FAM3C Promotes Ovarian Cancer Progression and Mediates Olaparib Sensitivity by Activating the HIF-1α/STAT3 Pathway.

Abstract

The family with sequence similarity 3 (FAM3) family has four members (FAM3A, FAM3B, FAM3C, and FAM3D), which have been proven to contribute to tumorigenesis. However, their correlations with ovarian cancer (OV) prognosis and regulatory functions in OV are poorly understood. Here, the expression of four FAM3 family members in OV was analyzed, and functional assays were conducted to explore the effects and underlying mechanisms of FAM3C in OC progression and chemical resistance. FAM3C was upregulated in OV tissues, and higher FAM3C was associated with poorer overall survival and shorter progression-free survival in OV patients. Upregulating FAM3C promoted OV cell proliferation and growth and reduced DNA damage and sensitivity to olaparib. In contrast, downregulating FAM3C restrained OV cell proliferation, promoted DNA damage, and enhanced olaparib sensitivity. Mechanistically, FAM3C overexpression promoted p-STAT3 and HIF-1α expression, which was suppressed after treatment with the HIF-1α inhibitor LW6 or the STAT3 inhibitor static. In vivo assay confirmed that inhibiting STAT3 reversed the FAM3C-mediated promotive effects on tumor growth and enhanced the sensitivity of A2780 cells to olaparib. Taken together, our findings demonstrate that FAM3C promotes OV development and reduces olaparib sensitivity by activating the HIF-1α/STAT3 pathway. FAM3C could serve as a potential diagnostic marker and anticancer target in OV.