Abstract / Summary
Ovarian carcinoma is highly aggressive and often diagnosed late. TM4SF1 has been implicated in several cancers, but its role in ovarian cancer remains unclear. This study investigated whether TM4SF1 regulates malignant phenotypes through PI3K/AKT/mTOR signaling. The clinical relevance was assessed by analyzing TM4SF1 expression in ovarian cancer versus normal tissues, as well as its association with tumor stage and overall survival, using datasets from TCGA, GTEx, and GEO. SKOV3, A2780, and H08910PM cells were transfected for TM4SF1 overexpression or knockdown. Proliferation, apoptosis, cell-cycle progression, migration, and invasion were assessed using CCK-8, flow cytometry, wound-healing, and Transwell assays. Pathway activation and TM4SF1-PI3K association were evaluated by Western blotting, immunofluorescence, co-immunoprecipitation, and rescue experiments with PI3K/AKT modulators. Bioinformatics analysis revealed that TM4SF1 is significantly upregulated in ovarian cancer tissues compared to normal ovarian tissues, although its expression level was not significantly correlated with clinical stage or overall survival. In vitro, TM4SF1 overexpression promoted proliferation, cell-cycle progression, migration, and invasion while suppressing apoptosis, whereas TM4SF1 silencing produced opposite effects. TM4SF1 increased phosphorylation of PI3K, AKT, mTOR, S6K1, and 4E-BP1 without markedly altering total PI3K, AKT, or mTOR levels. Immunofluorescence and co-immunoprecipitation indicated that TM4SF1 formed a complex with PI3K, and PI3K or AKT inhibition largely reversed TM4SF1-driven malignant behaviors. TM4SF1 promotes the aggressive behavior of ovarian carcinoma cells through its association with PI3K, which subsequently triggers the PI3K/AKT/mTOR signaling cascade. However, whether TM4SF1 binds PI3K directly or acts through intermediary proteins remains to be determined.