Dysregulation of the ESRP2-NF2-YAP/TAZ axis promotes hepatobiliary carcinogenesis in non-alcoholic fatty liver disease.

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Nonalcoholic Fatty Liver Disease (NAFLD), the hepatic correlate of the metabolic syndrome, is a major risk factor for hepatobiliary cancer (HBC). Although chronic inflammation is thought to be the root cause of all these diseases, the mechanism whereby it promotes HBC in NAFLD remains poorly understood. Here we aim to evaluate the hypothesis that inflammation-related dysregulation of the ESRP2-NF2-YAP/TAZ axis promotes HB carcinogenesis.We use murine NAFLD models, liver biopsies from NAFLD patients, human liver cancer registry data, and studies in liver cancer cell lines.Our results confirm this hypothesis and support a model whereby chronic inflammation suppresses hepatocyte expression of ESRP2, an RNA splicing factor that directly targets and activates NF2, a tumor suppressor that is necessary to constrain YAP/TAZ activation.The resultant loss of NF2 function permits sustained YAP/TAZ activity that drives hepatocyte proliferation and de-differentiation, advantaging growth of cells with mutations that enable them to survive chronic oncogenic stress.Nonalcoholic fatty liver disease (NAFLD) increases the risk for hepatobiliary carcinogenesis. However, the underlying mechanism remains unknown. Our study demonstrates that chronic inflammation suppresses hepatocyte expression of ESRP2, an adult RNA splicing factor that activates NF2. Thus, inactive (fetal) NF2 loses the function to activate Hippo kinases and downstream YAP/TAZ activities increase, promoting hepatobiliary carcinogenesis in chronically injured liver, such as NAFLD. Liver cancer patients with more fetal NF2 mRNA have poor survival probability.

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Authors: Jeongeun Hyun, Muthana Al Abo, Rajesh Kumar Dutta, Seh Hoon Oh, Kun Xiang, Xiyou Zhou, Raquel Maeso-Díaz, Rebecca Caffrey, Arun J Sanyal, Jennifer A Freedman, Steven R Patierno, Cynthia A Moylan, Manal F Abdelmalek, Anna Mae Diehl