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

JOURNAL OF HEPATOLOGY

卷:75

Article

Hyun, Jeongeun^1,2,3,4,5,6  Al Abo, Muthana⁷  Dutta, Rajesh Kumar¹  Oh, Seh Hoon¹  Xiang, Kun⁸  Zhou, Xiyou¹  Maeso-Diaz, Raquel¹  Caffrey, Rebecca⁹  Sanyal, Arun J.¹⁰  Freedman, Jennifer A.^1,7  Patierno, Steven R.^1,7  Moylan, Cynthia A.¹  Abdelmalek, Manal F.¹  Diehl, Anna Mae¹ 

[1] Duke Univ, Dept Med, Duke Univ Hlth Syst, Durham, NC USA

[2] Duke Univ, Sch Med, Regenerat Next, Durham, NC USA

[3] Dankook Univ, Inst Tissue Regenerat Engn ITREN, Cheonan, South Korea

[4] Dankook Univ, Dept Nanobiomed Sci, Cheonan, South Korea

[5] Dankook Univ, BK21 Plus NBM Global Res Ctr Regenerat Med, Cheonan, South Korea

[6] Dankook Univ, Coll Dent, Dept Regenerat Dent Med, Cheonan, South Korea

[7] Duke Univ, Duke Canc Inst, Sch Med, Durham, NC USA

[8] Duke Univ, Dept Biomed Engn, Pratt Sch Engn, Durham, NC 27706 USA

[9] Sanyal Biotechnol LLC, Norfolk, VA USA

[10] Virginia Commonwealth Univ, Dept Internal Med, Div Gastroenterol Hepatol & Nutr, Richmond, VA USA

关键词: epithelial splicing regulatory protein-2 (ESRP2);    neurofibromatosis-2 (NF2);    hippo kinase;    alternative RNA splicing;    nonalcoholic fatty liver disease (NAFLD);    hepatocellular carcinoma (HCC);    liver cancer;    yes-associated protein (YAP);   

DOI  :  10.1016/j.jhep.2021.04.033

来源: Elsevier

【 摘 要 】

Background & Aims: Non-alcoholic fatty liver disease (NAFLD), the hepatic correlate of the metabolic syndrome, is a major risk factor for hepatobiliary cancer (HBC). Although chronic inflam-mation is thought to be the root cause of all these diseases, the mechanism whereby it promotes HBC in NAFLD remains poorly understood. Herein, we aim to evaluate the hypothesis that inflammation-related dysregulation of the ESRP2-NF2-YAP/TAZ axis promotes HB carcinogenesis. Methods: We use murine NAFLD models, liver biopsies from patients with NAFLD, human liver cancer registry data, and studies in liver cancer cell lines. Results: Our results confirm the hypothesis that inflammation related dysregulation of the ESRP2-NF2-YAP/TAZ axis promotes HB carcinogenesis, supporting 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 dedifferentiation. Conclusion: Herein, we report on a novel mechanism by which chronic inflammation leads to sustained activation of YAP/TAZ activity; this imposes a selection pressure that favors liver cells with mutations enabling survival during chronic oncogenic stress. Lay summary: Non-alcoholic fatty liver disease (NAFLD) increases the risk of 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 ability to activate Hippo kinases, leading to the increased activity of downstream YAP/TAZ and promoting hepatobiliary carcinogenesis in chronically injured livers. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

【 授权许可】

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