Bile Acids Activate YAP to Promote Liver Carcinogenesis
Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels, via la signalisation Hippo, des niveaux élevés d'acides biliaires peuvent induire le développement d'un cancer du foie
Elevated bile acid levels increase hepatocellular carcinoma by unknown mechanisms. Here, we show that mice with a severe defect in bile acid homeostasis due to the loss of the nuclear receptors FXR and SHP have enlarged livers, progenitor cell proliferation, and Yes-associated protein (YAP) activation and develop spontaneous liver tumorigenesis. This phenotype mirrors mice with loss of hippo kinases or overexpression of their downstream target, YAP. Bile acids act as upstream regulators of YAP via a pathway dependent on the induction of the scaffold protein IQGAP1. Patients with diverse biliary dysfunctions exhibit enhanced IQGAP1 and nuclear YAP expression. Our findings reveal an unexpected mechanism for bile acid regulation of liver growth and tumorigenesis via the Hippo pathway. "Bile acids are upstream regulators of the Hippo pathway "The signaling scaffold protein IQGAP1 is induced by bile acid overload "IQGAP1 is sufficient to increase YAP expression "BAs promote hepatocarcinogenesis via IQGAP1 induction and YAP activation Apart from digesting fat, bile acids (BAs) also act as signaling molecules for nuclear and G protein-coupled receptors. Anakk, Moore, and colleagues show that the pathological accumulation of BAs can lead to liver cancer. Using various genetic as well as dietary mouse models, they found that BAs activate YAP, a transcriptional coactivator of the organ size control pathway, via the scaffolding protein IQGAP1. Overexpression of IQGAP1 is sufficient to induce YAP; therefore, decreasing IQGAP1 and BAs may protect against liver cancer.
http://linkinghub.elsevier.com/retrieve/pii/S2211124713006141