Apoptosis

Transcriptome sequencing (RNA-Seq) reveals non-coding pseudogene CDC27P9 role in cervical cancer

Non-Coding regions contains genomic remnants called as Pseudogenes. For a long time, pseudogenes have been regarded as non-functional. This study investigates the previously unstudied Pseudogene CDC27P9 role in cervical cancer. Whole RNA-transcriptome profiling was performed from blood samples of n = 10 cervical cancer patients and n = 10 age matched healthy controls. CDC27P9 expression was validated in patient samples using RT-PCR. The putative CDC27P9-encoded protein structure was predicted using ChimeraX 1.9, refined predicted protein using (GROMACS 2022.2) and evaluated by Ramachandran plot. Post docking using (HADDOCK2.4) with parent gene CDC27 and other interacting genes, a 100ns MD Simulation (GROMACS 2022.2) was done. Functional studies done by siRNA-mediated silencing of CDC27P9 in HeLa cells to study Anaphase Promoting Complex/Cyclosome Pathway using RT-PCR. Cell Cycle, Mitochondrial Membrane Potential Loss and Apoptosis, using Flow Cytometry. Cell death and Chromatin Condensation was visualised using Laser Scanning Confocal Microscopy and validated in multimode microplate reader. Transcriptome sequencing revealed CDC27P9 upregulated with log

Targeting ferroptosis for precision medicine in cervical cancer

Cervical cancer (CC) is a prevalent malignant tumor in the female reproductive system, with rising incidence rates among younger women posing a significant public health challenge. Human papillomavirus (HPV) infection is the primary cause, driving carcinogenesis by promoting abnormal proliferation of tumor cells. Ferroptosis is a form of regulated necrosis that is caused by an iron-dependent accumulation of lipid peroxides with rupture of the plasma membrane. Targeting ferroptosis-related molecules and pathways can selectively induce cervical cancer cell death, while alterations in the expression of ferroptosis-related genes provide promising biomarkers for prognostic assessment. Advances in research on biomarkers and molecular targets are improving predictions of therapeutic outcomes, overcoming drug resistance, and optimizing immunotherapy strategies, thereby opening new avenues for precision medicine. This review focuses on the molecular mechanisms underlying ferroptosis in cervical cancer, discusses its potential applications in early diagnosis and prognosis evaluation, and summarizes the latest advancements in targeted therapy, aiming to provide a novel perspective for the clinical management of cervical cancer.

Pulsed electromagnetic fields inhibit IL-37 to alleviate CD8+ T cell dysfunction and suppress cervical cancer progression

Pulsed electromagnetic field (PEMF) therapy is a potential non-invasive treatment to modulate immune responses and inhibit tumor growth. Cervical cancer (CC) is influenced by IL-37-mediated immune regulation, making PEMF therapy a potential strategy to impede CC progression. This study aimed to elucidate the effects of PEMF on IL-37 regulation and its molecular mechanisms in CC. CC cell-xenografted mouse models, including IL-37 transgenic (IL-37tg) mice, were used to assess tumor growth through in vivo fluorescence imaging and analyze CC cell apoptosis via flow cytometry. TCGA-CESC transcriptome and clinical data were analyzed to identify key inflammation and immune-related genes. CD8

Targeting PNPO to suppress tumor growth via inhibiting autophagic flux and to reverse paclitaxel resistance in ovarian cancer

AbstractOur previous study showed that pyridoxine 5’-phosphate oxidase (PNPO) is a tissue biomarker of ovarian cancer (OC) and has a prognostic implication but detailed mechanisms remain unclear. The current study focused on PNPO-regulated lysosome/autophagy-mediated cellular processes and the potential role of PNPO in chemoresistance. We found that PNPO was overexpressed in OC cells and was a prognostic factor in OC patients. PNPO significantly promoted cell proliferation via the regulation of cyclin B1 and phosphorylated CDK1 and shortened the G2M phase in a cell cycle. Overexpressed PNPO enhanced the biogenesis and perinuclear distribution of lysosomes, promoting the degradation of autophagosomes and boosting the autophagic flux. Further, an autolysosome marker LAMP2 was upregulated in OC cells. Silencing LAMP2 suppressed cell growth and induced cell apoptosis. LAMP2-siRNA blocked PNPO action in OC cells, indicating that the function of PNPO on cellular processes was mediated by LAMP2. These data suggest the existence of the PNPO-LAMP2 axis. Moreover, silencing PNPO suppressed xenographic tumor formation. Chloroquine counteracted the promotion effect of PNPO on autophagic flux and inhibited OC cell survival, facilitating the inhibitory effect of PNPO-shRNA on tumor growth in vivo. Finally, PNPO was overexpressed in paclitaxel-resistant OC cells. PNPO-siRNA enhanced paclitaxel sensitivity in vitro and in vivo. In conclusion, PNPO has a regulatory effect on lysosomal biogenesis that in turn promotes autophagic flux, leading to OC cell proliferation, and tumor formation, and is a paclitaxel-resistant factor. These data imply a potential application by targeting PNPO to suppress tumor growth and reverse PTX resistance in OC.

The CXCL8-CXCR2 axis promotes M2 macrophage polarization in ovarian cancer via RASGRP4-mediated mTOR-STAT3 signaling

This study aimed to investigate whether CXCL8-CXCR2 axis in regulating M2 macrophage polarization via RASGRP4 related signaling in ovarian cancer. Data from The Cancer Genome Atlas (TCGA) database was used to assess the correlation between CXCR2 expression and M2 macrophage infiltration. THP-1 human monocytic cells were utilized to analyze the effects of CXCL8 on RASGRP4 expression and M2 polarization. In vivo experiments were conducted using xenograft models to evaluate the impact of CXCL8 and RASGRP4 on tumor growth and macrophage polarization. Among the CXCR2 co-expressed genes, RASGRP4 showed the highest positive correlation with M2 macrophage infiltration in ovarian cancer. Higher expression of RASGRP4 is associated with poorer progression-free survival in patients with serous ovarian cancer. CXCR2 knockdown or inhibition (using SB225002) reduced IL-8-induced upregulation of RASGRP4 mRNA and protein in THP-1 cells. Additionally, PLCβ2 silencing attenuated IL-8-induced RASGRP4 expression. Knockdown of RASGRP4 in THP-1 cells reduced M2 polarization, while overexpression restored it. The CXCL8-CXCR2 axis further enhances M2 polarization through RASGRP4-mediated mTOR-STAT3 signaling. In xenograft ovarian tumor models, knockdown of CXCL8, CXCR2, or RASGRP4 reduced tumor growth and M2 macrophage infiltration. In summary, the CXCL8-CXCR2 axis promotes M2 macrophage polarization via RASGRP4-mediated mTOR-STAT3 signaling in ovarian cancer. Targeting this pathway may be a promising therapeutic strategy to reprogram tumor-associated macrophages and enhance treatment efficacy.

The functions of lncRNAs in the HPV-negative cervical cancer compared with HPV-positive cervical cancer

Cervical cancer is one of the most common female malignancies. Human papillomaviruses (HPV) are the main causative agents of virtually all cervical carcinomas. Nevertheless, emerging evidence has demonstrated that a small proportion of cervical cancer patients are HPV negative. Long noncoding RNAs (lncRNAs) have been identified to play a crucial role in cervical cancer development. Here, this review describes the incidence and development of HPV-negative cervical cancer. Moreover, HPV-negative cervical cancers are more likely diagnosed at non-squamous type, older ages, more advanced stage and metastases, and associated with poorer prognosis as compared to HPV-positive cervical cancer. Furthermore, the significant role and functions of lncRNAs underlying HPV-negative cervical cancer is clarified.

Differences in chemotaxis of human mesenchymal stem cells and cervical cancer cells

In the last decade, there has been a rapid expansion in tumor targeted therapy using mesenchymal stem cells (MSCs) based on their unique tropism towards cancer cells. Despite similarities in morphology, immunophenotype, and differential potent in vitro, MSCs originated from different tissues do not necessarily have equivalent biological behaviors. It is important to screen the most chemotactic MSCs to cancer cells. In this study, different MSCs were isolated from various human tissues including adipose, umbilical cord, amniotic membrane, and chorion. The chemotaxis of human MSCs to cervical cancer cells was measured by CCK-8, ELISA and Transwell invasion assays. Western blotting was performed to explore the underlying mechanisms. MSCs derived from distinct sources can be differently recruited to cervical cancer cells, among which chorion-derived MSC (CD-MSC) possessed the strongest tropic capacity. CXCL12 was found to be highly secreted by cervical cancer cells, in parallel with the expression of CXCR4 in all MSCs. CD-MSC displayed the highest level of CXCR4. These results indicated that CXCL12/CXCR4 pathway contributed to the different chemotaxis to cervical cancer cells of each MSCs. This study proposed that CD-MSC with the highest CXCR4 expression is a promising therapeutic vehicle for targeted therapy in cervical cancer.

Inhibition of SIRT1/HSF1 pathway contributes to doxorubicin-induced nephrotoxicity in ovarian tumor-bearing mice

Doxorubicin (DOX) is a common drug used in chemotherapy to treat for advanced ovarian cancer, but it can cause organ damage, particularly to the kidneys. This study aimed to investigate whether the SIRT1/HSF1 pathway is associated with DOX-induced nephrotoxicity. Bioinformatics analysis was performed using single-cell RNA sequencing (scRNA-seq) data from DOX-treated kidneys to investigate the potential mechanism of DOX-induced renal damage. To explore the role of HSF1 in DOX-induced nephrotoxicity, the lentivirus HSF1 (Lv-HSF1) was injected after tumor implantation, followed by DOX administration. DOX prevented ovarian tumor growth but caused renal injury in mice, as evidenced by elevated UACR, increased blood BUN levels, and abnormalities in kidney structure and fibrosis. Bioinformatic analysis revealed fewer podocytes in the kidneys of DOX-exposed mice than in those of control mice, which was further confirmed by examining renal tissue and murine podocyte cells. Gene set enrichment analysis revealed significant enrichment of HSF1-dependent transactivation and HSF1 activation pathways specifically within podocytes obtained from DOX-treated mice, which was also validated in renal tissue samples. Furthermore, HSF1A attenuated DOX-induced podocyte injury in vitro. Lv-HSF1-targeted podocytes mitigate DOX-induced podocyte injury in vivo. Notably, SIRT1 expression was significantly downregulated in both kidney tissues and podocytes subjected to DOX treatment. The observed damage to podocytes induced by DOX may be attributed to an increase in HSF1 acetylation facilitated through the downregulation of SIRT1, a process that can be counteracted by the administration of the SIRT1 agonist RSV. Collectively, these findings demonstrated that suppression of the SIRT1/HSF1 signaling pathway contributes to DOX-mediated nephrotoxicity in mice bearing ovarian tumors.

YTHDF1-mediated m6A modification promotes cisplatin resistance in ovarian cancer via the FZD7/Wnt/β-catenin pathway

Cisplatin resistance significantly hinders the efficacy of ovarian cancer treatment, presenting a major challenge in improving patient outcomes. This study identifies the m6A reader protein YTHDF1 as a key regulator of cisplatin resistance in ovarian cancer through its modulation of the FZD7/Wnt/β-catenin signaling pathway. Using cisplatin-resistant ovarian cancer cell lines (A2780/DDP and SKOV3/DDP), we observed elevated YTHDF1 expression, which positively correlated with tumor cell proliferation and migration. Silencing YTHDF1 reduced FZD7 expression, inhibited Wnt/β-catenin signaling, and restored cisplatin sensitivity both in vitro and in vivo. Mechanistic investigations revealed that YTHDF1 binds to m6A-modified FZD7 mRNA, enhancing its stability and translation. Functional studies in xenograft mouse models demonstrated that targeting YTHDF1 suppressed tumor growth and enhanced apoptosis in cisplatin-resistant ovarian cancer cells. These findings highlight the YTHDF1-FZD7 axis as a novel therapeutic target for overcoming cisplatin resistance, paving the way for improved treatment strategies in ovarian cancer.

SHCBP1 promotes cisplatin resistance of ovarian cancer through AKT/mTOR/Autophagy pathway

Ovarian cancer caused the highest cancer-related mortality among female reproductive system malignancies. Platinum-based chemotherapy is still the footstone of the chemotherapy for ovarian cancer. However, the molecular mechanisms underlying cisplatin insensitivity and resistance remain unclear. SHC SH2 domain-binding protein 1 (SHCBP1) plays critical roles in the progression and drug resistance of different types of cancer. However, the biological function of SHCBP1 in ovarian cancer progression and cisplatin resistance remains obscure. In this study, we found that SHCBP1 was upregulated in ovarian cancer and the upregulated SHCBP1 has growth-promoting effect on ovarian cancer cells. Furthermore, SHCBP1 silencing sensitize ovarian cancer cells to cisplatin (hereafter referred to as CDDP). Mechanism analysis revealed that SHCBP1 activated the Akt/mTOR pathway and further inhibited autophagy in ovarian cancer cells. Meanwhile, autophagy inhibitors combined with SHCBP1 knockdown enhances CDDP sensitivity. In addition, knockdown of SHCBP1 restricted the proliferation of tumors and increased the cisplatin sensitivity in vivo. These findings suggested that upregulated SHCBP1 promoted the proliferation and CDDP resistance of ovarian cancer. The combination of SHCBP1 inhibition and cisplatin treatment might lead to substantial progress in ovarian cancer targeted therapy.

Targeting PAX8 sensitizes ovarian cancer cells to ferroptosis by inhibiting glutathione synthesis

Ovarian cancer is a malignant tumor originating from the ovary, characterized by its high mortality rate and propensity for recurrence. In some patients, especially those with recurrent cancer, conventional treatments such as surgical resection or standard chemotherapy yield suboptimal results. Consequently, there is an urgent need for novel anti-cancer therapeutic strategies. Ferroptosis is a distinct form of cell death separate from apoptosis. Ferroptosis inducers have demonstrated promising potential in the treatment of ovarian cancer, with evidence indicating their ability to enhance ovarian cancer cell sensitivity to cisplatin. However, resistance of cancer cells to ferroptosis still remains an inevitable challenge. Here, we analyzed genome-scale CRISPR-Cas9 loss-of function screens and identified PAX8 as a ferroptosis resistance protein in ovarian cancer. We identified PAX8 as a susceptibility gene in GPX4-dependent ovarian cancer. Depletion of PAX8 rendered GPX4-dependent ovarian cancer cells significantly more sensitive to GPX4 inhibitors. Additionally, we found that PAX8 inhibited ferroptosis in ovarian cancer cells. Combined treatment with a PAX8 inhibitor and RSL3 suppressed ovarian cancer cell growth, induced ferroptosis, and was validated in a xenograft mouse model. Further exploration of the molecular mechanisms underlying PAX8 inhibition of ferroptosis mutations revealed upregulation of glutamate-cysteine ligase catalytic subunit (GCLC) expression. GCLC mediated the ferroptosis resistance induced by PAX8 in ovarian cancer. In conclusion, our study underscores the pivotal role of PAX8 as a therapeutic target in GPX4-dependent ovarian cancer. The combination of PAX8 inhibitors such as losartan and captopril with ferroptosis inducers represents a promising new approach for ovarian cancer therapy.

LncRNA FGD5-AS1 promotes the malignant phenotypes of ovarian cancer cells via targeting miR-142-5p

Long non-coding RNAs (lncRNAs) have been reported to participate in regulating gene expression and are related to tumor progression. FGD5 antisense RNA 1 (FGD5-AS1) facilitates the progression of various tumors. However, the expression and function of FGD5-AS1 in ovarian cancer (OC) and its mechanism of action are not yet clear. Real-time polymerase chain reaction (RT-PCR) was employed to explore the expression levels of FGD5-AS1 and miR-142-5p in OC. The relationship between the expression of FGD5-AS1 and clinicopathological indicators of OC patients was analyzed by χ

Antiproliferative effect of bacterial cyclodipeptides in the HeLa line of human cervical cancer reveals multiple protein kinase targeting, including mTORC1/C2 complex inhibition in a TSC1/2-dependent manner

Cervix adenocarcinoma rendered by human papillomavirus (HPV) integration is an aggressive cancer that occurs by dysregulation of multiple pathways, including oncogenes, proto-oncogenes, and tumor suppressors. The PI3K/Akt/mTOR pathway, which cross-talks with the Ras-ERK pathway, has been associated with cervical cancers (CC), which includes signaling pathways related to carcinoma aggressiveness, metastasis, recurrence, and drug resistance. Since bacterial cyclodipeptides (CDPs) possess cytotoxic properties in HeLa cells with inhibiting Akt/S6k phosphorylation, the mechanism of CDPs cytotoxicity involved was deepened. Results showed that the antiproliferative effect of CDPs occurred by blocking the PI3K/Akt/mTOR pathway, inhibiting the mTORC1/mTORC2 complexes in a TSC1/TSC2-dependent manner. In addition, the CDPs blocked protein kinases from multiple signaling pathways involved in survival, proliferation, invasiveness, apoptosis, autophagy, and energy metabolism, such as PI3K/Akt/mTOR, Ras/Raf/MEK/ERK1/2, PI3K/JNK/PKA, p27Kip1/CDK1/survivin, MAPK, HIF-1, Wnt/β-catenin, HSP27, EMT, CSCs, and receptors, such as EGF/ErbB2/HGF/Met. Thus, the antiproliferative effect of the CDPs made it possible to identify the crosstalk of the signaling pathways involved in HeLa cell malignancy and to suggest that bacterial CDPs may be considered as a potential anti-neoplastic drug in human cervical adenocarcinoma therapy.

Deubiquitinating enzyme OTUD4 stabilizes RBM47 to induce ATF3 transcription: a novel mechanism underlying the restrained malignant properties of ccRCC cells

RETRACTED ARTICLE: Progesterone induces apoptosis by activation of caspase-8 and calcitriol via activation of caspase-9 pathways in ovarian and endometrial cancer cells in vitro

Previously we have shown inhibition of endometrial cancer cell growth with progesterone and calcitriol. However, the mechanisms by which the two agents attenuate proliferation have not been well characterized yet. Herein, we investigated how progesterone and calcitriol induce apoptosis in cancer cells. DNA fragmentation was upregulated by progesterone and calcitriol in ovarian and endometrial cancer cells. Time-dependent treatment of ovarian cancer cells, ES-2, and TOV-21G with progesterone enhanced caspase -8 activity after 12 h, whereas OV-90, TOV-112D, HEC-1A, and HEC-59 cells showed increased activity after 24 h. Caspase 9 activity was increased in all cell lines after 24 h treatment with calcitriol. Pretreatment of cancer cells with a caspase-8 inhibitor (z-IETD-fmk) or caspase-9 inhibitor (Z-LEHD-fmk) significantly attenuated progesterone and calcitriol induced caspase-8 and caspase-9 expression, respectively. The expression of FasL, Fas, FAD, and pro-caspase-8, which constitute the death-inducing signaling complex (DISC), was upregulated in progesterone treated cancer cells. Knockdown of FAS or FADD with specific siRNAs significantly blocked progesterone-induced caspase-8. Cleavage of the BID was not affected by caspase-8 activation suggesting the absence of cross-talk between caspase-8 and caspase-9 pathways. Calcitriol treatment decreased mitochondrial membrane potential and increased the release of cancer cytochrome C. These findings indicate that progesterone induces apoptosis through activation of caspase-8 and calcitriol through caspase-9 activation in cancer cells. A combination of progesterone-calcitriol activates both extrinsic and intrinsic apoptotic pathways in cancer cells.

USP43 impairs cisplatin sensitivity in epithelial ovarian cancer through HDAC2-dependent regulation of Wnt/β-catenin signaling pathway

AbstractEpithelial ovarian cancer (EOC) is the leading cause of cancer death all over the world. USP43 functions as a tumor promoter in various malignant cancers. Nevertheless, the biological roles and mechanisms of USP43 in EOC remain unknown. In this study, USP43 was highly expressed in EOC tissues and cells, and high expression of USP43 were associated with a poor prognosis of EOC. USP43 overexpression promoted EOC cell proliferation, enhanced the ability of migration and invasion, decreased cisplatin sensitivity and inhibited apoptosis. Knockdown of USP43 in vitro effectively retarded above malignant progression of EOC. In vivo xenograft tumors, silencing USP43 slowed tumor growth and enhanced cisplatin sensitivity. Mechanistically, USP43 inhibited HDAC2 degradation and enhanced HDAC2 protein stability through its deubiquitylation function. USP43 diminished the sensitivity of EOC cells to cisplatin through activation of the Wnt/β-catenin signaling pathway mediated by HDAC2. Taken together, the data in this study revealed the functions of USP43 in proliferation, migration, invasion, chemoresistance of EOC cells, and the mechanism of HDAC2-mediated Wnt/β-catenin signaling pathway. Thus, USP43 might serve as a potential target for the control of ovarian cancer progression.

CSN5 overexpression promotes the integral progression of cervical cancer by enhancing ENO3-mediated glycolysis

Cervical cancer (CC) remains a significant global health challenge. A deeper understanding of the molecular mechanisms driving CC progression is crucial for developing improved therapeutic strategies. CSN5 is vital in cell functions and cancer, but its role in CC is unclear. This study aims to explore CSN5's role and its target gene in CC progression, assessing their potential as therapeutic targets. We employed an integrated approach combining bioinformatics analysis, proteomic profiling, and in vitro and in vivo functional assays. Immunohistochemistry was used to analyze CSN5 and ENO3 expression in CC and normal tissues. CSN5 upregulation was associated with advanced clinical stage and poor differentiation. Furthermore, CSN5 overexpression enhanced cellular proliferation and glycolytic metabolism but, paradoxically, suppressed migration, invasion, and the epithelial-mesenchymal transition (EMT). These pro-tumorigenic effects were confirmed in vivo, and the glycolytic inhibitor 2-DG was found to reverse the phenotypes induced by CSN5. Protein sequencing highlighted ENO3's role in CSN5-mediated tumorigenesis, regulating EMT and glycolysis by stabilizing its ubiquitination degradation through CSN5. Crucially, silencing ENO3 attenuated the oncogenic effects of CSN5 both in vitro and in vivo. Our findings unveil a novel mechanistic paradigm in which CSN5 promotes CC progression by co-opting ENO3 to enhance glycolytic flux while concurrently suppressing cell motility. This study not only deepens the understanding of CC pathogenesis but also identifies the CSN5-ENO3 axis as a promising target for novel therapeutic interventions.

YAP/TAZ-TEAD activity promotes the malignant transformation of cervical intraepithelial neoplasia through enhancing the characteristics and Warburg effect of cancer stem cells

AbstractA number of studies have confirmed that Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ)-transcriptional enhanced associate domain (TEAD) activity is the driver of cancer development. However, the role and mechanism of the YAP/TAZ-TEAD pathway in cervical intraepithelial neoplasia (CIN) remain to be clarified. Therefore, this study was designed to observe the effect of YAP/TAZ-TEAD activity on the development of CIN and provide new ideas for the diagnosis and treatment of CIN. Firstly, cervical tissues were collected from CIN patients in different stages [CIN grade 1 (CIN1) tissue, CIN grade 2/3 (CIN 2/3) and squamous cell carcinoma (SCC)] and healthy volunteers. Next, the expression levels of YAP, TAZ and TEAD in cervical tissues and cells were observed by immunohistochemistry, qRT-PCR and western blot. Besides, Z172 and Z183 cells were transfected with siRNA-YAP/TAZ (si-YAP/TAZ) and YAP/TAZ overexpression vector (YAP-5SA). Also, Z172 cells were co-transfected with YAP-5SA and si-TEAD2/4. Subsequently, the stemness characteristics, glycolysis level and malignant transformation of cells in each group were observed by sphere-formation assay, commercial kit, MTT, Transwell, scratch experiment, xenotransplantation and western blot.The expression of YAP, TAZ and TEAD increased significantly in cervical cancer tissue and cell line at the stage of CIN2/3 and SCC. When YAP/TAZ was knocked down, the stemness characteristics, glycolysis level and malignant transformation of cancer cells were notably inhibited; while activating YAP/TAZ exhibited a completely opposite result. In addition, activating YAP/TAZ and knocking down the TEAD expression at the same time significant weakened the effect of activated YAP/TAZ signal on precancerous cells and reduced inhibitory effect of knocking down TEAD alone. YAP/TAZ-TEAD signal activates the characteristics and Warburg effect of cancer stem cells, thereby promoting the malignant transformation of CIN.

The emerging role of cholesterol metabolism in gynecologic cancer development and therapy

The significance of cholesterol metabolism in cancer is a topic of renewed interest. Cholesterol is an essential factor for mammal cells, for it is not only involved in constituting the cell membrane, but also serves as a precursor to steroid hormones and bile acids. Numerous studies have provided increasing evidence of its high relevance to cancer progression. Targeting cholesterol metabolism by using cholesterol metabolism inhibitors has offered another therapeutic strategy for reversing drug resistance in tumors. Here, the regulatory process of cholesterol homeostasis under normal physiological conditions was introduced. Then, the mechanism by which cholesterol metabolism disorder caused gynecologic cancer development and therapy resistance was summarized. Finally, the therapeutic strategies targeting cholesterol metabolism were also discussed in this review.

GJB2 as a novel prognostic biomarker associated with immune infiltration and cuproptosis in ovarian cancer

Cuproptosis, a recently identified copper-dependent cell death mechanism, remains poorly unexplored in ovarian cancer (OC). This study systematically evaluates clinically significant cuproptosis-related genes (CRGs) as potential prognostic biomarkers in OC. Cox regression analysis and LASSO algorithms were used to develop a prognostic risk model incorporating 5 CRGs (CD8B2, GJB2, GRIP2, MELK, and PLA2G2D) within the TCGA cohort. This model stratified OC patients into high-risk and low-risk groups, with the high-risk group exhibiting significantly shorter overall survival compared to the low-risk group. The model's predictive accuracy for prognosis in OC patients was validated in the TCGA training cohort, TCGA testing cohort, and ICGC external validation cohorts. Among these 5 signature genes, the number of cuproptosis genes associated with GJB2 is the largest, so we selected GJB2 for further validation. qPCR revealed that GJB2 was highly expressed in OC cells and tumor tissues. The high expression of GJB2 was closely associated with poor prognosis in OC patients. Functionally, GJB2 silencing suppressed OC cell proliferation and migration while its overexpression promoted malignant progression and EMT. Furthermore, GJB2 regulated copper homeostasis and reduced cuproptosis sensitivity, while also facilitating immune escape by inhibiting CD8

LINC00511 promotes cervical cancer progression by regulating the miR-497-5p/MAPK1 axis

Abstract Background Long non-coding RNA (lncRNA) exhibits a crucial role in multiple human malignancies. The expression of lncRNA LINC00511, reportedly, is aberrantly up-regulated in several types of tumors. Our research was aimed at deciphering the role and mechanism of LINC00511 in the progression of cervical cancer (CC). Method Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to quantify the expression levels of LINC00511, miR-497-5p and MAPK1 mRNA in CC tissues and cell lines. Cell counting kit-8 (CCK-8), 5-bromo-2’-deoxyuridine (BrdU) and Transwell assays were conducted for detecting the proliferation, migration and invasion of CC cells. Dual-luciferase reporter gene experiments were performed to verify the targeting relationships amongst LINC00511, miR-497-5p and MAPK1. Besides, MAPK1 expression in CC cells was detected via Western blot after LINC00511 and miR-497-5p were selectively regulated. Results Up-regulation of LINC00511 expression in CC tissues and cell lines was observed, which was in association with tumor size, clinical stage and lymph node metastasis of the patients. LINC00511 overexpression facilitated the proliferation, migration and invasion of CC cells, while opposite effects were observed after knockdown of LINC00511. Mechanistically, LINC00511 was capable of targeting miR-497-5p and up-regulating MAPK1 expression. Conclusion LINC00511/miR-497-5p/MAPK1 axis regulates CC progression.

Mechanisms of apoptosis-related non-coding RNAs in ovarian cancer: a narrative review

Ovarian cancer remains a major challenge in oncology due to its complex biology and late-stage diagnosis. Recent advances in molecular biology have highlighted the crucial role of non-coding RNAs (ncRNAs) in regulating apoptosis and cancer progression. NcRNAs, including microRNAs, long non-coding RNAs, and circular RNAs, have emerged as significant players in the molecular networks governing ovarian cancer. Despite these insights, the precise mechanisms by which ncRNAs influence ovarian cancer pathology are not fully understood. This complexity, combined with the heterogeneity of the disease and the development of treatment resistance, poses substantial obstacles to effective therapeutic development. Additionally, the lack of reliable early detection methods further complicates treatment strategies. This manuscript reviews the current state of research on ncRNAs in ovarian cancer, discusses the challenges in translating these findings into clinical applications, and outlines potential future directions. Emphasis is placed on the need for integrated approaches to unravel the intricate roles of ncRNAs, improve early detection, and develop personalized treatment strategies to address the diverse and evolving nature of ovarian cancer. While these findings provide valuable insights, it is crucial to recognize that many results are based on preclinical studies and require further validation to establish their clinical applicability.

RAB25 confers resistance to chemotherapy by altering mitochondrial apoptosis signaling in ovarian cancer cells

Ovarian cancer remains one of the most frequent causes of cancer-related death in women. Many patients with ovarian cancer suffer from de novo or acquired resistance to chemotherapy. Here, we report that RAB25 suppresses chemotherapy-induced mitochondrial apoptosis signaling in ovarian cancer cell lines and primary ovarian cancer cells. RAB25 blocks chemotherapy-induced apoptosis upstream of mitochondrial outer membrane permeabilization by either increasing antiapoptotic BCL-2 proteins or decreasing proapoptotic BCL-2 proteins. In particular, BAX expression negatively correlates with RAB25 expression in ovarian cancer cells. BH3 profiling assays corroborated that RAB25 decreases mitochondrial cell death priming. Suppressing RAB25 by means of RNAi or RFP14 inhibitory hydrocarbon-stapled peptide sensitizes ovarian cancer cells to chemotherapy as well as RAB25-mediated proliferation, invasion and migration. Our data suggest that RAB25 is a potential therapeutic target for ovarian cancer.

m6A modification and its clinical applications in gynaecological cancer

N6-methyladenosine (m6A) RNA modification plays a pivotal role in gynaecological cancers by regulating tumor initiation, progression, and therapeutic resistance. m6A RNA modification include writers (METTL3/14, RBM15, ZC3H13, WTAP), which catalyze methylation; erasers (ALKBH5, FTO), which remove methyl groups; and readers (YTHDC1, YTHDF1/2/3, IGF2BP1/2/3, HNRNPC/G, HNRNPA2BP1), which interpret m6A marks to regulate the RNA fate. These regulators alter basic RNA metabolism, such as splicing, mRNA stability, translation, and degradation. In gynaecological cancers, both oncogenic and tumor suppressive signaling pathways are also altered by these regulators. Due to their diagnostic, prognostic and predictive value, m6A regulators have emerged as promising biomarkers in gynaecological cancers in recent years. This review highlights the role of m6A regulators and critically evaluates their biomarker and clinical potential in gynaecological cancers.

microRNA-499a promotes the progression and chemoresistance of cervical cancer cells by targeting SOX6

Emerging evidence has indicated that microRNAs are involved in multiple processes of cancer development. Previous studies have demonstrated that microRNA-499a (miR-499a) plays both oncogenic and tumor suppressive roles in several types of malignancies, and genetic variants in miR-499a are associated with the risk of cervical cancer. However, the biological roles of miR-499a in cervical cancer have not been investigated. Quantitative real-time PCR was used to assess miR-499a expression in cervical cancer cells. Mimics or inhibitor of miR-499a was transfected into cervical cancer cells to upregulate or downregulate miR-499a expression. The effects of miR-499a expression change on cervical cancer cells proliferation, colony formation, tumorigenesis, chemosensitivity, transwell migration and invasion were assessed. The potential targets of miR-499a were predicted using online database tools and validated using real-time PCR, Western blot and luciferase reporter experiments. miR-499a was significantly upregulated in cervical cancer cells. Moreover, overexpression of miR-499a significantly enhanced the proliferation, cell cycle progression, colony formation, apoptosis resistance, migration and invasion of cervical cancer cells, while inhibiting miR-499a showed the opposite effects. Further exploration demonstrated that Sex-determining region Y box 6 was the direct target of miR-499a. miR-499a-induced SOX6 downregulation mediated the oncogenic effects of miR-499a in cervical cancer. Inhibiting miR-499a could enhance the anticancer effects of cisplatin in the xenograft mouse model of cervical cancer. Our findings for the first time suggest that miRNA-499a may play an important role in the development of cervical cancer and could serve as a potential therapeutic target.

MARCH5 promotes aerobic glycolysis to facilitate ovarian cancer progression via ubiquitinating MPC1

AbstractMARCH5 is a ring-finger E3 ubiquitin ligase located in the outer membrane of mitochondria. A previous study has reported that MARCH5 was up-regulated and contributed to the migration and invasion of OC cells by serving as a competing endogenous RNA. However, as a mitochondrial localized E3 ubiquitin ligase, the function of MARCH5 in mitochondrial-associated metabolism reprogramming in human cancers remains largely unexplored, including OC. We first assessed the glycolysis effect of MARCH5 in OC both in vitro and in vivo. Then we analyzed the effect of MARCH5 knockdown or overexpression on respiratory activity by evaluating oxygen consumption rate, activities of OXPHOS complexes and production of ATP in OC cells with MARCH5. Co-immunoprecipitation, western-blot, and in vitro and vivo experiments were performed to investigate the molecular mechanisms underlying MARCH5-enhanced aerobic glycolysis s in OC. In this study, we demonstrate that the abnormal upregulation of MARCH5 is accompanied by significantly increased aerobic glycolysis in OC. Mechanistically, MARCH5 promotes aerobic glycolysis via ubiquitinating and degrading mitochondrial pyruvate carrier 1 (MPC1), which mediates the transport of cytosolic pyruvate into mitochondria by localizing on mitochondria outer membrane. In line with this, MPC1 expression is significantly decreased and its downregulation is closely correlated with unfavorable survival. Furthermore, in vitro and in vivo assays revealed that MARCH5 upregulation-enhanced aerobic glycolysis played a critical role in the proliferation and metastasis of OC cells. Taken together, we identify a MARCH5-regulated aerobic glycolysis mechanism by degradation of MPC1, and provide a rationale for therapeutic targeting of aerobic glycolysis via MARCH5-MPC1 axis inhibition.

Hypoxic glycolysis-driven histone lactylation activates NHE7 to promote endometrial cancer progression via COX6C-mediated endoplasmic reticulum stress

Endometrial Cancer (EC) is one of the most prevalent malignancies in the female reproductive system. Hypoxia is a hallmark of the tumor microenvironment that drives metabolic reprogramming, endoplasmic reticulum (ER) stress, and aggressive behavior in cancer cells. However, the underlying mechanisms remain incompletely understood. This study aimed to investigate hypoxia-mediated regulation of EC progression, focusing on the role of SLC9A7 (Solute Carrier Family 9 Member A7, NHE7). EC cells were exposed to hypoxic conditions (1% O Hypoxia promoted the malignant phenotypes and stemness of EC cells. NHE7 was identified as a potential target gene of the hypoxia pathway and was positively correlated with poor prognosis in EC. Furthermore, overexpression of NHE7 in xenografts accelerated tumor growth. Mechanistically, NHE7 enhanced oxidative phosphorylation (OXPHOS) by elevating COX6C (Cytochrome C Oxidase Subunit 6C) expression, further driving ER stress. Hypoxia-driven glycolysis elevated histone lactylation, which transcriptionally activated NHE7. This regulation was reversed by glycolysis or lactate production inhibitors. Hypoxia-driven glycolysis induces histone lactylation, leading to the upregulation of NHE7 expression. This process enhances OXPHOS-induced ER stress by upregulating COX6C expression, ultimately contributing to the malignant progression of EC.

Sodium butyrate induces ferroptosis in endometrial cancer cells via the RBM3/SLC7A11 axis

Ferroptosis is a form of programmed cell death with important biological functions in the progression of various diseases, and targeting ferroptosis is a new tumor treatment strategy. Studies have shown that sodium butyrate plays a tumor-suppressing role in the progression of various tumors, however, the mechanism of NaBu in endometrial cancer is unclear. Cell viability, clone formation, proliferation, migration, invasion abilities and cell cycle distribution were assessed by CCK8 assay, Clone formation ability assay, EdU incorporation, Transwell chambers and flow cytometry. The level of ferroptosis was assayed by the levels of ROS and lipid peroxidation, the ratio of GSH/GSSG and the morphology of mitochondria. Molecular mechanisms were explored by metabolome, transcriptome, RNA-pulldown and mass spectrometry. The in-vivo mechanism was validated using subcutaneous xenograft model. In this study, NaBu was identified to inhibit the progression of endometrial cancer in vitro and in vivo. Mechanistically, RBM3 has a binding relationship with SLC7A11 mRNA. NaBu indirectly downregulates the expression of SLC7A11 by promoting the expression of RBM3, thereby promoting ferroptosis in endometrial cancer cells. In conclusion, Sodium butyrate can promote the expression of RBM3 and indirectly downregulate the expression of SLC7A11 to stimulate ferroptosis, which may be a promising cancer treatment strategy.