Membrane-spanning 4-domains subfamily A 15 (MS4A15) belongs to transmembrane proteins and has been recognized as a regulator of various biological events including cell metabolism. Dysregulation of cell metabolism is a component of malignant transformation in numerous types of tumors, including ovarian cancer (OC). Nevertheless, whether MS4A15 is involved in OC progression remains obscure, as well as the underlying mechanisms. In the present study, we found that MS4A15 expression was significantly up-regulated in tumor tissues from OC patients compared with the matched normal adjacent samples. Higher MS4A15 expression predicted poorer overall survival rate in patients with OC. Our in vitro studies subsequently showed that MS4A15 knockdown markedly reduced the proliferation of OC cells, while its over-expression accelerated the proliferative capacity of OC cells through mediating the progression of G0/G1 cell cycle. Consistently, stable MS4A15 knockdown strongly inhibited the tumor growth in the established xenograft mouse models, along with evidently decreased expression of KI-67 positive staining. However, xenograft mouse models with MS4A15 over-expression exerted significantly accelerated tumor growth rates. We then found that MS4A15 reprogrammed energy metabolism to enhance OC progression. Under normal status, MS4A15 enhanced de novo lipid synthesis in OC cells. Upon glucose starvation, MS4A15 elevated oxidative phosphorylation (OXPHOS) to protect OC cells from starvation-induced cell death. Taken together, our findings demonstrated that MS4A15 may play an essential role in promoting OC growth mainly via reprogramming energy metabolism, and thus could be considered as a novel therapeutic target for OC treatment.
Keywords: Lipid synthesis; MS4A15; OXPHOS; Ovarian cancer; Proliferation.
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