Peritoneal
metastases are frequently found in high-grade serous
carcinoma (HGSOC) patients and are commonly associated with a poor prognosis. The tumor microenvironment (TME) is a complex milieu that plays a critical role in epigenetic alterations driving
tumor development and metastatic progression. However, the impact of epigenetic alterations on metastatic
ovarian cancer cells in the harsh peritoneal microenvironment remains incompletely understood. Here, we identified that miR-33b is frequently silenced by promoter hypermethylation in HGSOC cells derived from metastatic omental
tumor tissues. Enforced expression of miR-33b abrogates the oncogenic properties of
ovarian cancer cells cocultured in omental
conditioned medium (OCM), which mimics the
ascites microenvironment, and in vivo
tumor growth. Of note, restoration of miR-33b inhibited OCM-upregulated de novo lipogenesis and
fatty acid β-oxidation in
ovarian cancer cells, indicating that miR-33b may play a novel
tumor suppressor role in the
lipid-mediated oncogenic properties of metastatic
ovarian cancer cells found in the omentum. Mechanistic studies demonstrated that miR-33b directly targets
transforming growth factor beta-activated kinase 1 (TAK1), thereby suppressing the activities of
fatty acid synthase (FASN) and
carnitine palmitoyltransferase 1A (CPT1A) in modulating
lipid metabolic activities and simultaneously inhibiting the phosphorylation of NF-κB signaling to govern the oncogenic behaviors of
ovarian cancer cells. Thus, our data suggest that a
lipid-rich microenvironment may cause epigenetic silencing of miR-33b, which negatively modulates
ovarian cancer peritoneal
metastases, at least in part, by suppressing TAK1/FASN/CPT1A/NF-κB signaling.