Ling Ouyang

Long noncoding RNA VPS9D1 ‐ AS1 promotes the progression of endometrial cancer via regulation of the miR‐187‐3p / S100A4 axis

Abstract VPS9D1‐AS1 functions as an oncogene in many cancers. However, its role and potential mechanism in the progression of endometrial cancer (EC) are not fully understood. VPS9D1‐AS1 levels in EC and adjacent normal tissues were investigated using the TCGA‐UCEC cohort and 24 paired clinical samples. The roles of VPS9D1‐AS1 and miR‐187‐3p in cell cycle, proliferation, and apoptosis were evaluated by loss‐ and gain‐of‐function experiments. In addition, the effect of VPS9D1‐AS1 on tumor growth was further investigated in vivo. Rescue experiments were performed to investigate the involvement of the miR‐187‐3p/S100A4 axis in VPS9D1‐AS1 knockdown‐mediated antitumor effects. VPS9D1‐AS1 was highly expressed in EC tissues. VPS9D1‐AS1 knockdown, similar to miR‐187‐3p overexpression, significantly inhibited cell proliferation, inhibited colony formation, induced cell cycle arrest, and facilitated apoptosis of KLE cells. MiR‐187‐3p bound directly to VPS9D1‐AS1 and the 3′UTR of S100A4. Furthermore, VPS9D1‐AS1 negatively regulated miR‐187‐3p while positively regulating S100A4 expression in EC cells. MiR‐187‐3p knockdown or S100A4 overexpression partially reversed the tumor suppressive function of VPS9D1‐AS1 knockdown. The results suggest that VPS9D1‐AS1 affects EC progression by regulating the miR‐187‐3p/S100A4 axis. This may provide a promising therapeutic target to help treat EC.

Identification of prognosis-related hub genes of ovarian cancer through bioinformatics analyses and experimental verification

Ovarian cancer (OC) is a lethal and highly prevalent disease in women worldwide. The disease is often diagnosed in late stages, which leads to its rapid progression and low survival rate. This study aims to identify new prognostic genes for OC. Based on 2 datasets from the National Center for Biotechnology Information Gene Expression Omnibus public database, we constructed 2 Weighted Gene Co-expression Network Analysis networks. Then, we selected and intersected 2 key modules to screen key genes. Enrichment analyses were performed, and a protein-protein interaction network was constructed. The cytoHubba plugin of Cytoscape and survival analysis were used to screen hub genes related to prognosis. The expression of hub genes was analyzed by GEPIA and verified by quantitative Real-Time PCR. Gene alteration frequency analysis, gene set variation analysis, immune infiltration analysis, drug sensitivity analysis, tumor mutation burden, and neoantigen analyses were conducted to determine the prognostic value and molecular mechanisms of the hub genes. In total, 214 key genes were selected from 2 Weighted Gene Co-expression Network Analysis networks, and 3 hub genes, namely ALDH1A2, CLDN4, and GPR37, were identified as prognostic candidates through cytoHubba and survival analysis. Three hub genes were significantly associated with overall survival of OC patients. GEPIA and quantitative Real-Time PCR indicated that ALDH1A2 expression was significantly downregulated, while expression of CLDN4 and GPR37 was upregulated in OC samples compared with normal samples. CIBERSORT showed that 3 hub genes were closely associated with the infiltrating immune cells. GDSC showed that hub genes expression influenced IC50 values of chemotherapeutic drugs. OC patients with high expression of ALDH1A2 and CLDN4 had lower TMB and low ALDH1A2 expression could produce a larger number of neoantigens. In conclusion, the 3 hub genes (ALDH1A2, CLDN4 and GPR37) identified through bioinformatics analyses in the present study may serve as OC prognosis biomarkers. The study findings offer valuable insights into OC progression and mechanisms.

Odd-skipped related 1 plays a tumor suppressor role in ovarian cancer via promoting follistatin-like protein 1 transcription

Zinc-finger transcription factor odd-skipped related 1 (OSR1) is involved in the progression of certain types of cancers, via regulating the transcription of downstream genes. However, the function of OSR1 in ovarian cancer (OC) progression remains unclear. The present study aimed to explore the OSR1 expression pattern in OC tissues and cell lines. Functional assays were performed to explore the regulatory effects of OSR1 on OC cell growth, migration and invasion in vitro and in vivo. Results of the present study demonstrated that OSR1 was significantly downregulated in OC tissues compared with healthy ovarian tissues (P < 0.01). Moreover, SKOV-3 and OVCAR-3 cells with low OSR1 expression were used for functional studies, and results demonstrated that OSR1 overexpression suppressed cell growth by inhibiting cell cycle progression and inducing cell apoptosis in vitro. OC cells with higher OSR1 expression levels exhibited reduced levels of migration and invasion, when compared with the corresponding control. In addition, OSR1 expression in xenografts models resulted in diminished tumor volume and suppressed tumorigenesis. OSR1 enhanced follistatin-like protein 1 (FSTL1) expression at the transcriptional level through directly binding to the promoter of FSTL1, which was commonly reported to exert a tumor suppressor role in OC progression. Moreover, FSTL1 knockdown reversed the action of OSR1 overexpression in OC progression, including cell viability, migration, invasion, and apoptosis. In conclusion, these results indicated that OSR1 may function as a tumor suppressor through augmenting FSTL1 transcription in OC progression, suggesting that the OSR1/ FSTL1 axis may exhibit potential as a therapeutic target for OC therapy.

KCMF1 promotes malignant progression by NXN ubiquitin-dependent degradation in ovarian cancer.

Ovarian cancer, one of the most lethal gynecologic malignancies, exhibits marked tumor heterogeneity. Potassium channel modulatory factor 1 (KCMF1), a RING zinc-finger protein with E3 ubiquitin ligase activity, has been implicated in tumorigenesis. However, the role of KCMF1 in ovarian cancer remains unclear. In this study, we found that KCMF1 was up-regulated in ovarian cancer tissues and that high KCMF1 expression correlated with poor survival of patients. Functional assays revealed that KCMF1 knockdown suppressed cell viability, hampered cell cycle progression, and inhibited proliferation in ovarian cancer cells. Moreover, silencing KCMF1 inhibited epithelial-mesenchymal transition (EMT), migration, and invasion in vitro. In vivo experiments confirmed that KCMF1 knockdown inhibited tumor growth and metastasis in nude mice. Conversely, KCMF1 overexpression had opposite effects in vitro and in vivo. IP-LC/MS and Label-free proteomic analysis identified nucleoredoxin (NXN), a multifunctional redox-active protein, as a potential substrate of KCMF1. Silencing NXN facilitated cell proliferation, migration, and invasion through activating the β-catenin signaling pathway. Mechanistically, we discovered that KCMF1 interacted with NXN and facilitates its degradation through K63-linked ubiquitination, thereby reducing NXN expression. Taken together, our study showed that KCMF1 promotes ovarian cancer progression through NXN, and KCMF1 might be a novel target for ovarian cancer therapy.