MAD2L2, a key regulator in ovarian cancer and promoting tumor progression.

Ovarian cancer (OVCA), a prevalent gynecological malignancy, ranks as the fourth most common cancer among women. Mitotic Arrest Deficient 2 Like 2 (MAD2L2), a chromatin-binding protein and a component of DNA polymerase ζ, has been previously identified as an inhibitor of tumor growth in colorectal cancer. However, the roles of MAD2L2 in OVCA, including its expression, impact, and prognostic significance, remain unclear. We employed bioinformatics tools, Cox Regression analysis, and in vitro cell experiments to investigate its biological functions. Our findings reveal that MAD2L2 typically undergoes genomic alterations, such as amplifications and deep deletions. Moreover, we observed an overexpression of MAD2L2 mRNA in OVCA patients, correlating with reduced survival rates, particularly in those with Grade IV tumors. Furthermore, analysis of mRNA biofunctions indicated that MAD2L2 is predominantly localized in the organellar ribosome, engaging mainly in NADH dehydrogenase activity. This was deduced from the results of gene ontology enrichment analysis, which also identified its role as a structural constituent in mitochondrial translation elongation. These findings were corroborated by KEGG pathway analysis, further revealing MAD2L2's involvement in tumor metabolism and the cell death process. Notably, MAD2L2 protein expression showed significant associations with various immune cells, including CD4+T cells, CD8+T cells, B cells, natural killer cells, and Myeloid dendritic cells. Additionally, elevated levels of MAD2L2 were found to enhance cell proliferation and migration in OVCA cells. The upregulation of MAD2L2 also appears to inhibit the ferroptosis process, coinciding with increased mTOR signaling activity in these cells. Our study identifies MAD2L2 as a novel regulator in ovarian tumor progression and offers new insights for treating OVCA.

Regulatory mechanism of GPER in the invasion and migration of ectopic endometrial stromal cells in endometriosis.

Endometriosis (EMS) is a chronic inflammatory disorder of high incidence that causes serious reproductive consequences. High estrogen production is a consistently observed endocrine feature of EMS. The present study aims to probe the molecular mechanism of G protein-coupled estrogen receptor 1 (GPER) in the invasion and migration of ectopic endometrial stromal cells (Ect-ESCs) and provides a new rationale for EMS treatment. Eutopic and ectopic endometrial tissues were collected from 41 EMS patients, and primary ESCs were separated. GPER, miR-16-5p, and miR-103a-3p levels in cells and tissues were determined by qRT-PCR or Western blot assay. Cell viability, proliferation, invasion, and migration were evaluated by CCK-8, colony formation, and Transwell assays. The upstream miRNAs of GPER were predicted by databases, and dual-luciferase assay was performed to validate the binding of miR-16-5p and miR-103a-3p to GPER 3'UTR. GPER was highly expressed in EMS tissues and Ect-ESCs. Inhibition of GPER mitigated the proliferation, invasion, and migration of Ect-ESCs. GPER was regulated by miR-16-5p and miR-103a-3p. Overexpression of miR-16-5p and miR-103a-3p negatively regulated GPER expression and inhibited the invasion and migration of Ect-ESC. In conclusion, GPER promoted the invasion and migration of Ect-ESCs, which can be reversed by upstream miR-16-5p and miR-103a-3p.

Withaferin A inhibits proliferation of human endometrial cancer cells via transforming growth factor-ß (TGF-ß) signalling.

The present study was designed to evaluate the anticancer effects of withaferin A against the human endometrial cancer via modulation of transforming growth factor-ß (TGF-ß) signalling. The results of the present study revealed that withaferin A exerts a dose and time-dependent antiproliferative effects against the human KLE endometrial cancer cells with comparatively lower toxicity against the THESCs normal cells. The IC50 of withaferin A against the KLE endometrial cancer cells was found to 10 µM. The results showed that withaferin A induced apoptosis and G2/M cell cycle arrest of the KLE cells which was associated with alteration of the apoptosis and cell cycle related proteins. In addition, the transwell assays showed that the migration and invasion of the KLE cells were inhibited by 53 and 40%, respectively. Finally, the effects of withaferin A were also examined on the TGF-ß signalling pathway. The results showed that withaferin A blocked TGF-ß-dependent Smad2 phosphorylation and expression of other TGF-ß-related proteins in KLE cells. Summing up, the results suggest that withaferin A inhibits the proliferation of the human endometrial carcinoma via TGF-ß signalling.