Induction of miR-15a expression by tripterygium glycosides caused premature ovarian failure by suppressing the Hippo-YAP/TAZ signaling effector Lats1

Tripterygium glycosides (TGs) are chemotherapeutic drugs and immunosuppressant agents for the treatment of cancer and autoimmune diseases. We have previously reported that TGs induces premature ovarian failure (POP) by inducing cytotoxicity in ovarian granulosa cells (OGCs). Hence, we report that TGs suppress the expression of the Hippo-YAP/TAZ pathway in murine OGCs in vitro and in vivo. We found that the expressions of miR-181b, miR-15a, and miR-30d, were elevated significantly in the POF. Luciferase reporter assays confirmed that miR-15a targets Lats1 through a miR-15a binding site in the Lats1 3'UTR. Overexpression of miR-15a in mOGCs not only inhibited proliferation and growth of mOGCs, but also induced aging of mOGCs. Western blot and qPCR analysis indicated that miR-15a suppresses the expression of the Hippo-YAP/TAZ pathway in mOGCs. When the exogenous miR-15a was expressed on mouse OGCs, it could elevate the cytotoxicity effect of TG on mOGCs. We conclude that tripterygium glycosides promote cytotoxicity, senescence, and apoptosis in ovarian granulosa cells by inducing endogenous miR-15a expression and inhibiting the Hippo-YAP/TAZ pathway.