The role of R-spondin 1 through activating Wnt/beta-catenin in the growth, survival and migration of ovarian cancer cells

摘要

Aberrant activation of the Wnt/beta-catenin has been shown to promote progression in various cancers, including ovarian cancer. However, the molecular mechanisms involved in Wnt/beta-catenin activation are not well elucidated. In the work, we identify that R-spondin 1 is an upstream regulator in Wnt/beta-catenin pathway to promote growth, survival and migration in ovarian cancer cells. We observe the upregulation of transcript and protein levels of R-spondin 1 in ovarian cancer cell lines and tissues compared to normal counterparts. R-spondin 1 upregulation via genetic (overexpression) and pharmacological (recombinant protein) approaches facilitates growth and migration of normal ovarian cells. R-spondin 1 downregulation via siRNA knockdown decreases proliferation and migration, and induces apoptosis in ovarian cancer cells. In addition, recombinant R-spondin 1 protects ovarian cancer cell against chemotherapy whereas R-spondin I knockdown sensitizes ovarian cancer cell response to chemotherapy. Importantly, increasedji-catenin activities and mRNA expression levels of Wnt/beta-catenin-targeted genes are detected in normal ovarian cells overexpressing R-spondin 1. In contrast, R-spondin 1 inhibition suppresses Wnt/beta-catenin signaling in ovarian cancer cells. We further identify that R-spondin 1 regulates ovarian cancer biological activities via activating Wnt/beta-catenin. Our work is the first to highlight the critical roles of R-spondin 1 in ovarian cancer progression and chemoresistance. Our work also provides a proper understanding on the regulation of Wnt/beta-catenin pathway in ovarian cancer.