한빛사 논문
Jeongeun Hyun1,2,3,4,5, Muthana Al Abo6, Rajesh Kumar Dutta1, Seh Hoon Oh1, Kun Xiang7, Xiyou Zhou1, Raquel Maeso-Díaz1, Rebecca Caffrey8, Arun J. Sanyal9, Jennifer A. Freedman1,6, Steven R. Patierno1,6, Cynthia A. Moylan1, Manal F. Abdelmalek1, Anna Mae Diehl1,*
1Department of Medicine, Duke University, Duke University Health System, Durham, NC, USA
2Regeneration Next, Duke University School of Medicine, Durham, NC, USA
3Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, South Korea
4Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, South Korea
5Department of Regenerative Dental Medicine, College of Dentistry, Dankook University, Cheonan, South Korea
6Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA
7Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, USA
8Sanyal Biotechnology LLC, Norfolk, VA, USA
9Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
*Corresponding author
Abstract
Background & Aims
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.
Methods
We use murine NAFLD models, liver biopsies from NAFLD patients, human liver cancer registry data, and studies in liver cancer cell lines.
Results
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.
Conclusions
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.
Lay summary
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.
Keywords : 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
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