Journal
CELL DEATH DISCOVERY
Volume 7, Issue 1, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41420-021-00589-8
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Funding
- 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University
- research and development important project of the Science and Technology Bureau in Sichuan [2018SZ0188]
- National Natural Science Foundation of China [81872020]
- Science Fund for Creative Research Groups of the National Natural Science Foundation of China [81621003]
- Sichuan University postdoctoral interdisciplinary Innovation FundSichuan University postdoctoral interdisciplinary Innovation Fund
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The study shows that Ursodeoxycholic acid (UDCA) can suppress YAP signaling by activating TGR5, inhibiting tumor growth in colorectal cancer (CRC) and regulating the cAMP/PKA signaling pathway to inhibit RhoA activity. This provides a new understanding of the importance of maintaining normal intestinal bile acid metabolism in cancer patients, offering a new approach for potential therapeutic intervention in CRC.
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.
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