Abstract
The Hippo/YAP pathway plays an important role in the development of cancers. Previous studies have reported that bile acids can activate YAP (Yes Associated Protein) to promote tumorigenesis and tumor progression. Ursodeoxycholic acid (UDCA) is a long-established old drug used for cholestasis treatment. So far, the effect of UDCA on YAP signaling in colorectal cancer (CRC) is not well defined. This study means to explore relationship of UDCA and YAP in CRC. UDCA suppressed YAP signaling by activating the membrane G-protein-coupled bile acid receptor (TGR5). TGR5 mainly regulated cAMP/PKA signaling pathway to inhibit RhoA activity, thereby suppressing YAP signaling. Moreover, the restoration of YAP expression alleviated the inhibitory effect of UDCA on CRC cell proliferation. In AOM/DSS-induced CRC model, UDCA inhibited tumor growth in a concentration-dependent manner and decreased expression of YAP and Ki67. UDCA plays a distinguished role in regulating YAP signaling and CRC growth from the primary bile acids and partial secondary bile acids, demonstrating the importance of maintaining normal intestinal bile acid metabolism in cancer patients. It also presents a potential therapeutic intervention for CRC.
Highlights
The Hippo/YAP pathway regulates organ size, tumor formation, and function of stem cells
The UDAC prevented tumor growth in a dose-dependent manner by decreasing YAP expression in vivo. These findings show that ursodeoxycholic acid (UDCA) and primary Bile acids (BAs) or some secondary bile acids have opposite effects on YAP signaling and colorectal cancer (CRC) growth, indicating the importance of maintaining normal intestinal bile acid metabolism in cancer patients
MTT assays showed that UDCA inhibited the proliferation of UDCA acted through RhoA to inhibit the YAP pathway in CRC cells
Summary
The Hippo/YAP pathway regulates organ size, tumor formation, and function of stem cells. Previous studies have reported that the primary BAs, and some secondary bile acids such as DCA and LCA, are promoters of tumorigenesis of various cancers including hepatocellular carcinoma and CRC [13, 14]. The effect of UDAC on YAP signaling and its implication in CRC has not been elucidated despite UDCA sharing the same receptors with the primary BAs and some secondary bile acids. The UDAC prevented tumor growth in a dose-dependent manner by decreasing YAP expression in vivo These findings show that UDCA and primary BAs or some secondary bile acids have opposite effects on YAP signaling and CRC growth, indicating the importance of maintaining normal intestinal bile acid metabolism in cancer patients. UDCA supplementation may confer potential therapeutic effects in CRC with high TGR5 expression
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