Bile Acids Activate YAP to Promote Liver Carcinogenesis
Copyright policy )Bile Acids Activate YAP to Promote Liver Carcinogenesis
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.
- University of Illinois at Urbana Champaign United States
- The University of Texas MD Anderson Cancer Center United States
- University of Illinois at Urbana–Champaign United States
- BAYLOR COLLEGE OF MEDICINE
- University of Illinois Urbana-Champaign United States
Male, Cytoplasmic and Nuclear, Carcinogenesis, Medical Physiology, Cell Cycle Proteins, Inbred C57BL, Serine-Threonine Kinase 3, Oral and gastrointestinal, Mice, Receptors, 2.1 Biological and endogenous factors, Aetiology, Biology (General), Child, Cells, Cultured, Cancer, Cultured, Hepatocyte Growth Factor, Liver Disease, Liver Neoplasms, Adaptor Proteins, Biological Sciences, Protein-Serine-Threonine Kinases, Biological sciences, ras GTPase-Activating Proteins, Child, Preschool, Liver Cancer, Carcinoma, Hepatocellular, Adolescent, QH301-705.5, Cells, Knockout, Chronic Liver Disease and Cirrhosis, Protein Serine-Threonine Kinases, Bile Acids and Salts, Rare Diseases, Proto-Oncogene Proteins, Animals, Humans, Hippo Signaling Pathway, Preschool, Adaptor Proteins, Signal Transducing, Carcinoma, Signal Transducing, Infant, Newborn, Infant, Hepatocellular, YAP-Signaling Proteins, Stem Cell Research, Newborn, Phosphoproteins, Enzyme Activation, Mice, Inbred C57BL, Biochemistry and Cell Biology, Digestive Diseases, Transcription Factors
Male, Cytoplasmic and Nuclear, Carcinogenesis, Medical Physiology, Cell Cycle Proteins, Inbred C57BL, Serine-Threonine Kinase 3, Oral and gastrointestinal, Mice, Receptors, 2.1 Biological and endogenous factors, Aetiology, Biology (General), Child, Cells, Cultured, Cancer, Cultured, Hepatocyte Growth Factor, Liver Disease, Liver Neoplasms, Adaptor Proteins, Biological Sciences, Protein-Serine-Threonine Kinases, Biological sciences, ras GTPase-Activating Proteins, Child, Preschool, Liver Cancer, Carcinoma, Hepatocellular, Adolescent, QH301-705.5, Cells, Knockout, Chronic Liver Disease and Cirrhosis, Protein Serine-Threonine Kinases, Bile Acids and Salts, Rare Diseases, Proto-Oncogene Proteins, Animals, Humans, Hippo Signaling Pathway, Preschool, Adaptor Proteins, Signal Transducing, Carcinoma, Signal Transducing, Infant, Newborn, Infant, Hepatocellular, YAP-Signaling Proteins, Stem Cell Research, Newborn, Phosphoproteins, Enzyme Activation, Mice, Inbred C57BL, Biochemistry and Cell Biology, Digestive Diseases, Transcription Factors
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