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

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, aberrant 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, invasiveness and chemosensitivity to PTX, and functioning at least in part via inhibition of ZNRF2 signaling. The stability and availability and ease in measurement of circulating hsa-miR-105 make it a valuable diagnostic/prognostic biomarker candidate for chemotherapy of EOC.