The Activation of miR‐203a by SFRP4 Micropeptides Targets Epithelial–Mesenchymal Transition and Autophagy in Ovarian Cancer Stem Cells

ABSTRACT

Cancer stem cells (CSCs) are characterized by various properties such as hyperactive Wnt pathway, increased chemoresistance, angiogenesis, autophagy, EMT and decreased apoptotic activity. SFRP4 micropeptides, SC‐301 and SC‐401 derived from cysteine rich domain (CRD) and netrin like domain (NLD) domains respectively have shown to exhibit significant anti‐CSC properties. In this study, based on our preliminary investigation, which showed that miR‐203a was downregulated in ovarian CSCs and was subsequently activated by treatment with SFRP4 micropeptides, we investigated whether miR‐203a plays any part in SFRP4 micropeptide‐mediated ovarian CSC inhibition in PA‐1 and SKOV‐3 cell lines. SFRP4 micropeptide‐treated and miR‐203a mimic‐overexpressing ovarian CSCs were subjected to various assays, and the results showed that miR‐203a overexpression by the SFRP4 micropeptide treatment resulted in disruption of sphere‐forming capacity and induction of caspase activity in ovarian CSCs. Furthermore, miR‐203a expression upon micropeptide treatment resulted in the increased levels of E‐cad and decreased levels of N‐cad, Snail and Twist, indicating reversal of EMT along with the significant reduction in migratory potential of ovarian CSCs. Our findings for the first time indicated the possible role of miR‐203a in regulating autophagy in ovarian CSCs, and reactivation of miR‐203a by SFRP4 micropeptides was sufficient to halt the autophagic machinery in ovarian CSCs.