Shunyu Hou

SENP8 regulates a non-canonical NEDD8-dependent pathway to stabilize STAT1, promote CCL2/CCL5 transcription, and maintain germ cell proliferation and migration.

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.

Epithelial ovarian cancer (EOC) has the worst prognosis in all of gynecologic malignant tumors because of its high recurrence. Cellular senescence is widel

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.

Background: Visceral obesity-related genes (VORGs) have been implicated in cancer progression, but their biological and clinical relevance in ovarian cancer (OC) remains uncertain. Methods: Prognostic modeling of VORGs was carried out using the The Cancer Genome Atlas (TCGA) and GSE53963 datasets. This model was further investigated in its association with tumor immunity, immune checkpoint inhibitor (ICI) response, and chemotherapy outcomes. Additionally, single-cell data were analyzed to explore gene expression within the tumor microenvironment of this model, specifically identifying high expression of the key gene MARVELD1 in tumor stem cells. The functionality of MARVELD1 was validated experimentally through Cell Counting Kit-8 (CCK-8), transwell, and colony formation assays. Results: OC patients were stratified into four molecular subtypes based on overall survival (OS)-associated VORG expression profiles. Differentially expressed genes (DEGs) between subtypes with prognostic relevance were identified and subsequently analyzed using least absolute shrinkage and selection operator (LASSO) regression and stepwise Cox modeling, resulting in a robust four-gene prognostic model comprising CXCL9, IGF2, FCGBP, and MARVELD1. This model effectively classified patients into high- and low-risk groups, with the high-risk group demonstrating significantly poorer outcomes (P < 0.001). In addition, risk scores showed strong correlations with immune checkpoint gene expression and predicted chemotherapy sensitivity, underscoring their utility in forecasting therapeutic responses. Single-cell transcriptomic analysis revealed heterogeneous expression of model genes across subpopulations, with MARVELD1 prominently enriched in tumor stem cells. MARVELD1 was found to modulate early cellular processes through pathways such as reactive oxygen species. Finally, in vitro experiments confirmed that MARVELD1 knockdown significantly inhibited OC cell proliferation, invasion, and colony formation, further validating its oncogenic role. Conclusion: A VORG-based prognostic model was established that correlates with OC prognosis, tumor immune microenvironment, and treatment sensitivity. These findings suggest that MARVELD1 and related pathways may serve as potential targets to improve prognostic stratification and guide therapy in OC.

Objectives: Defective in cullin neddylation 1 domain containing 2 (DCUN1D2) belongs to the DCNLs family and can induce cell growth arrest and is also related to neddylation. While its potential role in spermatogenesis is hypothesized, the functional significance of DCUN1D2 in male germ cells remains undefined. Methods: To investigate this, germ cell and Sertoli cell-specific Dcun1d2-knockouts were generated. Sperm parameters were analyzed via computer-assisted sperm analysis (CASA), while histological and immunofluorescence staining were employed to evaluate spermatogenic progression and apoptosis. Results: Compared with the control group, Dcun1d2 conditional knockout (cKO) mice exhibited no significant differences in histology, semen quality, sperm apoptosis or fertility tests. Conclusions: This study indicated that DCUN1D2 has no significant effect on mouse spermatogenesis or male fertility. These findings will help avoid redundant studies and provide new information for the study of human fertility genes.

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.

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.

As a common malignant tumor among women, ovarian cancer poses a serious threat to their health. This study demonstrates that long non-coding RNA NRSN2-AS1 is over-expressed in ovarian cancer tissues using patient sample and tissue microarrays. In addition, NRSN2-AS1 is shown to promote ovarian cancer cell proliferation and metastasis both in vitro and in vivo. Mechanistically, NRSN2-AS1 stabilizes protein tyrosine kinase 2 (PTK2) to activate the β-catenin pathway via repressing MG-53-mediated ubiquitinated degradation of PTK2, thereby facilitating ovarian cancer progression. Rescue experiments verify the function of the NRSN2-AS1/PTK2/β-catenin axis and the effects of MG53 on this axis in ovarian cancer cells. In conclusion, this study demonstrates the key role of the NRSN2-AS1/PTK2/β-catenin axis for the first time and explores its potential clinical applications in ovarian cancer.