CD24 induced cellular quiescence-like state and chemoresistance in ovarian cancer cells via miR-130a/301a-dependent CDK19 downregulation.

ABSTRACT

Cancer stem-like cell (CSC) is thought to be responsible for ovarian cancer recurrence. CD24 serves as a CSC marker for ovarian cancer and regulates the expression of miRNAs, which are regulators of CSC phenotypes. Therefore, CD24-regulated miRNAs may play roles in manifesting the CSC phenotypes in ovarian cancer cells. Our miRNA transcriptome analysis showed that 94 miRNAs were up or down-regulated in a CD24-high clone from an ovarian cancer patient compared to a CD24-low one. The CD24-dependent expression trend of the top 7 upregulated miRNAs (miR-199a-3p, 34c, 199a-5p, 130a, 301a, 214, 34b*) was confirmed in other 8 clones (4 clones for each group). CD24 overexpression upregulated the expression of miR-199a-3p, 34c, 199a-5p, 130a, 301a, 214, and 34b* in TOV112D (CD24-low) cells compared to the control, while CD24 knockdown downregulated the expression of miR-199a-3p, 199a-5p, 130a, 301a, and 34b* in OV90 (CD24-high) cells. miR-130a and 301a targeted CDK19, which induced a cellular quiescence-like state (increased G0/G1 phase cell population, decreased cell proliferation, decreased colony formation, and decreased RNA synthesis) and resistance to platinum-based chemotherapeutic agents. CD24 regulated the expression of miR-130a and 301a via STAT4 and YY1 phosphorylation mediated by Src and FAK. miR-130a and 301a were positively correlated in expression with CD24 in ovarian cancer patient tissues and negatively correlated with CDK19. Our results showed that CD24 expression may induce a cellular quiescence-like state and resistance to platinum-based chemotherapeutic agents in ovarian cancer via miR-130a and 301a upregulation. CD24-miR-130a/301a-CDK19 signaling axis could be a prognostic marker for or a potential therapeutic target against ovarian cancer recurrence.