Background: Ovarian cancer (OC) has the highest mortality rate among all gynecological malignancies. A hypoxic microenvironment is a common feature of solid tumors, including ovarian cancer, and an important driving factor of tumor cell survival and chemo- and radiotherapy resistance. Previous research identified the hypoxia-associated gene angiopoietin-like 4 (ANGPTL4) as both a pro-angiogenic and pro-metastatic factor in tumors. Hence, this work aimed to further elucidate the contribution of ANGPTL4 to OC progression. Methods: The expression of hypoxia-associated ANGPTL4 in human ovarian cancer was examined by bioinformatics analysis of TCGA and GEO datasets. The CIBERSORT tool was used to analyze the distribution of tumor-infiltrating immune cells in ovarian cancer cases in TCGA. The effect of ANGPTL4 silencing and overexpression on the proliferation and migration of OVCAR3 and A2780 OC cells was studied in vitro, using CCK-8, colony formation, and Transwell assays, and in vivo, through subcutaneous tumorigenesis assays in nude mice. GO enrichment analysis and WGCNA were performed to explore biological processes and genetic networks associated with ANGPTL4. The results obtained were corroborated in OC cells in vitro by western blotting. Results: Screening of hypoxia-associated genes in OC-related TCGA and GEO datasets revealed a significant negative association between ANGPTL4 expression and patient survival. Based on CIBERSORT analysis, differential representation of 14 distinct tumor-infiltrating immune cell types was detected between low- and high-risk patient groups. Silencing of ANGPTL4 inhibited OVCAR3 and A2780 cell proliferation and migration in vitro and reduced the growth rate of xenografted OVCAR3 cells in vivo. Based on results from WGCNA and previous studies, western blot assays in cultured OC cells demonstrated that ANGPTL4 activates the Extracellular signal-related kinases 1 and 2 (ERK1/2) pathway and this results in upregulation of c-Myc, Cyclin D1, and MMP2 expression. Suggesting that the above mechanism mediates the pro-oncogenic actions of ANGPTL4T in OC, the pro-survival effects of ANGPTL4 were largely abolished upon inhibition of ERK1/2 signaling with PD98059. Conclusions: Our work suggests that the hypoxia-associated gene ANGPTL4 stimulates OC progression through activation of the ERK1/2 pathway. These findings may offer a new prospect for targeted therapies for the treatment of OC.

Background: Ovarian cancer is a common gynecological tumor with high malignant potential and poor prognosis. TRIM8, is involved in the development of various tumors, but its precise regulatory role in ovarian cancer is still unknown.Aims: The aim of this study was to explore the specific mechanism by which TRIM8 regulates ovarian cancer.Materials and Methods: We used bioinformatics analysis to screen for high expression of TRIM8 in ovarian cancer. The expression of TRIM8 in healthy and cancerous ovarian tissues was assessed by immunofluorescence. TRIM8 was silenced or overexpressed in ovarian cancer cell lines, with cell proliferation and migration evaluated by CCK8, transwell and clonal formation assays. The effect of TRIM8 on ovarian cancer cells in vivo was assessed by subcutaneous tumor formation experiments in nude mice. The potential interacting protein VDAC2 was identified by mass spectrometry. The mechanism underlying TRIM8 regulation of VDAC2 was evaluated by co‐immunoprecipitation and western blotting.Results: TRIM8 was overexpressed in ovarian cancer. TRIM8 promoted the proliferation and migration of ovarian cancer cells in vitro and the growth of subcutaneous tumors in mice in vivo. TRIM8 interacted with VDAC2, weakened the stability of the protein, and promoted its polyubiquitination and subsequent degradation. Knockdown of VDAC2 increased the resistance of ovarian cancer cells to iron death, whereas overexpression of VDAC2 attenuated ovarian cancer progression induced by TRIM8 overexpression.Discussion: TRIM8 promotes ovarian cancer proliferation and migration by targeting VDAC2 for ubiquitination and degradation, these finding may provide new targets for the treatment of ovarian cancer.Conclusion: TRIM8 degraded VDAC2 through the ubiquitination pathway, increased the resistance of ovarian cancer cells to iron death, and promoted the proliferation and migration of ovarian cancer.

Vaginal intraepithelial neoplasia (VaIN) is a precancerous lesion for invasive vaginal cancer, which is highly malignant and difficult to treat. This study aimed to identify the risk factors for VaIN and emphasize the importance of screening and monitoring patients with a history of cervical intraepithelial neoplasia and ongoing human papillomavirus (HPV) infection. Patients suspected of having VaIN were admitted to the Department of Gynecology and Obstetrics at the Affiliated Suzhou Hospital of Nanjing Medical University between February 2014 and August 2022. Medical records of these patients were retrospectively reviewed. A total of 274 patients underwent colposcopy due to suspected VaIN, and the diagnosis was confirmed in 167 patients based on biopsy pathology reports. Multivariate analysis in which odds ratios (ORs) with a 95% confidence interval (95% CI) were calculated revealed that vaccine-related HPV-infected patients (OR = 4.30, 95% CI: 1.75–10.58), and postmenopausal patients (OR = 5.94, 95% CI: 1.95–18.09), had a significantly increased risk of developing high-grade VaIN. However, patients with prior surgical treatment had a reduced risk (OR = 0.58, 95% CI: 0.34–0.99), which may be attributed to regular monitoring. HPV16, 58, 52, and 33 were among the most prevalent HPV types, with HPV16 positivity associated with higher-grade VaIN. Patients with concurrent cervical high-grade squamous epithelial lesions also exhibited high-grade VaIN, indicating a potential link between cervical and vaginal intraepithelial lesions. Our study highlights the complex interplay between risk factors such as prior surgical treatment, human papillomavirus infection, and menstrual status in the progression of VaIN. This underscores the importance of comprehensive evaluation and management strategies for VaIN.

Objectives: SPRY (repeats in splA and RyR) domain-containing SOCS (suppressor of cytokine signaling) box protein 1 (SPSB1) is an E3 ligase adaptor protein that has been implicated in various cellular processes and physiological pathways. However, its role in spermatogenesis remains poorly understood. The objective of this study was to investigate the impact of SPSB1 deficiency on spermatogenesis and male fertility in mice. Methods: We generated Spsb1 knockout (Spsb1-KO) mice to explore the effects of SPSB1 deficiency on sperm quality. To assess sperm parameters, we utilized computer-assisted sperm analysis (CASA), which provides precise measurements of sperm motility, concentration, and morphology. Additionally, histological and immunohistochemical analyses were performed to evaluate the influence of SPSB1 deficiency on spermatogenesis. Results: Our results showed no significant differences in semen quality, fertility, or histological findings between Spsb1-KO and wild-type (WT) mice. Conclusions: This study demonstrates that SPSB1 is not essential for spermatogenesis or male fertility in mice. These findings provide a valuable resource for future genetic investigations into human fertility and help prevent unnecessary duplication of research efforts in this area.

Globally, among gynecological malignancies, ovarian cancer (OC) stands as an important factor contributing to mortality. E3 ubiquitin ligase activity is a common characteristic found in the tripartite motif (TRIM) proteins, contributing significantly to post-translational modifications of various proteins. Among these TRIM proteins, TRIM15 has been linked to multiple cancer types. Nevertheless, the function of TRIM15 concerning OC has yet to be elucidated. We aimed to explore the role of TRIM15 in OC and shed light on the underlying mechanisms thereof. A bioinformatics analysis was conducted to investigate the variance in TRIM15 expression between normal ovarian tissues and OC tissues, and to explore the prognostic significance of TRIM15 in patients with OC. TRIM15 protein expression in OC tissues was detected using immunofluorescence. The impact of TRIM15 silencing and overexpression on the proliferation and migration of OC cells was assessed through various functional experiments, such as CCK-8, colony formation, and Transwell assays. Mass spectrometry analysis was performed to identify TRIM15-interacting substrates. The mechanism underlying substrate ubiquitination mediated by TRIM15 was further explored. Based on The Cancer Genome Atlas (TCGA) data and immunofluorescence analysis, OC tissues exhibited significant upregulation of TRIM15 expression. si-RNA-mediated silencing of TRIM15 suppressed the in vitro proliferation and migration of OVCAR3 and A2780 cells. Paxillin was selected as an interacting protein with TRIM15 by mass spectrometry. Mechanically, we discovered that TRIM15 mediated the ubiquitination of Paxillin via Lys11- and Lys29-linked polyubiquitin chains. Subsequent co-IP experiments revealed that TRIM15 could also enhance the interactions between Paxillin and its tyrosine kinase, FAK, thereby promoting the phosphorylation of Paxillin. We revealed a previously unknown mechanism by which TRIM15 ubiquitinates and phosphorylates Paxillin to promote OC progression. These findings suggest that targeting TRIM15 holds promise as a therapeutic approach to treat OC.