Maintenance of stemness by miR-589-5p in hepatocellular carcinoma cells promotes chemoresistance via STAT3 signaling

Abstract

The strength and duration of STAT3 signaling are tightly controlled by multiple negative feedback mechanisms under physical conditions. However, how these serial feedback loops are simultaneously disrupted in cancers, leading to constitutive activation of STAT3 signaling in hepatocellular carcinoma (HCC), remains obscure. Here we report that miR-589-5p is elevated in HCC tissues, which is caused by recurrent gains. Overexpression of miR-589-5p correlates with poor overall and relapse-free survival in HCC patients. Upregulating miR-589-5p enhances spheroid formation ability, fraction of CD133 positive and side population cells, expression of cancer stem cell factors and the mitochondrial potential, and represses the apoptosis induced by doxorubicin in vitro and tumorigenicity in vivo in HCC cells; conversely, silencing miR-589-5p yields an opposite effect. Our findings further demonstrate miR-589-5p promotes the cancer stem cell characteristics and chemoresistance via targeting multiple negative regulators of STAT3 signaling pathway, including SOCS2, SOCS5, PTPN1 and PTPN11, leading to constitutive activation of STAT3 signaling. Collectively, our results unravel a novel mechanism by which miR-589-5p promotes the maintenance of stemness and chemoresistance in HCC, providing a potential rational registry of anti-miR-589-5p combining with conventional chemotherapy against HCC.

Keywords: Cancer stem cell; Chemotherapeutic resistance; Hepatocellular carcinoma; STAT3 signaling pathway; miR-589-5p.