Journal
Correlation between CD44 and membrane fluidity—a study on biopsies of high-grade serous ovarian tumor
CD40 ligation-induced ERK activation leads to enhanced radiosensitivity in cervical carcinoma cells via promoting autophagy
CD40, a member of the tumor necrosis factor (TNF) receptor superfamily, plays an important role not only in the immune system but also in tumor progression. CD40 ligation reportedly promotes autophagy in immune cells. However, the effects of CD40 ligation on autophagy and its mechanism in solid tumor cells are still unclear. In this study, we find that CD40 ligation promotes autophagosome formation and consequently promotes autophagic flux in cervical cancer cells. Mechanistically, this effect relies on ERK contributing to CD40 ligation-induced ATG13 upregulation by p53. Furthermore, we demonstrate that CD40 ligation-induced autophagy increases the radiosensitivity of cervical cancer cells. Taken together, our results provide new evidence for the involvement of the CD40 pathway in autophagy and radiotherapy in cervical cancer cells.
Alpha-lipoic acid targets <italic>KLF7</italic> expression to inhibit cervical cancer progression
It is unclear what part KLF7 plays in cervical cancer. In this study, immunohistochemical and bioinformatics analyses reveal that KLF7 expression is lower in normal cervical tissues than in cervical cancer tissues, and the high level of
Long noncoding RNA UCA1 knockdown inhibits cisplatin-resistant cervical cancer tumorigenesis via the miR-195-5p/IKBKB axis
Cisplatin resistance is a major cause of poor prognosis in patients with cervical cancer. Dysregulation of long noncoding RNAs (lncRNAs) plays a key role in chemoresistance. Our results reveal that the lncRNA UCA1 is upregulated in cisplatin (DDP)-resistant cervical cancer tissues and HeLa cells. Mechanistically, the lncRNA UCA1 acts as a sponge for miR-195-5p, targeting IKBKB. UCA1 enhances proliferation, migration, and invasion while reducing apoptosis in DDP-resistant HeLa cells via the miR-195-5p/IKBKB axis. Additionally, UCA1 upregulates BNIP3Δex2 and p-p65 expressions and downregulates BNIP3 expression in DDP-resistant HeLa cells. Abnormal expressions of BNIP3Δex2 and BNIP3 significantly alter the malignant progression of HeLa/DPP cells.
Circular RNA hsa_circ_0007444 inhibits ovarian cancer progression through miR-23a-3p/DICER1 axis
Ovarian cancer is the second leading cause of death in women with gynecological malignancy in China. Circular RNAs are a class of noncoding regulatory RNAs reported to be involved in cancer development and progression. Previous studies, including our own, have indicated that hsa_circ_0007444 is downregulated in ovarian cancer tissues. This study aims to elucidate the function and mechanism of hsa_circ_0007444 in ovarian cancer progression. The expression of hsa_circ_0007444 is determined by quantitative real-time PCR (qRT-PCR). Cell proliferation, invasion, migration and apoptosis are examined by cell counting-kit 8 (CCK-8), transwell and flow cytometry assays. Tumor growth and metastasis are assessed
Metabolic reprogramming of the ovarian cancer microenvironment in the development of antiangiogenic resistance
Antiangiogenic therapies, such as treatment with bevacizumab, display modest survival benefits in ovarian cancer (OC) patients. After a transient response, the upregulation of compensatory proangiogenic pathways and the adoption of alternative vascularization processes lead to the development of resistance. Considering the high mortality rate of OC, there is an urgent need to uncover the underlying mechanisms of antiangiogenic resistance for the development of novel and effective treatment strategies. Recent investigations have confirmed that metabolic reprogramming in the tumor microenvironment (TME) exerts an essential effect on tumor aggressiveness and angiogenesis. In this review, we provide an overview of the metabolic crosstalk between OC and the TME, highlighting the regulatory mechanisms underlying the development of antiangiogenic resistance. Metabolic interventions may interrupt this complex and dynamic interactive network, providing a promising therapeutic option to improve clinical outcome in OC patients.
COM33 suppresses carboplatin-induced epithelial-mesenchymal transition via inhibition of Twist1 in ovarian cancer
Despite favorable responses to platinum-based chemotherapy in ovarian cancer (OC), chemoresistance is still a major cause of treatment failure. Hence, we develop a novel synthetic agent, COM33, to relieve the chemoresistance caused by carboplatin. The anti-cancerous effects of the combination of COM33 and carboplatin on OC are evaluated by cell viability, wound healing, and transwell invasion assays. A mechanistic investigation is carried out by using RNA-Seq analysis and then verified by western blot analysis and immunofluorescence microscopy. The safety and efficacy
Microbiome-metabolome analysis reveals cervical lesion alterations
Cervical cancer (CC) continues to be one of the most common cancers among females worldwide. It takes a few years or even decades for CC to arise in a minority of women with cervical precancers. An increasing corpus of studies today indicates that local microecology and carcinogenesis are intimately related. To investigate the changes in cericovaginal microecology with the development of cervical cancer, we performed 16S rDNA sequencing and metabolomic analysis in cericovaginal fluid from 10 LSIL patients, 10 HSIL patients, 10 CC patients and 10 healthy controls to reveal the differential flora and metabolites during cervical carcinogenesis. Carcinogenesis is associated with alterations in microbiome diversity, individual taxa, and functions with notable changes in
Metabolomics variation profiling of vaginal discharge identifies potential targets for cervical cancer early warning
AHNAK2 is a biomarker and a potential therapeutic target of adenocarcinomas
Adenocarcinoma is the second largest histological type of cervical cancer, second only to cervical squamous cell carcinoma. At present, despite the clinical treatment strategies of cervical adenocarcinoma and cervical squamous cell carcinoma being similar, the outcome and prognosis of cervical adenocarcinoma are significantly poor. Therefore, it is urgent to find specific biomarker and therapeutic target for cervical adenocarcinoma. In this study, we aim to reveal and verify the potential biomarkers and therapeutic targets of cervical adenocarcinoma. Weighted correlation network analysis (WGCNA) reveals the differentially-expressed genes significantly related to the histological characteristics of the two cervical cancer subtypes. We select the genes with the top 20 significance for further investigation. Through microarray and immunohistochemical (IHC) analyses of a variety of tumor tissues, we find that among these 20 genes,
Inhibition of the PIN1-NRF2/GPX4 axis imparts sensitivity to cisplatin in cervical cancer cells
The incidence of cervical cancer (CC) ranks the fourth in female malignant tumors globally. Chemoresistance is one of the main causes of treatment failure in advanced recurrent CC. Prolyl isomerase 1 (PIN1) is overexpressed in a variety of tumors, and is closely associated with the malignant potential of tumor cells, such as transformation, proliferation, invasion and metastasis. In the present study, we demonstrate that cell death induced by suppression of PIN1 could be inhibited by ferrostatin-1 (Fer-1) and ferroptosis biomarkers including lactate dehydrogenase (LDH) release, lipid peroxidation and malondialdehyde (MDA) are upregulated by downregulating PIN1. We then discover that abrogation of PIN1 greatly decreases the level of glutathione peroxidase 4 (GPX4) and the level of PIN1 is positively correlated with the level of GPX4. Furthermore, the knockdown of PIN1 promotes ferroptosis induced by RSL3. The mechanism involves PIN1 silencing which downregulates GPX4 by decreasing the level of nuclear factor E2-related factor 2 (NRF2). Furthermore, overexpression of NRF2 inhibits RSL3-mediated ferroptosis of CC cells when PIN1 is silenced. In addition, our results indicate that cisplatin (DDP) induces ferroptosis, which is restrained by overexpression of PIN1. The PIN1 inhibitor, KPT-6566, promotes the cytotoxic effect of DDP. The present study reveals that PIN1 affects ferroptosis and sensitivity to DDP in CC cells via the NRF2/GPX4 axis, thereby identifying PIN1 as a potential therapeutic target for CC.
Down-regulation of lncRNA LUADT1 suppresses cervical cancer cell growth by sequestering microRNA-1207-5p
Emerging evidence has proved the essential roles of long non-coding RNAs (lncRNAs) in cervical carcinoma (CC). LncRNA lung adenocarcinoma-associated transcript 1 (LUADT1) is overexpressed and plays an oncogenic role in various cancers; however, the function and clinical values of LUADT1 in CC remain unclear. In this study we found that LUADT1 is highly expressed in CC tissues and cells. Up-regulated LUADT1 is significantly correlated with the more aggressive status and poorer survival of CC patients. studies show that LUADT1 depletion suppresses CC proliferation, and leads to cell apoptosis and cell cycle arrest. Furthermore, the xenograft mouse assay demonstrates that LUADT1 knockdown remarkably suppresses tumor growth. Mechanistically, LUADT1 binds to miR-1207-5p and inhibits miR-1207-5p expression in CC cells. Septin 9 (SEPT9) is identified as a miR-1207-5p target which is negatively regulated by LUADT1. Overexpression of SEPT9 abrogates the suppressed proliferation of CC cells induced by LUADT1 knockdown. These results demonstrate that LUADT1 sponges miR-1207-5p and consequently modulates SEPT9 expression in CC. Our study suggests the possible application of LUADT1 as a prognostic and therapeutic target to inhibit CC.
Astatine-211 and actinium-225: two promising nuclides in targeted alpha therapy
PDK1 promotes epithelial ovarian cancer progression by upregulating BGN
Pyruvate dehydrogenase kinase 1 (PDK1) is a new therapeutic target that is dysregulated in multiple tumors. This study aims to explore the potential role and regulatory mechanism of PDK1 in epithelial ovarian cancer (EOC). We detect PDK1 expression in EOC tissues and cells using qRT-PCR and western blot analysis, and the effects of PDK1 on EOC cell malignant behaviors are explored. RNA sequencing analyses are performed to explore the differentially expressed genes in
Exosomal integrin alpha 3 promotes epithelial ovarian cancer cell migration via the S100A7/p-ERK signaling pathway
Epithelial ovarian cancer (EOC) is a highly aggressive malignancy with a poor prognosis due to late-stage diagnosis and the lack of reliable biomarkers for early detection. Exosomes, small vesicles involved in intercellular communication, play a critical role in cancer progression by promoting migration, proliferation, and metastasis. This study investigates the role of exosomal proteins in EOC cell migration and identifies potential biomarkers. Exosomes are isolated from the ascites fluid of EOC patients (C-Exos) and benign ovarian disease patients (B-Exos), and mass spectrometry analysis of clinical samples reveals 185 differentially expressed proteins, with integrin alpha 3 (ITGA3) being strongly associated with poor prognosis. ITGA3 is transported via exosomes to recipient EOC cells, where it is released into the cytoplasm and translocated to the cell membrane. This localization enables ITGA3 to activate the intracellular signaling pathways that drive EOC migration. Immunoprecipitation mass spectrometry of clinical samples reveals that ITGA3 may influence EOC migration through the S100A7/p-ERK signaling pathway. Mechanistically, ITGA3 activates ERK signaling through S100A7, promoting cell migration.
Lactate activates CCL18 expression via H3K18 lactylation in macrophages to promote tumorigenesis of ovarian cancer
This study investigates the role of lactate in the genesis and progression of ovarian cancer (OV) and explores the underlying mechanisms. Serum lactate levels show a positive correlation with tumor grade and poor prognosis in patients with OV. Bioinformatics analysis identifies
Abrogation of KLF5 sensitizes <italic>BRCA1</italic>-proficient pancreatic cancer to PARP inhibition
Poly ADP-ribose polymerase (PARP) inhibitor monotherapies are selectively effective in patients with pancreatic, breast, prostate, and ovarian cancers with
miR-34b-3p-mediated regulation of STC2 and FN1 enhances chemosensitivity and inhibits proliferation in cervical cancer
Dysregulation of microRNA (miRNA) expression in cancer is a significant factor contributing to the progression of chemoresistance. The objective of this study is to explore the underlying mechanisms by which miR-34b-3p regulates chemoresistance in cervical cancer (CC). Previous findings have demonstrated low expression levels of miR-34b-3p in both CC chemoresistant cells and tissues. In this study, we initially characterize the behavior of SiHa/DDP cells which are CC cells resistant to the chemotherapeutic drug cisplatin (DDP). Subsequently, miR-34b-3p mimics are transfected into SiHa/DDP cells. It is observed that overexpression of miR-34b-3p substantially inhibits the proliferation, migration, and invasion abilities of SiHa/DDP cells and also enhances their sensitivity to DDP-induced cell death. Quantitative RT-PCR and western blot analysis further reveal elevated expression levels of STC2 and FN1 in SiHa/DDP cells, contrary to the expression pattern of miR-34b-3p. Moreover, STC2 and FN1 contribute to DDP resistance, proliferation, migration, invasion, and decreased apoptosis in CC cells. Through dual-luciferase assay analysis, we confirm that STC2 and FN1 are direct targets of miR-34b-3p in CC. Finally, rescue experiments demonstrate that overexpression of either STC2 or FN1 can partially reverse the inhibitory effects of miR-34b-3p overexpression on chemoresistance, proliferation, migration and invasion in CC cells. In conclusion, our findings support the role of miR-34b-3p as a tumor suppressor in CC. This study indicates that targeting the miR-34b-3p/STC2 or FN1 axis has potential therapeutic implications for overcoming chemoresistance in CC patients.
Long noncoding RNA KCNMB2-AS1 acts as an oncogene in ovarian cancer
Dual regulation of Akt and glutathione caused by isoalantolactone effectively triggers human ovarian cancer cell apoptosis
Ovarian cancer is one of leading causes of cancer death in gynecological tumor. Isoalantolactone (IL), present in several medicinal plants, exhibits various biological activities, and its mechanism underlying anti-ovarian cancer activity needs to be further investigated. Here, we find that IL inhibits the proliferation of SKOV-3 and OVCAR-3 cells by causing G2/M phase arrest and inducing apoptosis. Moreover, IL decreases intracellular glutathione (GSH) level, and induces reactive oxygen species (ROS) generation in SKOV-3 cells. Furthermore, IL induces inactivation of Akt which is required for the cytotoxicity of IL. In addition, overexpression of Akt attenuates the IL-induced growth inhibition and ROS generation. GSH supplementation moderately increases the expression of phospho-Akt. Further investigation reveals that pretreatment with L-buthionine-sulfoximine (a GSH biosynthesis inhibitor) restores the Akt-mediated attenuation of growth inhibition induced by IL. Moreover, co-treatment with IL and wortmannin (an Akt pathway inhibitor) increases the growth inhibition attenuated by pretreatment with N-acetyl-L-cysteine (a precursor for GSH biosynthesis). These results indicate that inactivation of Akt and downregulation of GSH level induced by IL are related to each other. In conclusion, combined targeting Akt and GSH is an effective strategy for cancer therapy and IL can be a promising anticancer agent for further exploration.
CPT1C promotes the potential of gastric cancer ovarian metastasis through up-regulating fatty acid oxidation
RP5-1148A21.3 (lncRP5) exerts oncogenic function in human ovarian carcinoma
Ovarian cancer (OC) is a fatal gynecological malignancy that is difficult to diagnose at early stages. Various long non-coding RNAs (lncRNAs) are aberrantly expressed in OC and exert regulatory effects on OC; however, the underlying mechanism requires in-depth investigation. This work is designed to explore the molecular regulatory axis of a newly identified lncRNA in OC, that is, lncRNA RP5-1148A21.3 (lncRP5). RT-qPCR shows lncRP5 is significantly upregulated in OC patients and cell lines, and it is mainly located in the cytoplasm of OC cells. The results of CCK-8, colony formation, and transwell assays demonstrate that overexpression of lncRP5 greatly contributes to malignant behaviors of OC cells, while inhibition of lncRP5 shows the opposite effects. Moreover, the binding relationship between lncRP5 and miR-545-5p is predicted by bioinformatics and is further verified by luciferase assay. Functionally, the regulatory effects of lncRP5 and miR-545-3p are negatively related; miR-545-5p serves as a tumor suppressor in OC. Further studies demonstrate that PTP4A1 is the target gene of miR-545-5p. Overexpression of PTP4A1 abrogates the inhibitory function of miR-545-5p on OC cell growth and metastasis. The lncRP5/miR-545-5p/PTP4A1 axis is subsequently demonstrated in vivo, and knockdown of lncRP5 notably inhibits tumor growth. This study provides a novel regulatory mechanism of OC, which may contribute to the diagnosis and therapy of OC.
KAT8 facilitates the proliferation of cancer cells through enhancing E7 function in HPV-associated cervical cancer
Persistent human papillomavirus (HPV) infection serves as the principal etiological factor in cervical cancer, with the oncoprotein E7, which is encoded by the virus, playing a key role in tumorigenesis. However, targeted therapeutic strategies against E7 remain underexplored. KAT8, a lysine acetyltransferase, significantly contributes to oncogenesis through the regulation of transcription. However, its involvement in cervical cancer remains inadequately characterized. This study employs HPV18-positive HeLa and HPV16-positive SiHa cell lines to investigate how KAT8 modulates E7 expression and function in cervical cancer cells. Upon
HSPA8-mediated stability of the CLPP protein regulates mitochondrial autophagy in cisplatin-resistant ovarian cancer cells
Currently, platinum agents remain the mainstay of chemotherapy for ovarian cancer (OC). However, cisplatin (DDP) resistance is a major reason for chemotherapy failure. Thus, it is extremely important to elucidate the mechanism of resistance to DDP. Here, we establish two DDP-resistant ovarian cancer cell lines and find that caseinolytic protease P (CLPP) level is significantly downregulated in DDP-resistant cell lines compared to wild-type ovarian cancer cell lines (SK-OV-3 and OVcar3). Next, we investigate the functions of CLPP in DDP-resistant and wild-type ovarian cancer cells using various assays, including cell counting kit-8 assay, western blot analysis, immunofluorescence staining, and detection of reactive oxygen species (ROS) and apoptosis. Our results show that
Overexpression of LPCAT1 enhances endometrial cancer stemness and metastasis by changing lipid components and activating TGF-β/Smad2/3 signaling pathway
The incidence of endometrial cancer (EC) increases annually and tends to occur in younger women. A particularly important relationship exists between EC and metabolic disorders. As one of the most important components of lipid metabolism, phospholipids play an indispensable role in metabolic balance. LPCAT1 is a key enzyme regulating phospholipid metabolism. In this study, we perform further investigations to seek mechanistic insight of LPCAT1 in EC. Our results demonstrate that silencing of LPCAT1 inhibits the growth of endometrial cancer, while overexpression of LPCAT1 results in enhanced stemness and metastasis in endometrial cancer cell lines. Meanwhile, the contents of various phospholipids including phosphatidylethanolamine (PE), phosphatidylcholine (PC), and triglyceride (TG) change significantly after overexpression of LPCAT1. In addition, through RNA-sequencing and western blot analysis, we observe that the TGF-β/Smad2/3 signaling pathway is of great importance in the tumor-promoting function of LPCAT1. LPCAT1 promotes the expressions of stem cell-related transcription factors and epithelial-mesenchymal transition (EMT) related proteins through the TGF-β/Smad2/3 signaling pathway. Moreover, we find that TSI-01, which can inhibit the activity of LPCAT1, is able to restrain the proliferation of EC cell lines and promote cell apoptosis. Collectively, we demonstrate that LPCAT1 enhances the stemness and metastasis of EC by activating the TGF-β/Smad2/3 signaling pathway and that TSI-01 may have potential use for the treatment of EC.
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