals of 6–12, 12–24 and >24 months. Following PARPi exposure the PFS was similar for patients with BRCAm EOC and non BRCAm EOC. Among patients with BRCAm EOC PARPi exposure significantly reduced PFS following 2nd and 3rd PBC. PARPi exposure nullifies established prognostic factors (i.e. platinum-free interval and BRCA mutational status) in platinum-sensitive recurrent ovarian cancer.

Circular RNA circ_0005667 promotes cisplatin resistance of endometrial carcinoma cells by regulating IGF2BP1 through miR-145-5p

Background Circular RNA (circRNA) plays a significant role in cisplatin (DDP) resistance. The purpose of this study was to explore the role of circ_0005667 in DDP resistance of endometrial carcinoma (EC) cells. Methods The expression of circular RNA circ_0005667, microRNA-145-5p (miR-145-5p) and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in DDP-sensitive and DDP-resistant EC tissues and EC cells was determined by quantitative real-time PCR (qRT-PCR). The expression of apoptosis-related proteins, drug resistance-related proteins and IGF2BP1 proteins were detected by western blot. The half-maximal inhibitory concentration (IC50) of DDP was determined using a cell counting kit-8 (CCK-8) assay. For functional assays, cell proliferation, migration, invasion and cell apoptosis were determined using 5-ethynyl-2’-deoxyuridine (EdU) assay, wound healing assay, transwell assay and flow cytometry assay, respectively. The binding relationship between miR-145-5p and circ_0005667 or IGF2BP1 was verified by dual-luciferase reporter assay. A xenograft experiment was applied to clarify the functional role of circ_0005667 in vivo. Results Levels of circ_0005667 and IGF2BP1 were markedly increased, whereas miR-145-5p was downregulated in DDP-resistant EC tissues and cells. The circ_0005667 deficiency could enhance DDP sensitivity, inhibit cell proliferation, migration and invasion and promote cell apoptosis in DDP-resistant EC cells in vitro. Mechanistically, circ_0005667 modulated IGF2BP1 expression through sponging miR-145-5p. In addition, miR-145-5p depletion attenuated circ_0005667 silencing-induced effects in EC cells. The regulation of miR-145-5p in DDP resistance involved low IGF2BP1 expression. In vivo experiments revealed that circ_0005667 silencing could improve the sensitivity of the tumor to DDP. Conclusion Circ_0005667 enhanced DDP resistance in EC by elevating IGF2BP1 through sponging miR-145-5p.

Targeted therapy clinical trials in ovarian cancer: improved outcomes by gene mutation screening

Epithelial ovarian cancer is the most common and leading cause of death for gynaecologic cancer in the western world. Current standard treatments with limited selection of chemotherapies cannot meet patients’ urgent needs. Novel targeted therapies may improve patients’ survival rate with less side effects that have been demonstrated by using approved medicines such as poly ADP-ribose polymerase and angiogenesis inhibitors. Many classes of targeted therapies impacting cell signalling pathways related to ovarian cancer tumorigenesis have been investigated in clinical trial studies. Gene mutation screening is a powerful tool for improvement of success rate of the trials for better patient selection and interpretation of clinical outcomes. Increasing number of patients are being screened for genetic alterations particularly in ‘basket’ trials that are offering new, genetic-oriented therapies to patients. Thus, in this review, we have searched databases of Pubmed and Clinicaltrials.gov for the past and current phase III and selected phase II ovarian cancer clinical trials with focus on gene profiling. Lessons from both successful and failed trials and implications of ongoing trials are discussed.

Overexpression of circ_CELSR1 facilitates paclitaxel resistance of ovarian cancer by regulating miR-149-5p/SIK2 axis

Circular RNAs (circRNAs) have emerged as vital regulators in the chemoresistance of diverse human tumors, including ovarian cancer. In the present study, we attempted to explore the function of circ_CELSR1 in paclitaxel resistance of ovarian cancer. Quantitative real-time PCR (qRT-PCR) was conducted for the expression of circ_CELSR1, miR-149-5p and salt inducible kinase 2 (SIK2). Cell Counting Kit-8 (CCK-8) assay was performed to evaluate the half-maximal inhibitory concentration (IC50) of paclitaxel and cell viability. Colony formation assay was adopted for cell colony formation. Flow cytometry analysis was conducted to analyze cell cycle process and apoptosis. Western blot assay was utilized to determine the protein levels. RNA immunoprecipitation (RIP) and dual-luciferase reporter assays were conducted to verify the association between miR-149-5p and circ_CELSR1 or SIK2. Murine xenograft model assay was carried out to determine the effect of circ_CELSR1 in paclitaxel resistance in vivo. Circ_CELSR1 was upregulated in paclitaxel-resistant ovarian cancer tissues and cells. Circ_CELSR1 knockdown enhanced paclitaxel sensitivity and cell apoptosis and repressed cell viability, colony formation and cell cycle process in paclitaxel-resistant ovarian cancer cells. For mechanism analysis, circ_CELSR1 could positively modulate SIK2 expression via sponging miR-149-5p. MiR-149-5p inhibition effectively restored the impacts of circ_CELSR1 knockdown on paclitaxel resistance and cell progression in paclitaxel-resistant ovarian cancer cells. MiR-149-5p overexpression suppressed paclitaxel resistance and cell progression in paclitaxel-resistant ovarian cancer cells by interacting with SIK2. In addition, circ_CELSR1 silencing impeded paclitaxel resistance of ovarian cancer in vivo. Circ_CELSR1 improved the resistance of ovarian cancer to paclitaxel by regulating miR-149-5p/SIK2 axis.

Demonstrating the effect of SHP2 inhibitor on cervical squamous cell carcinoma from the perspective of ZAP70

SHP2, encoded by the PTPN11 gene, plays an important role in regulating immune cell functions in tumor microenvironment. Several SHP2 inhibitors have entered the clinical trial stage, but cervical squamous cell carcinoma (CSCC) has not been included in the indications. In Tlymphocytes, SHP2 can promote the dephosphorylation of ZAP70 kinase in the T cell receptor signaling complex after recruitment to the PD-1 cytoplasmic tail. In this study, we used bioinformatics tools to confirm that ZAP70 has a widespread impact on the immunity of CSCC, which is closely related to the survival of CSCC. The effect of ZAP70 on the survival of cervical cancer may not depend on the structure or amplification, but on the enhancement of function. And we identified ZAP70 and PTPN11 protein–protein interactions. SHP2 inhibitor is worth to be studied in the treatment of CSCC.

Weekly versus triweekly cisplatin-alone adjuvant chemoradiotherapy after radical hysterectomy for stages IB–IIA cervical cancer with risk of recurrence

Weekly and triweekly cisplatin-alone concomitant chemoradiotherapy regimens after radical surgery were compared in stages IB–IIA cervical cancer with intermediate- or high-risk factors to identify the better therapeutic regimen. We retrospectively analyzed patients with stages IB–IIA cervical cancer who received radical hysterectomy followed by concurrent adjuvant chemoradiotherapy to compare the efficiency between weekly and triweekly regimen groups. We evaluated between-group differences in survival, recurrence, compliance, and adverse effects. A total of 217 patients were included in this study (triweekly group vs. weekly group; 97 vs. 120). The mean follow-up was 47.2 months. The 5-year disease-free survival (DFS) was 84.4% or 76.5% for patients treated with triweekly cisplatin chemotherapy or the weekly regimen, respectively (P = 0.110). The 5-year overall survival (OS) was 82.4 and 78.6% for the same treatment groups, respectively (P = 0.540). The DFS of the patients with pelvic lymph node metastasis were marginally better in triweekly regimen group compared with the weekly group (P = 0.031). Grades 3–4 leukopenia was significantly more common in the triweekly group (P = 0.028). The weekly cisplatin chemotherapy group experienced the same therapeutic effect as the triweekly cisplatin-alone chemotherapy group but with less toxicity. However, triweekly cisplatin regimen reduced the recurrence in patients with pelvic lymph node metastasis.

Circular RNA circVPRBP serves as a microRNA-106b-5p sponge to regulate proliferation and metastasis of cervical cancer cells via tripartite motif-containing protein 3

Cervical cancer is a common malignant gynecological tumor for females all over the world. Circular RNAs (circRNAs) are being found to have relevance to various human cancers, including cervical cancer. This study is designed to explore the role and mechanism of circRNA DDB1- and CUL4-associated factor 1 (circVPRBP, also known as hsa_circ_0065898) on the progression of cervical cancer. CircVPRBP, microRNA-106b-5p (miR-106b-5p), and tripartite motif-containing protein 3 (TRIM3) levels were determined by real-time quantitative PCR. Cell proliferative ability, apoptosis rate, cell cycle progression, migration, and invasion were detected by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide, 5-ethynyl-2′-deoxyuridine, colony formation assay, flow cytometry, and transwell assays. Protein levels of matrix metallopeptidase 2 (MMP2) and matrix MMP9, and TRIM3 were measured by western blot assay. The binding relationship between miR-106b-5p and circVPRBP or TRIM3 was predicted by Starbase and then verified by a dual-luciferase reporter and RNA immunoprecipitation assays. The biological role of circVPRBP on cervical tumor growth was examined by the xenograft tumor model in vivo. CircVPRBP and TRIM3 were decreased, and miR-106b-5p was increased in cervical cancer tissues and cell lines. Furthermore, circVPRBP could suppress cell growth and metastasis of cervical cancer cells in vitro. Mechanically, circVPRBP could regulate TRIM3 expression by sponging miR-106b-5p. Also, circVPRBP upregulation repressed tumor growth of cervical cancer cells in vivo. CircVPRBP could inhibit the malignant biological behavior of cervical cancer cells by miR-106b-5p/TRIM3 axis, providing a promising therapeutic target for cervical cancer treatment.

Circ_0009035 regulates the progression of cervical cancer by targeting miR-1305/CREBRF axis

Circular RNAs (circRNAs) have a crucial role in the occurrence of many diseases, such as tumors. Yet the roles of circ_0009035 (circRACGAP1) in cervical cancer are not fully characterized. The expression levels of circRACGAP1, miR-1305 and cAMP-responsive element-binding protein 3 regulatory factor (CREBRF) were detected by using real-time quantitative PCR or western blot. Cell counting kit-8 assay, 5-ethynyl-2’-deoxyuridine, colony formation assay, transwell assay and tube formation assay were used to detect cell proliferation, migration and invasion and angiogenesis, respectively. Flow cytometry assay was used to analyze the cell apoptosis. Dual-luciferase reporter assay and RNA immunoprecipitation assay were performed to analyze the targeting about miR-1305 and circ_0009035 or CREBRF. Xenograft model was built to study the role of circ_0009035 in vivo. Immunohistochemistry was used to detect the expression of Ki67, epithelial cadherin and vimentin. First, we found that circ_0009035 expression was significantly upregulated in tumor cells and tissues; second, knockdown of circ_0009035 could inhibit cell proliferation, migration and invasion and promote cell apoptosis. Subsequently, circ_0009035 was found to be able to target miR-1305, and the expression of miR-1305 in tumor tissues and cells was significantly lower. MiR-1305 inhibitor could restore cell-related progression of cervical cancer inhibited by si-circ_0009035. Finally, miR-1305 could target CREBRF, and circ_0009035 could regulate CREBRF expression by targeting miR-1305, thereby affecting cervical cancer tumorigenesis. In summary, our study confirmed that circ_0009035 could influence the development of cervical cancer through the targeted regulation of miR-1305/CREBRF.

CircASAP1 promotes the development of cervical cancer through sponging miR-338-3p to upregulate RPP25

Circular RNAs have been identified as vital regulators to regulate the development of human cancers, including cervical cancer. Therefore, this study was designed to clarify the underlying mechanism of circASAP1 in cervical cancer. The real-time quantitative PCR assay was applied to quantify the expression levels of circASAP1, microRNA (miR)-338-3p, and ribonuclease P and MRP subunit p25 (RPP25) in cervical cancer tissues and cells. The cell proliferation ability was measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-2H-tetrazol-3-ium bromide and colony-forming assays. The protein expression levels of cyclin D1, proliferating cell nuclear antigen, and RPP25 were assessed by western blot assay. Flow cytometry assays were used to determine the apoptosis and cell cycle distribution of cervical cancer cells. The transwell assay was employed to test the migration and invasion abilities of cervical cancer cells. The interaction relationship between miR-338-3p and circASAP1 or RPP25 was confirmed by dual-luciferase reporter assay and RNA pull-down assay. The xenograft experiment was established to clarify the functional role of circASAP1 inhibition in vivo. CircASAP1 was overexpressed in cervical cancer tissues and cells compared with negative groups. Additionally, the loss-of-functional experiments implied that knockdown of circASAP1 impeded proliferation, migration, and invasion while induced apoptosis and cell cycle arrest in cervical cancer cells along with repressed tumor growth in vivo through regulation of miR-338-3p. In addition, RPP25 was a target mRNA of miR-338-3p, and overexpression of miR-338-3p suppressed proliferation, migration, and invasion while induced apoptosis and cell cycle arrest in cervical cancer cells by suppressing RPP25 expression. Mechanistically, circASAP1 could function as a sponge for miR-338-3p to increase the expression of RPP25, and further regulated proliferation, migration, invasion, apoptosis, and cell cycle program of cervical cancer cells, which might be potential markers for cervical cancer diagnosis.

Long noncoding RNA ALOX12-AS1 inhibits cervical cancer cells proliferation via targeting miR-3171

Cervical cancer is a common female malignancy worldwide, and the molecular mechanism of cervical tumorigenesis remains poorly understood. A large piece of evidence have demonstrated the important roles of long noncoding RNAs (lncRNAs) in tumorigenesis, cancer progression and drug resistance. In this study, we comprehensively analyzed the lncRNAs expression pattern in cervical cancer using RNA sequencing and microarray data from the cancer genome atlas, gene expression omnibus and Genotype Tissue Expression. Moreover, we assessed the correlation between lncRNA expression levels and cervical cancer patient’s survival. We uncovered hundreds of lncRNAs that are upregulated or downregulated in cervical cancer tissues. Among these aberrantly lncRNAs, some are significantly associated with cervical patients’ poorer prognosis, such as ALOX12-AS1 and LINC00173. ALOX12-AS1 expression is downregulated in cervical cancer, and over-expression of ALOX12-AS1 could inhibit cervical cancer cells proliferation in vitro. Further, mechanistically investigation revealed that ALOX12-AS1 could interact with AGO2 and sponge miR-3171, thereby antagonizing its’ repression of tumor suppressor phosphatase and tensin homolog expression in cervical cancer cell. Taken together, this study provides lncRNA candidates in cervical cancer and highlights the critical role of ALOX12-AS1 in cervical cancer.

Survival advantage of bevacizumab rechallenge in recurrent ovarian cancer regardless of platinum sensitivity

Bevacizumab has demonstrated significant efficacy in both first-line and recurrent settings of epithelial ovarian cancer; however, evidence regarding the benefit of bevacizumab retreatment after prior exposure in real-world populations remains limited. This study aimed to evaluate the efficacy of bevacizumab retreatment compared with nonbevacizumab regimens in recurrent metastatic ovarian carcinoma, irrespective of platinum sensitivity status. This retrospective single-center study included 133 patients with recurrent epithelial ovarian cancer who had previously received bevacizumab-containing first-line therapy between January 2015 and May 2025. Patients were grouped according to second-line treatment: bevacizumab-containing chemotherapy ( n  = 51) or chemotherapy alone ( n  = 82). Patients undergoing secondary cytoreductive surgery were excluded. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier and Cox regression models. Median PFS-2 after second-line treatment was significantly longer in the bevacizumab group compared with the nonbevacizumab group (9.7 vs. 3.0 months; P  < 0.001). This benefit was consistent across both platinum-sensitive and platinum-resistant subgroups. Multivariate analysis confirmed that omission of bevacizumab independently predicted worse PFS-2 (hazard ratio = 3.33, 95% CI: 2.17–5.11, P  < 0.001). Although OS-2 was numerically longer in the bevacizumab group (14.1 vs. 8.2 months), the difference was not statistically significant ( P  = 0.091). Bevacizumab retreatment following prior first-line use was associated with improved PFS regardless of platinum sensitivity, suggesting a potential survival advantage in recurrent ovarian cancer. Prospective, randomized studies including both platinum-sensitive and platinum-resistant patients with larger sample sizes are warranted to confirm these findings and determine the optimal use of bevacizumab beyond first-line therapy.

FSP1 expression as a predictor of platinum resistance and recurrence in epithelial ovarian cancer

The objective of this study is to assess the differential expression of ferroptosis suppressor protein 1 (FSP1) in relation to clinical features, platinum resistance, and recurrence in epithelial ovarian cancer (EOC). In addition, the potential significance of FSP1 in EOC as a predictor of platinum resistance and recurrence in EOC was explored. Patients with pathologically confirmed EOC who underwent surgical treatment were included in this analysis. Immunohistochemistry was employed to evaluate FSP1 expression in ovarian tissues, with quantitative analysis performed on the samples. Clinical data were collected during follow-up, and patients were categorized according to platinum resistance and recurrence criteria. Statistical analysis was conducted using SPSS version 27.0. A total of 40 tissue samples from patients with EOC were analyzed, along with 21 samples from benign ovarian tumors and 20 samples from normal ovarian tissues. The expression of FSP1 was significantly higher in the EOC group compared to both benign and normal tissue groups. Meanwhile, the expressions of FSP1 were higher in groups with clinically advanced stages, high-grade carcinoma, presence of cancerous ascites, lymph node metastasis, and in the clear cell EOC group, compared to those with clinically early stages, low-grade carcinoma, absence of cancerous ascites, no lymph node metastasis, and other pathological subtypes. A positive linear correlation was identified between FSP1 expression in EOC tissues and serum levels of CA125 and human epididymis protein 4 at the time of diagnosis. The elevated expression of FSP1 is positively correlated with serum CA125 and human epididymis protein 4 levels at the time of diagnosis, which is a risk factor for EOC drug resistance and recurrence. These findings suggest that FSP1 may serve as a valuable biomarker for predicting platinum resistance and recurrence in patients with EOC.

Stereotactic body radiotherapy and poly (ADP-ribose) polymerase inhibitors in ovarian cancer: a knowledge and attitudes survey in collaboration with the Italian Association of Radiation Oncology (AIRO) and Multicenter Italian Trials in Ovarian Cancer (MITO) groups

The aim of this study was to present a nationwide survey on the specialist’s attitudes towards stereotactic body radiotherapy (SBRT) combined with poly (ADP-ribose) polymerase inhibitors (PARPi) with oligometastatic/oligoprogressive/oligorecurrent ovarian cancer (oMPR-OC) patients. The 19-item questionnaire was developed by specialists and distributed online. Replies were stratified by categories and analyzed using descriptive statistics. Respondents (N = 100) were radiation oncologists (57%), medical oncologists (32%), and gynecologic oncologists (11%). Fifty-four percent of respondents considered medical oncologists as the primary oncologists for oMPR-OC, while 23% preferred radiation oncologists and 15% favored gynecologic oncologists. Seventy-three percent discuss these cases in the Multidisciplinary Tumor Board, while 15, 6, and 2% send the patients straight to SBRT, surgery, or chemotherapy, respectively. Seventy-four percent of the experts interviewed were treated with SBRT less than 10 oMPR-OC patients. Concomitant treatment was highly heterogeneous, but it had little to no reported side effects. A significant variation in how PARPi is managed during SBRT was found: 34% do not interrupt the administration, while 52% pause and restart it later. Forty-three percent of respondents believe that the PARPi dosage should not be reduced when administered concurrently with SBRT. Sixty-nine percent of respondents believe that the SBRT dose should not be decreased while receiving PARPi if the constraints are met. The majority of respondents (40%) favored expert consensus for enhancing the clinical management of oMPR-OC, while 34% preferred clinical guidelines. A lack of or low toxicity with the combination of PARPi and SBRT was perceived, and a significant degree of heterogeneity concerning clinical protocols for their combination. Moreover, it emphasizes the low number of patients who have received this treatment approach nationwide.

KLF4 activates LATS2 to promote cisplatin sensitivity in ovarian cancer through DNA damage

We aimed to investigate the role of large tumor suppressor kinase 2 (LATS2) in cisplatin (DDP) sensitivity in ovarian cancer. Bioinformatic analysis explored LATS2 expression, pathways, and regulators. Quantitative reverse transcription-PCR measured LATS2 and KLF4 mRNA levels. Dual-luciferase and chromatin immunoprecipitation assays confirmed their binding relationship. Cell viability, half maximal inhibitory concentration (IC50) values, cell cycle, and DNA damage were assessed using CCK-8, flow cytometry, and comet assays. Western blot analyzed protein expression. The effect of LATS2 on the sensitivity of ovarian cancer to DDP was verified in vivo. LATS2 and KLF4 were downregulated in ovarian cancer, with LATS2 enriched in cell cycle, DNA replication, and mismatch repair pathways. KLF4, an upstream regulator of LATS2, bound to its promoter. Overexpressing LATS2 increased G1-phase cells, reduced cell viability and IC50 values, and induced DNA damage. Silencing KLF4 alone showed the opposite effect on LATS2 overexpression. Knocking out LATS2 reversed the effects of KLF4 overexpression on cell viability, cell cycle, IC50 values, and DNA damage in ovarian cancer cells. Inhibiting LATS2 inactivated the Hippo-YAP signaling pathway. In vivo experiments showed that overexpression of LATS2 enhanced the sensitivity of ovarian cancer to DDP. KLF4 activates LATS2 via DNA damage to enhance DDP sensitivity in ovarian cancer, providing a potential target for improving treatment outcomes.

Fructose-1,6-bisphosphatase 2 represses cervical cancer progression via inhibiting aerobic glycolysis through promoting pyruvate kinase isozyme type M2 ubiquitination

Growing evidence has shown that aerobic glycolysis, as a hallmark of cancer cells, plays a crucial role in cervical cancer. The aim of the study is to uncover whether fructose-1,6-bisphosphatase 2 (FBP2) is involved in cervical cancer progression via the aerobic glycolysis pathway. FBP2 levels were determined by quantitative PCR (qPCR) and western blotting. Cell growth viability and apoptosis were tested by cell counting kit-8 (CCK-8) and flow cytometry assays. Immunoprecipitation assay was applied for the detection of the FBP2 effect on pyruvate kinase isozyme type M2 (PKM2) ubiquitination. FBP2 level was decreased in cervical cancer, which is closely linked to shorter overall survival. FBP2 decreased cell growth and aerobic glycolysis and increased cell apoptosis, as well as decreased PKM2 expression and increased its ubiquitination level. The above-mentioned roles of FBP2 were weakened followed by PKM2 overexpression. FBP2 inhibited cervical cancer cell growth via inhibiting aerobic glycolysis by inducing PKM2 ubiquitination.

Treatment of HRD-positive elderly ovarian cancer patient: a case report

The standard treatment for advanced ovarian cancer follows a comprehensive ‘surgery-chemotherapy-maintenance therapy’ mode, typically involving initial cytoreductive surgery aiming for R0 resection, six cycles of platinum-based chemotherapy, followed by maintenance therapy for those who have responded well to the treatment. However, frailty and high incidence of comorbidities in elderly patients often compromise surgical outcomes, necessitate chemotherapy dose reductions, and limit maintenance therapy continuation, resulting in a poor prognosis. Poly (Adenosine diphosphate (ADP)-ribose) polymerase inhibitors (PARPi) have revolutionized the management strategy of homologous recombination deficiency (HRD)-positive patients as a groundbreaking advancement in first-line maintenance therapy. Fluzoparib, the domestically developed PARPi in China, has demonstrated significant efficacy in BRCA-mutated ovarian cancer. In the field of supportive care, megestrol acetate (MA) is recommended as the first-line preferred therapeutic agent for cancer-related anorexia by major guidelines, though its role in first-line ovarian cancer therapy remains unexplored, and evidence for its combination with PARPi is lacking. This article reported a case of an 89-year-old female patient with high-grade serous ovarian carcinoma. Due to intolerance to surgery and chemotherapy, an innovative first-line primary treatment regimen combining fluzoparib with MA was initiated based on BRCA2 mutation and HRD-positive status. Imaging assessments revealed significant tumor reduction without disease progression or grade ≥3 adverse events observed throughout follow-up. This case highlights the potential of combining PARPi and hormone therapy as a ‘chemotherapy-free’ precision treatment model for elderly and HRD-positive ovarian cancer patients, offering a promising strategy to balance efficacy and tolerability in a population traditionally underserved by conventional regimens.

Persistent response of an ovarian cancer patient after a short-term single-agent immunotherapy: a case report

Epithelial ovarian cancer is extremely difficult to treat due to its high recurrence rate and acquired tolerance to chemotherapy. Immune checkpoint inhibitors (ICIs) are expected to be promising solutions for treatment failure. However, the low response rate to a single ICI agent was demonstrated in approximately all published clinical trials. Surprisingly patients with complete response were also noticed as an anecdote. Proper indicators of treatment response were urgently required. Programmed death- ligand 1 expression levels in the tumor tissues provide relatively limited discrimination. Tumor mutation burden (TMB) serves as a more reliable parameter. Here we presented an ovarian cancer case with multiple gene mutations and high TMB, who benefited from a short-term treatment of pembrolizumab and experienced a long-lasting complete response of 2 years till now. The patient was irradiated in the pelvic before pembrolizumab. Our study demonstrated that ICIs might provide survival benefits for ovarian cancer with high TMB and that pelvic radiation might have synergistical effects with immunotherapy.

A phase 1 study of regorafenib and sildenafil in adults with advanced solid tumors

The purpose of this study is to establish the recommended phase 2 dose for regorafenib in combination with sildenafil for patients with advanced solid tumors. Secondary outcomes included identification of antitumor effects of regorafenib and sildenafil, toxicity of the combination, determination of PDE5 expression in tumor samples, and the impact of sildenafil on the pharmacokinetics of regorafenib. This study was a phase 1, open-label single-arm dose-escalation trial using a 3 + 3 design. Additional patients were enrolled at the maximum tolerated dose (MTD) until a total of 12 patients were treated at the MTD. A total of 29 patients were treated in this study. The median duration of treatment was 8 weeks. The recommended phase 2 doses determined in this study are regorafenib 160 mg daily with sildenafil 100 mg daily. The most common toxicities included palmar-plantar erythrodysesthesia syndrome (20 patients, 69%) and hypophosphatemia (18 patients, 62%). Two patients (7%) experienced grade 4 lipase increase. Objective responses were not observed; however, 14 patients (48%) had a period of stable disease during the study. Stable disease for up to 12 months was observed in patients with ovarian cancer as well as up to 20 months for a patient with cervical cancer. The combination of regorafenib and sildenafil at the recommended phase 2 dose is safe and generally well tolerated. Disease control in patients with gynecologic malignancies was especially encouraging. Further evaluation of the combination of regorafenib and sildenafil in gynecologic malignancies is warranted. Clinical Trial Registration Number: NCT02466802.

APG-115 synergizes with bortezomib to induce apoptosis in cervical cancer cells

Despite significant advancements in vaccination, screening, and therapeutic strategies have substantially reduced cervical cancer incidence, effective treatment for this disease remains a major clinical challenge. This study reveals that APG-115, a murine double minute 2 (MDM2) inhibitor, upregulates the transcription and expression of MDM2, p53, and p21, effectively inhibiting cell proliferation and inducing apoptosis in cervical cancer cells. Mechanistically, APG-115 suppresses the activation of the AKT and ERK signaling pathways and reduces the expression of antiapoptotic proteins BCL-2, BCL-xL, and MCL-1, while promoting the expression of pro-apoptotic proteins BAK, BAX, and BIM. Notably, the combination of APG-115 with bortezomib enhances p53 and p21 expression, synergistically induces cell apoptosis. In the cervical cancer xenograft models, APG-115 and bortezomib significantly downregulated the expression of Ki67 and BCL-2 while markedly increasing p21 protein levels, effectively suppressing tumor growth and inducing apoptosis. The combination further amplified the effects on Ki67, BCL-2, and p21 expression, leading to enhanced tumor growth inhibition. In summary, this study demonstrates that APG-115 exerts antitumor effects in cervical cancer, and its combination with bortezomib further enhances this inhibitory effect, probably through maximal activation of p53 and inhibition of BCL-2, suggesting a potential application of APG-115 in the treatment of cervical cancer.

Advanced ovarian clear cell carcinoma with RAD50 mutation treated by PARP inhibitor pamiparib combined with anti-angiogenesis therapy: a case report

Ovarian clear cell carcinoma (OCCC) is a relatively uncommon epithelial ovarian malignancy with unique clinical, histopathologic and genetic characteristics. Patients with advanced OCCC have poor outcomes and are resistant to standard chemotherapy. Targeted therapy offers a novel approach for treating OCCC. We report the case of a 45-year-old female patient with advanced OCCC who experienced relapse after standard treatment. Further, a frameshift mutation in the homologous recombination repair-related gene RAD50 (RAD50-p.I371Ffs*8) was identified by genetic testing. Next, the patient had received targeted combination therapy with poly (ADP-ribose) polymerase (PARP) inhibitor pamiparib and bevacizumab, achieving partial remission. Patient’s symptoms improved significantly compared to before. To date, the patient has been followed up for more than half a year with favorable survival and high quality of life. The case report suggested that parmiparib-targeted therapy is a viable treatment option for advanced OCCC patients with RAD50 mutation.

Mechanism of gemcitabine combined with lobaplatin in interventional treatment of locally advanced cervical cancer

In order to investigate the mechanism of gemcitabine combined with lobaplatin in the interventional treatment of locally advanced cervical cancer (LACC), 90 patients with LACC were divided into control group (oxaliplatin + gemcitabine) and experimental group (lobaplatin + gemcitabine) according to different perfusion drugs and embolization drugs, 45 cases in each group. They were treated with arterial chemotherapy and arterial embolization. Postoperative recurrence, metastasis, and survival, as well as changes in serum vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) levels before and after treatment were observed in both groups. The results showed that the recurrence rate of cervical cancer at 0.5, 1, 2, 3, 4, and 5 years after operation in the experimental group was significantly lower than that in the control group, P < 0.05; there was no significant difference in the postoperative cervical cancer metastasis rate, P > 0.05. Before treatment, the serum VEGF in the experimental group and the control group were (642.76 ± 216.67) ng/L and (626.30 ± 275.43) ng/L, respectively, and MMP-9 were (580.61 ± 194.12) ng/L and (575.28 ± 202.55) ng/L, respectively. After treatment, the serum VEGF levels in the experimental group and the control group were (429.24 ± 132.69) ng/L and (554.63 ± 178.11) ng/L, respectively, and MMP-9 levels were (357.60 ± 123.11) ng/L and (461.83 ± 144.45) ng/L, respectively. There was no significant difference in the serum VEGF and MMP-9 levels between the two groups before treatment (P > 0.05); after treatment, the serum VEGF and MMP-9 levels in the experimental group were significantly lower than those in the control group, P < 0.05. Therefore, gemcitabine combined with lobaplatin interventional therapy can improve the cure rate of LACC by reducing VEGF and MMP-9 levels in the serum of patients.

Apoptotic and autophagic cell death induced in cervical cancer cells by a dual specific oncolytic adenovirus

Objective Oncolytic adenoviruses are capable of exerting anticancer effects via a variety of mechanisms, including apoptosis and autophagy. In the present study, the dual-specific antitumor oncolytic adenovirus, Ad-Apoptin-hTERT-E1a (ATV), was used to infect cervical cancer cell lines to test its antitumor effects. Methods To explore the use of apoptin in tumor gene therapy, a recombinant adenovirus ATV expressing the apoptin protein was assessed to determine its lethal and growth-inhibitory effects on human cervical cancer cell line (HeLa) cells in vitro. Nonapoptotic autophagy of HeLa cells infected with ATV was assessed by examining the cell morphology, development of acidic vesicular organelles and the conversion of microtubule-associated protein 1 light chain 3 (LC3) from its cytoplasmic to autophagosomal membrane form. Using gene silencing (knockdown of LC3 and Belin-1), autophagy-associated molecules (e.g. ATG5, ATG12 and ULK1) were monitored by real-time PCR and western blot. Results A series of experiments demonstrated that ATV could significantly induce apoptosis and autophagy in cervical cancer cells, and provided evidence that ATV not only induced apoptosis but also autophagy and ATG5, ATG12 and ULK1 related pathways were not entirely dependent on LC3 and Beclin-1. Conclusion These results indicate that ATV may have a potential application in tumor gene therapy.

CDKN2B-AS1 is overexpressed in polycystic ovary syndrome and sponges miR-181a to promote granulosa cell proliferation

MiR-181a suppresses the proliferation of mouse granulosa cells, which participate in polycystic ovary syndrome (PCOS), suggesting the potential role of miR-181a in PCOS. Our bioinformatics analysis revealed that miR-181a could bind CDKN2B-AS1, a lncRNA regulates ovarian endometriosis. This research was, therefore, conducted to explore the potential crosstalk between CDKN2B-AS1 and miR-181a in PCOS. Expression analysis of CDKN2B-AS1 and miR-181a in follicular fluid from 60 PCOS patients and 60 controls was done with reverse transcriptions-quantitative PCRs. The direct interaction between CDKN2B-AS1 and miR-181a was predicted by IntaRNA and confirmed by RNA pull-down assay. CDKN2B-AS1 in nuclear and cytoplasm of granulosa cells was detected by cellular fractionation assay. The role of CDKN2B-AS1 and miR-181a in granulosa cell proliferation was analyzed by 5-bromodeoxyuridinc assay. In this study, CDKN2B-AS1 was expressed in high amounts in PCOS, whereas miR-181a was downregulated in PCOS, CDKN2B-AS1 was detected in both nucleus and cytoplasm. Although CDKN2B-AS1 and miR-181a were not closely correlated, CDKN2B-AS1 directly interacted with miR-181a. CDKN2B-AS1 and miR-181a overexpression failed to affect the expression of each other. In addition, the inhibitory effect of miR-181a on granulosa cell proliferation was attenuated by CDKN2B-AS1. CDKN2B-AS1 is overexpressed in PCOS and may sponge miR-181a to promote granulosa cell proliferation. Our study characterized a novel CDKN2B-AS1/miR-181a pathway in PCOS. This novel pathway may serve as a potential target to treat PCOS.

Application of long non-coding RNA RBAT1 in improving diagnosis and prognosis of ovarian carcinoma

Tumorigenesis of bladder cancer and retinoblastoma is correlated with long non-coding RNA (lncRNA) RBAT1. However, the role of RBAT1 in ovarian carcinoma (OC) is unclear. Thus, the study explored the role of RBAT1 in OC. This research enrolled patients with OC (n = 68), irritable bowel disease (IBD, n = 68, females), digestive tract inflammation (DTI, n = 68, females), urinary tract infection (UTI, n = 68, females), endometriosis (EM, n = 68, females), and healthy controls (HCs, n = 68) to collect plasma sampled. OC and paired non-tumor tissues were collected from patients with OC. RBAT1 accumulation in all samples was analyzed using RT-qPCR. The role of plasma RBAT1 in OC diagnosis was examined using the ROC curves with OC patients as the true positive cases and other patients and HCs as the true negative cases. The role of RBAT1 in predicting the survival of OC patients was analyzed using the survival curve study. RBAT1 was overexpressed in both OC plasma and tissues. Plasma RBAT1 levels were correlated with RBAT1 levels in OC tissues but not in non-tumor tissues. Plasma RBAT1 could distinguish OC patients from other patients and HCs. Patients with high plasma RBAT1 levels had a shorter survival. RBAT1 is overexpressed in OC and might be applied to improve the diagnosis and prognosis of OC.

Activation of the caspase-1/gasdermin D pathway via α-linolenic acid-mediated GPR120 signaling induces pyroptosis and suppresses ovarian cancer tumor growth

To investigate the role and underlying mechanism of α-linolenic acid (ALA) in ovarian cancer (OC), particularly its relationship with pyroptosis and the GPR120/caspase-1/Gasdermin D (GSDMD) pathway. Human OC cell lines (SKOV3, A2780), THP-1 monocytes, and SKOV3 subcutaneous xenograft models in nude mice were employed. Key assays included cell counting kit-8 (CCK-8) for cell viability, lactate dehydrogenase release for membrane damage detection, ELISA for Interleukin-1β (IL-1β) and IL-18 measurement, Western blot and quantitative polymerase chain reaction (qPCR) for analyzing pyroptosis-related molecules, molecular docking for ALA-GPR120 binding, and flow cytometry. Mice were administered ALA at a dose of 50 mg/kg by intraperitoneal injection, twice weekly for 4 weeks, or saline. ALA induced pyroptosis in OC cells both in vitro and in vivo, accompanied by increased membrane damage, elevated levels of IL-1β and IL-18, and activation of pyroptosis-related molecules. It targeted and inhibited GPR120 to activate the caspase-1/GSDMD pathway, with GSDMD identified as a critical effector. ALA also promoted M1 macrophage polarization and inhibited OC cell activity. In vivo, ALA reduced tumor size, upregulated pyroptosis markers, downregulated GPR120, and caused no significant toxicity. ALA induces OC cell pyroptosis and modulates the tumor microenvironment via the GPR120/caspase-1/GSDMD pathway, safely inhibiting OC growth. This reveals a novel mechanism, supporting ALA as a potential therapeutic candidate for OC, though further research into downstream regulation is required.

A phase II study of anlotinib as first-line maintenance therapy for advanced ovarian cancer

Anlotinib, a tyrosine kinase inhibitor, has shown encouraging antitumor activity in platinum-resistant/refractory ovarian cancer. The efficacy of anlotinib as maintenance therapy in advanced ovarian cancer remains unclear. Therefore, we designed this study to evaluate the efficacy and safety of anlotinib maintenance therapy following first-line treatment with paclitaxel and platinum-based chemotherapy in advanced ovarian cancer. In this single-arm, phase II clinical trial, patients with newly diagnosed advanced ovarian cancer were received anlotinib monotherapy as maintenance therapy once after a response to platinum-based chemotherapy until tumor progression or intolerable toxicity. The primary endpoint was progression-free survival. From April 2020 to June 2021, 24 patients were enrolled in this study. The median follow-up was 40.17 months (interquartile range, 32.40–47.93 months). Of 21 patients with efficacy value, the median progression-free survival and median overall survival were 15.8 months (95% confidence interval, 6.8–24.8 months) and 43.8 months (95% confidence interval, 25.45–62.15 months). The quality-adjusted progression-free survival was 14.4 months and there were no observed treatment-related deaths or serious treatment-emergent adverse events, demonstrating the safety of anlotinib in maintenance therapy. Anlotinib shows significant potential as a first-line maintenance therapy for advanced ovarian cancer, extending survival and providing a reliable treatment option.

The impact of bevacizumab intraperitoneal perfusion combined with paclitaxel and platinum-based chemotherapy on serum stromal-derived factor-1α (SDF-1α) and chemokine ligand 5 (CXCL-5) levels in patients with ovarian cancer after tumor cell debulking surgery

The aim of this study is to investigate the impact of bevacizumab intraperitoneal perfusion combined with paclitaxel and platinum-based chemotherapy on serum stromal-derived factor-1α (SDF-1α) and chemokine ligand 5 (CXCL-5) levels in patients with ovarian cancer after tumor cell debulking surgery. This clinical study was conducted on a cohort of 89 ovarian cancer patients who underwent tumor debulking surgery at our hospital from February 2020 to February 2021. The patients were divided into two groups using a random number table: the control group (n = 44) received postoperative treatment with paclitaxel and platinum-based chemotherapy, while the research group (n = 45) received additional treatment with intraperitoneal perfusion of bevacizumab in addition to the control group’s treatment regimen. The analysis included an assessment of the clinical efficacy of both groups, changes in tumor biomarker levels before and after treatment, serum levels of SDF-1α and CXCL-5, T-lymphocyte subset levels, treatment-related adverse reactions, and a 2-year prognosis and survival assessment. The research group showed better performance compared to the control group in terms of disease remission rate (80.00% vs. 59.09%) and treatment effectiveness rate (95.56% vs. 75.00%) (P < 0.05). Before treatment, the levels of tumor biomarkers between the two groups were compared (P > 0.05). After treatment, the levels of serum ferritin, carbohydrate antigen 125, carbohydrate antigen 199, and human epididymis protein 4 in both groups significantly decreased compared to before treatment, with the research group having lower levels (P < 0.05). Before treatment, serum levels of SDF-1α and CXCL-5 between the two groups were compared (P > 0.05). After treatment, however, the levels of SDF-1α and CXCL-5 significantly decreased compared to before treatment, with the research group having lower levels than the control group (P < 0.05). Before treatment, there was no difference in T-lymphocyte levels between the two groups (P > 0.05). In the control group, there was no significant change in T-lymphocyte levels before and after treatment (P > 0.05). In the research group, however, after treatment, each indicator increased compared to before treatment, and posttreatment levels of all indicators were higher than those in the control group (P < 0.05). The adverse reactions were compared between the two groups (P > 0.05). The research group had a longer average survival time than the control group, with 1-year and 2-year survival rates higher than the control group (P < 0.05). There was, however, no significant difference between the two groups in terms of local recurrence and metastasis (P > 0.05). In conclusion, bevacizumab intraperitoneal perfusion combined with paclitaxel and platinum-based chemotherapy shows better clinical efficacy in the treatment of ovarian cancer after tumor cell debulking surgery. It can significantly reduce the levels of serum SDF-1α and CXCL-5 in patients, improve survival rates, and demonstrate good safety.

MiR-30a-5p/CHD1 axis enhances cisplatin sensitivity of ovarian cancer cells via inactivating the Wnt/β-catenin pathway

Oovarian cancer is a common lethal gynecological malignancy with a high occurrence and dismal prognosis on account of its drug resistance. MicroRNAs (miRNAs) are widely involved in the chemotherapy resistance of tumors, including miR-30a-5p. Herein, we probed the functional role and molecular mechanism of miR-30a-5p in the chemoresistance of ovarian cancer. We enrolled 48 ovarian cancer patients in this study. Statistical analysis and a series of experiments including quantitative reverse transcription polymerase chain reaction, western blot, methyl thiazolyl tetrazolium assay, colony formation assay, flow cytometry analysis, Transwell assay, luciferase reporter assay, RNA pull-down assay and TOP/FOP flash assay were explored in the study. Animal experiments were performed to verify the role of miR-30a-5p in vivo. In our study, miR-30a-5p showed a prominently low level in ovarian cancer tissues and cells. Importantly, its expression in cisplatin-resistant cell lines was more downregulated than in cisplatin-sensitive ones. Additionally, miR-30a-5p overexpression inhibited proliferative, migratory and invasive abilities of ovarian cancer cells while enhancing cell apoptosis and improving cell sensitivity to cisplatin in ovarian cancer. Further, miR-30a-5p targeted to chromodomain helicase DNA binding protein 1 (CHD1) and inhibited the expression of CHD1 in ovarian cancer. Moreover, rescue experiments manifested that miR-30a-5p weakened cisplatin resistance and the cellular process of ovarian cancer by mediating CHD1. Besides, miR-30a-5p regulated CHD1 expression to suppress Wnt/β-catenin signaling in ovarian cancer. The findings were verified by in vivo experiments. This article elucidated that miR-30a-5p/CHD1 axis inhibited the cellular process and enhanced cisplatin sensitivity of ovarian cancer cells through the Wnt/β-catenin pathway, which may provide a useful direction for the targeted chemotherapy of ovarian cancer.

Purvalanol A induces apoptosis and reverses cisplatin resistance in ovarian cancer

Cisplatin (DDP) resistance limits therapeutic efficacy in patients diagnosed with ovarian cancer. Purvalanol A (Pur) is a novel cyclin-dependent kinase (CDK) inhibitor that has been demonstrated to induce apoptosis in various cancer cells. The present study investigated the effect of the combination treatment of Pur and DDP, and the potential anticancer mechanisms in epithelial ovarian cancer (EOC) cells in vitro and in vivo. We found that Pur enhanced the anti-tumor efficacy of cisplatin in EOC cells. The combination of Pur and DDP had more significant effects on apoptosis induction in EOC cells compared with the individual-treatment groups and the control group. We further demonstrated that the combination of Pur and DDP may trigger apoptosis and autophagy in EOC cells by inducing reactive oxygen species (ROS). And the ROS/Akt/mammalian target of rapamycin signaling pathway as a potential mechanism for the initiation of autophagy induced by combination therapy. Similar results were observed in vivo. These results demonstrated that Pur sensitized the response of EOC cells to cisplatin in vitro and in vivo, reversing the resistance to cisplatin in ovarian cancer.

Herpesvirus entry mediator regulates the transduction of Tregs via STAT5/Foxp3 signaling pathway in ovarian cancer cells

The ratio of regulatory T cells (Treg) in peripheral blood of cancer patients has a closely correlation to the occurrence and development of ovarian cancer. In this study, our aim to explore the expression of herpesvirus entry mediator (HVEM) in ovarian cancer and its correlation with Tregs. The expression of HVEM in peripheral blood of ovarian cancer patients was detected by ELISA, and the ratio of CD4+ CD25 + Foxp3 positive Tregs cells was detected by flow cytometry. Ovarian cancer cell lines with high- and low-HVEM expression were constructed. CD4+ cells were co-cultured with ovarian cancer (OC) cells, and the expressions of IL-2 and TGF-β1 in the supernatant of cells were detected by ELISA, and western blot was used to detect the expressions of STAT5, p-STAT5, and Foxp3. The results indicated that the number of Treg cells in the peripheral blood of OC patients increased, and the expression of HVEM increased, the two have a certain correlation. At the same time, the overexpression of HVEM promoted the expression of cytokines IL-2 and TGF- β1, promoted the activation of STAT5 and the expression of Foxp3, leading to an increase in the positive rate of Treg, while the HVEM gene silence group was just the opposite. Our results showed that the expression of HVEM in OC cells has a positive regulation effect on Tregs through the STAT5/Foxp3 signaling pathway. To provide experimental basis and related mechanism for the clinical treatment of ovarian cancer.

MiR-4284 inhibits sensitivity to paclitaxel in human ovarian carcinoma SKOV3ip1 and HeyA8 cells by targeting DMC1

An increasing number of studies have confirmed that microRNAs (miRNAs) are involved in various biological processes, including tumor growth and drug resistance. MiR-4284 has been proved to be abnormally regulated in several cancers, but the function of miR-4284 in ovarian carcinoma (OC) is unclear. Paclitaxel resistance is a key obstacle in OC treatment. Here, the role of miR-4284 in cell sensitivity to paclitaxel in OC was investigated. Two OC cell lines (SKOV3ip1 and HeyA8) were utilized for the establishment of paclitaxel-resistant cell lines. Reverse transcription-quantitative PCR (RT-qPCR) was applied to analyze the levels of miR-4284 and potential mRNAs in OC cell lines. Western blotting was performed to evaluate the levels of DNA meiotic recombinase 1 (DMC1) protein and cell cycle-associated proteins. Identification of the relationship between miR-4284 and DMC1 was achieved by luciferase reporter assay. CCK-8 and flow cytometry assays were utilized for evaluating the impact of miR-4284 on the malignant characteristics of paclitaxel-resistant OC cells. MiR-4284 was upregulated in paclitaxel-resistant OC cell lines and correlated with an adverse prognosis in OC patients. Depletion of miR-4284 suppressed cell proliferation and cell cycle progression of paclitaxel-resistant OC. MiR-4284 targeted DMC1 which was downregulated in paclitaxel-resistant cells and reversed the inhibitory influence of miR-4284 silencing on the malignant characters of paclitaxel-resistant OC cells. MiR-4284 targets DMC1 to suppress sensitivity to paclitaxel in human OC cells.

Oncolytic viral therapy engenders a clinical response in a recurrent ovarian cancer patient

Platinum-resistant ovarian cancer frequently develops in response to multiple lines of chemotherapy, whereupon the disease becomes relatively intractable and clinical recourse is limited. We document a 58-year-old, advanced-stage, platinum-resistant ovarian cancer patient who previously failed numerous cytotoxic and targeted therapy regimens. She was referred to our gynecologic oncology service with a California (CA)-125 of 3194 U/mL and underwent a modified vaccinia virus coinciding with an Institutional Review Board-approved clinical trial. Following the oncolytic therapy and cycle 8 chemotherapy, the patient’s CA-125 declined to 440 U/mL; a computerized tomography scan of the abdomen and pelvis revealed a partial response to therapy. The favorable clinical benefit encountered in our case study indicates that the combination of oncolytic viral therapy and chemotherapy should be considered as a therapeutic option for heavily pretreated ovarian patients.

LncRNA HLA-F-AS1 attenuates the ovarian cancer development by targeting miR-21-3p/PEG3 axis

Dysregulated long noncoding RNA (lncRNA) HLA-F-AS1 is depicted in numerous cancers. However, its function in ovarian cancer has yet to be clarified. LncRNA HLA-F-AS1, miR-21-3p, and PEG3 expressions in ovarian cancer tissues and cells were measured via reverse transcription quantitative PCR. Scratch and CCK8 assays were performed to evaluate the cells’ migratory and proliferative abilities, respectively. To assess the expressions of the apoptosis-related proteins Bax and Bcl-2, Western blotting was conducted. Anti-AGO2 RNA immunoprecipitation (RIP) and dual-luciferase reporter assays were executed to study lncRNA HLA-F-AS1’s and PEG3 3′UTR’s interactions to miR-21-3p. Finally, the tumor growth in vivo was inspected by performing a xenograft experiment. Among the ovarian cancer tissues and cells, the expressions of PEG3 and lncRNA HLA-F-AS1 were depleted while an elevated miR-21-3p expression was observed. HLA-F-AS1’s overexpression attenuated ovarian cancer development in vivo and in vitro. MiR-21-3p targeted PEG3 3′UTR while HLA-F-AS1 targeted miR-21-3p. HLA-F-AS1 overexpression mitigated the enhancement brought about by miR-21-3p mimic on ovarian cancer cells’ proliferation and migration. Meanwhile, PEG3 overexpression abrogated miR-21-3p mimic’s function as an oncogene in the progression of ovarian cancer. Ovarian cancer development is suppressed when lncRNA HLA-F-AS1 targets the miR-21-3p/PEG3 axis. This may possibly be a novel therapeutic target for ovarian cancer.

Glucose deprivation enhances resistance to paclitaxel via ELAVL2/4-mediated modification of glycolysis in ovarian cancer cells

The dysregulation of glycolysis regardless of oxygen availability is one of the major characteristics of cancer cells. While the drug resistance of ovarian cancer cells has been extensively studied, the molecular mechanism of anticancer drug resistance under low-glucose conditions remains unknown. In this study, we investigated the pathway mediating drug resistance under low-glucose conditions by examining the relationship between embryonic lethal abnormal vision Drosophila homolog-like (ELAVL) protein and glycolysis-related enzymes. Ovarian cancer cells resistant to 2.5 nM paclitaxel were exposed to low-glucose media for 2 weeks, and the expression levels of ELAVL2, ELAVL4, glycolytic enzymes, and drug resistance-related proteins were elevated to levels comparable to those in cells resistant to 100 nM paclitaxel. Gene silencing of ELAVL2/4 using small interfering RNA prevented the upregulation of glycolysis-related enzymes, reduced lactate production, and sensitized 2.5 nM paclitaxel-resistant ovarian cancer cells to anticancer agents under hypoglycemic conditions. Furthermore, pharmacological inhibition of glycolytic enzymes with 2-deoxyglucose, a specific inhibitor of glycolysis, triggered caspase-dependent apoptosis, reduced lactate generation, and blocked the expression of drug resistance-related proteins under low-glucose conditions. These results suggest that the level of ELAVL2/4 is responsible for the development of chemoresistance through activation of the glycolysis pathway under glucose deprivation conditions.

E26 transformation-specific transcription factor 3 tips the balance: repressing tropomyosin 2 to fuel Yes-associated protein 1-driven cisplatin resistance in ovarian cancer

Cisplatin resistance remains a major challenge in the treatment of ovarian cancer, significantly limiting therapeutic efficacy. This study aimed to investigate the role of E26 transformation-specific transcription factor 3 (ELK3) in cisplatin resistance and elucidate the underlying molecular mechanism involving the tropomyosin 2 (TPM2)–Yes-associated protein 1 (YAP1) signaling axis. By silencing ELK3 and TPM2 in combination with cisplatin treatment, the regulatory effects of ELK3 and TPM2 on cisplatin sensitivity in ovarian cancer cells were evaluated. The interaction between ELK3 and the TPM2 promoter was verified via chromatin immunoprecipitation and dual-luciferase reporter assays. Western blotting was used to assess the expression of DNA damage marker gamma-histone H2AX and YAP1 to investigate the role of TPM2 in ELK3-mediated signaling and drug response. Cisplatin treatment markedly increased ELK3 expression. Knockdown of ELK3 enhanced cisplatin sensitivity by suppressing cell proliferation, promoting apoptosis, and increasing DNA damage. Mechanistically, ELK3 was directly bound to the promoter region of TPM2 and repressed its transcription. Downregulation of TPM2 subsequently led to increased activation of the YAP1 signaling pathway. Rescue experiments demonstrated that silencing TPM2 reversed the chemosensitizing effects of ELK3 knockdown. These findings highlight the ELK3/TPM2/YAP1 axis as a critical regulator of cisplatin resistance. By suppressing TPM2 and subsequently activating YAP1 signaling, our study identified ELK3 as a crucial transcriptional repressor that contributes to cisplatin resistance in ovarian cancer.

Hesperetin regulates transforming growth factor-β1/Smads pathway to suppress epithelial-mesenchymal transition -mediated invasion and migration in cervical cancer cell

Hesperetin is an abundant flavonoid in citrus fruits, and be confirmed to possess a chemo-preventive effect on cancer. Migration and invasion are the main causes of death of cervical cancer patients, in which epithelial-mesenchymal transition (EMT) can directly contribute to malignant phenotypes of tumor cells. The present study aims to investigate the inhibitory effect of hesperetin on EMT-mediated invasion and migration in cervical cancer cells through transforming growth factor-β1 (TGF-β1)/Smads pathway. Cell viability, cell migration and invasion ability, and cell morphology were evaluated and monitored using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assays, Transwell assays and optical microscope, respectively. The change of EMT marker protein E-cadherin and N-cadherin was assessed by immunofluorescence assay, whereas the protein expression of EMT bio-marker and TGF-β1/Smads pathway were detected through western blot analysis. In conclusion, hesperetin can suppress EMT-mediated invasion and migration of cervical cancer cells by inhibiting abnormal activation of TGF-β1/Smads pathway. The study provides an experimental basis for the prevention of the invasion and migration of cervical cancer.

Overexpression of microRNA-21 decreased the sensitivity of advanced cervical cancer to chemoradiotherapy through SMAD7

Drug resistance is a major problem in the treatment of advanced cervical cancer. The oncogenic microRNA-21 (miR-21) is involved in drug resistance in various cancers. However, the regulatory role of miR-21 and its target, Smad7 in drug resistance of cervical cancer remains to be elucidated. We compared miR-21 and Smad7 levels in human samples from chemoradiotherapy-resistance cervical cancer (resistant group) and chemoradiotherapy-sensitive cervical cancer (sensitive group) patients. Then, the miR-21 level was manipulated in HeLa and SiHa cervical cancer cells and the Smad7 level was determined by PCR and western blot. We also manipulated miR-21, Smad7 or both in cells, and measured cell viability using cell counting kit-8 method and epithelial–mesenchymal transition (EMT) biomarkers using Western blot. In human samples, resistant group has significantly higher miR-21 and lower Smad7 levels than sensitive group. In-vitro analysis demonstrated downregulated Smad7 after transfection with miR-21 mimics. When cells were transfected with Smad7 inhibitor, we observed increased drug resistance and changed levels of EMT-biomarkers after chemoradiotherapy, suggesting that downregulation of Smad7 decreased the sensitivity through EMT. When the cells were transfected with miR-21 inhibitor alone, we found increased sensitivity to chemoradiotherapy through EMT. However, such effects were attenuated when Smad7 was also downregulated after cotransfection. In summary, we provided clinical and experimental evidence that decreased miR-21 may improve drug resistance through EMT by direct targeting Smad7 in cervical cancer. Our data suggest that miR-21/Smad7 pathway may be an effective target for drug resistance in cervical cancer treatment.

Antitumor activity of a hydrogel loaded with lipophilic bismuth nanoparticles on cervical, prostate, and colon human cancer cells

The objective of this study was to analyze the antitumor activity of a hydrogel loaded with lipophilic bismuth nanoparticles on human cervical, prostate, and colon cancer cell lines. The effect of lipophilic bismuth nanoparticles on the viability of cancer cell lines (HeLa, DU145, and HCT-116) and non-cancer lung fibroblasts (HLF; LL 47[MaDo]) was determined with the MTT cell viability assay and compared with known antineoplastic drugs. The biocompatibility at an organismal level was verified in a murine model by histological examination. A lipophilic bismuth nanoparticle hydrogel at 50 µM time-dependently inhibited the growth of the three cancer cell lines, in a time-dependent way. A 1-hour exposure to 250 µM lipophilic bismuth nanoparticle hydrogel, inhibited the growth of the three cancer cell lines. The in-vitro efficacy of lipophilic bismuth nanoparticle was similar to the one of docetaxel and cisplatin, but without inhibiting the growth of non-cancer control cells. Histology confirmed the biocompatibility of lipophilic bismuth nanoparticles as there were no signs of cytotoxicity or tissue damage in any of the evaluated organs (kidney, liver, brain, cerebellum, heart, and jejunum). In conclusion, a lipophilic bismuth nanoparticle hydrogel is an innovative, low-cost alternative for the topical treatment of cervicouterine, prostate, and colon human cancers.

Metformin-induced E6/E7 inhibition prevents HPV-positive cancer progression through p53 reactivation

The human papillomavirus (HPV) is implicated in multiple lethal cancers, although it is more sensitive to certain therapies than HPV-negative cancers. Therefore, the development of more targeted therapeutic strategies is imperative. The HPV oncogenes E6/E7 are ideal targets for HPV-positive cancer, but there are no clinical strategies that have been proven to effectively target E6/E7. Notably, metformin significantly inhibits E6/E7 expression; however, the underlying mechanism and therapeutic potential remain unclear, limiting its clinical translation. Cell Counting Kit-8, ethynyl-2′-deoxyuridine, and terminal-deoxynucleotidyl transferase-mediated Nick end labeling assays were conducted to evaluate the effects of metformin on cell viability, proliferation, and apoptosis. Quantitative real-time PCR, western blotting, and immunofluorescence assays were performed to determine changes in E6/E7 and p53 expression levels following metformin treatment. Patient-derived organoids and in-vivo xenograft models were constructed to evaluate the anticancer activity of metformin against HPV-positive cancer. Our research demonstrated enhanced sensitivity of HPV-positive cancer cells to metformin. Mechanistic studies have revealed that metformin exerts anticancer effects by inhibiting E6/E7 expression, which is associated with p53 reactivation. Furthermore, we substantiated the anticancer potential of metformin in HPV-positive patient-derived organoids and in-vivo tumor models. Our study focused on the mechanism underlying the enhanced responsiveness of HPV-positive cancer to metformin, highlighting the clinical potential of metformin as a targeted therapeutic strategy for HPV-positive cancer.

Circ_0039569 contributes to the paclitaxel resistance of endometrial cancer via targeting miR-1271-5p/PHF6 pathway

Circular RNA (circRNA) has been confirmed to be involved in the chemoresistance process of cancers. However, whether circ_0039569 mediates the chemoresistance of endometrial cancer (EC) remains unclear. Quantitative real-time PCR was performed to analyze circ_0039569, microRNA (miR)-1271-5p and PHD finger protein 6 (PHF6) expression. Cell counting kit-8 assay was used to assess the paclitaxel (PTX) resistance of cells. Cell proliferation, apoptosis and invasion were determined using EdU assay, colony formation assay, flow cytometry and transwell assay. Protein expression was examined by western blot analysis. RNA interaction was verified by dual-luciferase reporter assay and RNA pull-down assay. Xenograft tumor models were constructed to explore the effect of circ_0039569 knockdown on the PTX sensitivity of EC tumors. Circ_0039569 was upregulated in PTX-resistant EC tissues and cells. Knockdown of circ_0039569 enhanced the PTX sensitivity of EC cells by inhibiting cell growth and invasion. MiR-1271-5p could be sponged by circ_0039569, and its inhibitor abolished the regulation of circ_0039569 knockdown on the PTX sensitivity of EC cells. PHF6 was targeted by miR-1271-5p, and its overexpression eliminated the promotion effect of miR-1271-5p on the PTX sensitivity of EC cells. Also, interference of circ_0036569 enhanced the PTX sensitivity of EC tumors by regulating the miR-1271-5p/PHF6 pathway. Collectively, circ_0039569 might contribute to the PTX resistance of EC through the regulation of the miR-1271-5p/PHF6 axis.

Mitochondrial protein LETM1 and its-mediated CTMP are potential therapeutic targets for endometrial cancer

Leucine zipper/EF hand-containing transmembrane-1 (LETM1) is an important mitochondrial protein, while its function in endometrial cancer remains unknown. This study aimed to explore the function of LETM1 in endometrial cancer and reveal the underlying mechanisms involving carboxy-terminal modulator protein (CTMP). Immunohistochemistry was performed to detect the expression of LETM1 and CTMP in normal, atypical hyperplastic and endometrial cancer endometrial tissues. LETM1 and CTMP were silenced in two endometrial cancer cell lines (ISK and KLE), which were verified by western blot. Cell viability, colony number, migration and invasion were detected by cell counting kit-8, colony formation, wound healing and trans-well assays, respectively. A xenograft mouse model was established to determine the antitumor potential of LETM1/CTMP silencing in vivo. In addition, CTMP was overexpressed to evaluate its regulatory relationship with LETM1 in endometrial cancer cells. The expression of LETM1 and CTMP proteins were higher in endometrial cancer tissues than atypical hyperplastic tissues and were higher in atypical hyperplastic tissues than normal tissues. LETM1 and CTMP were also upregulated in ISK and KLE cells. Silencing of LETM1 or CTMP could decrease the viability, colony number, migration and invasion of endometrial cancer cells and the weight and volume of tumor xenografts. In addition, CTMP was downregulated by LETM1 silencing in KLE cells, and its overexpression enhanced the malignant characteristics of si-LETM1-transfected KLE cells. Silencing of LETM1 inhibits the malignant progression of endometrial cancer through downregulating CTMP.

Expression and clinical significance of CXCL17 and GPR35 in endometrial carcinoma

Endometrial carcinoma is one of the most common gynecologic malignancies. CXCL17-CXCR8 (GPR35) axis is reported to play an indispensability role in tumors. Our purpose is to screen possible prognostic and immune-related factors in endometrial carcinoma by detecting the mRNA and protein expression of CXCL17 and CXCR8. We use the qRT-PCR method to test the mRNA expression of CXCL17 and CXCR8 in 35 pairs of endometrial carcinoma and adjacent tissue. The protein expression of CXCL17 and CXCR8 in 30 cases of normal proliferative endometrium, 30 cases of endometrial atypical hyperplasia and 50 cases of endometrial carcinoma was detected by tissue microarray immunohistochemistry. There was no significant difference in the positive expression rate between endometrial adenocarcinoma tissue and endometrial atypical hyperplasia tissue (P > 0.05). But significantly better than normal proliferative tissue (P < 0.001). Correlation analysis of CXCR8 and CXCL17 in endometrial carcinoma showed a positive correlation (r = 0.9123, P < 0.0001). For patients with endometrial cancer, the overall survival (OS) of patients with high CXCL17 expression was significantly higher than that low CXCL17 expression (log-rank test, P < 0.0001), whereas CXCR8 had no statistical significance. But the expression of CXCR8 is an independent prognostic factor of OS in endometrial carcinoma patients. Our study showed that CXCL17 and CXCR8 may be involved in the occurrence and development of endometrial cancer. High expression of CXCL17 may be used as a biomarker for predicting survival. Because CXCL17 and CXCL18 are related to lymphocytes and immune regulation, they are expected to become potential targets for immunotherapy.