Role of hsa-miR-105 during the pathogenesis of paclitaxel resistance and its clinical implication in ovarian cancer

Abstract

More than 70% of patients with epithelial ovarian cancer (EOC), one of the leading cause of gynecological cancer-related deaths worldwide, are diagnosed at an advanced stage of the disease. Currently, the mainstay for treatment of advanced EOC is tumor debulking surgery followed by combined platinum- and paclitaxel (PTX)-based chemotherapy. However, most patients eventually develop chemoresistance, which remains a major obstacle to successful treatment. Herein, by using clinical specimens and experimentally induced cell models, we found that the expression levels of hsa-miR-105 were significantly decreased in PTX-resistant EOC tissues and cell lines. Follow-up functional experiments demonstrated that repression of hsa-miR-105 conferred resistance to paclitaxel in EOC cells, whereas restoration of hsa-miR-105 expression in situ via intratumoral injection of hsa-miR-105 micrON™ agomir potentiated in vivo sensitivity to PTX and thereafter significantly inhibited tumor growth in a PTX-challenged xenograft model. Mechanistically, hsa-miR-105 exerted its tumor suppressor function by directly inhibiting the zinc and ring finger 2 (ZNRF2) signaling pathway. Importantly, aber- rant expression of hsa-miR-105 in both tumor and circulating samples predicted a poor post-chemotherapy prognosis in EOC patients. These findings collectively suggest that hsa-miR-105 may act as a potent tumor suppressor miRNA during the progression of EOC, likely affecting cell proliferation, invasive- ness and chemosensitivity to PTX, and functioning at least in part via inhibition of ZNRF2 signaling. The stability and avail- ability and ease in measurement of circulating hsa-miR-105 make it a valuable diagnostic/prognostic biomarker candidate for chemotherapy of EOC.