SIM2, associated with clinicopathologic features, promotes the malignant biological behaviors of endometrial carcinoma cells.

BACKGROUND: Endometrial carcinoma (EC) poses a significant threat to women's health. Identifying effective prognostic biomarkers and therapeutic targets is essential for improving survival rates in EC patients. This study aimed to identify key regulators involved in EC progression and investigate the biological functions of SIM bHLH transcription factor 2 (SIM2) in EC. METHODS: Gene expression profiles and clinical data from EC and control samples were retrieved from the TCGA and GEO databases. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were used to identify genes associated with EC tumorigenesis and progression. The least absolute shrinkage and selection operator (LASSO) method was applied to further screen prognostic genes and construct a prognostic risk model. The expression and biological function of SIM2 were analyzed using the GEPIA, HPA, and LinkedOmics databases. SIM2 knockdown and overexpression models were established in EC cell lines, and their function was validated through qRT-PCR, CCK-8, flow cytometry, and western blot. Additionally, an in vivo lung/liver metastasis model was employed to further validate the cancer-promoting properties of SIM2 in EC. RESULTS: WGCNA identified 343 EC-related genes. Cox regression analysis and LASSO were further applied to identify 13 prognostic genes, leading to the development of a robust prognostic risk model that effectively predicted EC patients' clinical outcomes. Significant differences in the tumor immune microenvironment were observed between the high- and low-risk groups. Among these 13 genes, SIM2 was significantly overexpressed in EC tissues, and its high expression was associated with poor prognosis in EC patients. SIM2 depletion inhibited EC cell viability, induced cell cycle arrest, and promoted apoptosis. Additionally, SIM2 knockdown increased the expression of cleaved caspase-3 and reduced the levels of Cyclin D1 and CDK4 proteins, while SIM2 overexpression showed the opposite effects. In vivo, silencing SIM2 notably suppressed the metastatic potential of EC cells. CONCLUSION: SIM2 serves as both a biomarker and a therapeutic target for EC diagnosis and prognosis prediction, which positively modulates the malignant phenotypes of EC cells.