The miR-141/Hippo is a novel signaling axis in tumour-stromal crosstalk network promoting ovarian cancer metastatic colonization

Abstract

Ovarian cancer is an insidious, aggressive and deadly disease in women worldwide. The high mortality rate is attributed to late diagnosis, a high incidence of recurrence and cancer metastasis. Indeed, cancer metastasis and associated complications are the main cause of cancer-related death. Different from other solid tumours, peritoneal metastases are very common by ovarian cancer and are associated with a poor prognosis. Metastatic colonization is the critical step of peritoneal metastases in ovarian cancer progression. Hence, a mechanistic understanding of the mechanism of the omental microenvironment promoting tumour colonization could significantly improve patient outcomes. According to the 'seed and soil' theory proposed by Stephen Paget, the interaction of the tumour-stroma niche is important for tumour colonization. Here, we propose a novel mechanism in the tumour-stromal crosstalk network to enhance ovarian cancer metastatic colonization. By analyzing miRNA expression profilings and functional studies, we have previously identified that the upregulated Hsa-miR-141-3p (miR-141) plays a role in enhancing anoikis resistance in metastatic progression of ovarian cancer through modulating KLF12/Sp1/survivin axis. Further investigations reveal that miR-141 is an exosomal miRNA markedly secreted by ovarian cancer cells and could induce stromal cells to produce GRO and EMMPRIN, which are frequently upregulated in ovarian cancer ascites. Ovarian cancer cells co-cultured with miR-141 stroma-conditioned medium showed a remarkable increase in cell proliferation and cell migration/invasion capacities that were further evidenced by the co-treatment of recombinant GRO/EMMPRIN. Proteomic analysis indicated that Yes Associated Protein 1 (YAP1), a critical effector of the Hippo pathway, is the targeted by miR-141 in stromal cells. Gene knockdown or overexpression of miR-141 caused the reduction of the YAP1/TAZ ratio, which, in turn, leads to transcriptional activation of GROa/EMMPRIN in stromal cells. Taken together, we suggest that ovarian cancer cell-secreted miR-141 reprograms stromal cells to produce GRO/EMMPRIN which are important to facilitate the metastatic colonization of ovarian cancer.