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Wang X, Zeldin S, Shi H, et al. TAZ-induced Cybb contributes to liver tumor formation in non-alcoholic steatohepatitis. J Hepatol. 2021;doi: 10.1016/j.jhep.2021.11.031.
Wang, X., Zeldin, S., Shi, H., Zhu, C., Saito, Y., Corey, K. E., Osganian, S. A., Remotti, H. E., Verna, E. C., Pajvani, U. B., Schwabe, R. F., & Tabas, I. (2021). TAZ-induced Cybb contributes to liver tumor formation in non-alcoholic steatohepatitis. Journal of hepatology, . https://doi.org/10.1016/j.jhep.2021.11.031
Wang, Xiaobo, et al. "TAZ-induced Cybb contributes to liver tumor formation in non-alcoholic steatohepatitis." Journal of hepatology vol. (2021). doi: https://doi.org/10.1016/j.jhep.2021.11.031
Wang X, Zeldin S, Shi H, Zhu C, Saito Y, Corey KE, Osganian SA, Remotti HE, Verna EC, Pajvani UB, Schwabe RF, Tabas I. TAZ-induced Cybb contributes to liver tumor formation in non-alcoholic steatohepatitis. J Hepatol. 2021 Dec 10; doi: 10.1016/j.jhep.2021.11.031. Epub 2021 Dec 10. PMID: 34902531.
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J Hepatol. 2021 Dec 10; doi: 10.1016/j.jhep.2021.11.031. Epub 2021 Dec 10.

TAZ-induced Cybb contributes to liver tumor formation in non-alcoholic steatohepatitis.

Journal of hepatology

Xiaobo Wang, Sharon Zeldin, Hongxue Shi, Changyu Zhu, Yoshinobu Saito, Kathleen E Corey, Stephanie A Osganian, Helen E Remotti, Elizabeth C Verna, Utpal B Pajvani, Robert F Schwabe, Ira Tabas

Affiliations

  1. Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: [email protected].
  2. Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
  3. Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA.
  4. Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
  5. Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
  6. Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY 10032, USA.
  7. Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: [email protected].

PMID: 34902531 DOI: 10.1016/j.jhep.2021.11.031

Abstract

BACKGROUND AND AIMS: A leading cause of hepatocellular carcinoma (HCC) is non-alcoholic steatohepatitis (NASH), but mechanisms linking NASH to eventual tumor formation remain poorly understood. Here we investigate the role of TAZ/WWTR1, which is induced in hepatocytes in NASH, in the progression of NASH to HCC.

METHODS: The roles of hepatocyte TAZ and its downstream targets were investigated in diet-induced and genetic models of NASH-HCC using gene-targeting, AAV8-H1-mediated gene silencing, or AAV8-TBG-mediated gene expression. The biochemical signature of the newly elucidated pathway was probed in liver specimens from humans with NASH-HCC.

RESULTS: When hepatocyte-TAZ was silenced in pre-tumor NASH mice using AAV8-H1-shTaz, subsequent HCC tumor development was suppressed. In this setting, this tumor-suppressing effect of shTaz was not dependent of TAZ silencing in the tumors themselves and could be dissociated from the NASH-suppressing effects of shTaz. The mechanism linking pre-tumor hepatocyte-TAZ to eventual tumor formation involved TAZ-mediated induction of the NOX2-encoding gene Cybb, which led to NADPH-mediated oxidative DNA damage. As evidence, DNA damage and tumor formation could be suppressed by treatment of pre-tumor NASH mice with AAV8-H1-shCybb; AAV8-TBG-OGG1, encoding the oxidative DNA-repair enzyme 8-oxoguanine glycosylase; or AAV8-TBG-NHEJ1, encoding the dsDNA repair enzyme non-homologous end-joining factor 1. In tumor-surrounding tissue in human NASH-HCC liver, there were strong correlations among TAZ, NOX2, oxidative DNA damage.

CONCLUSIONS: TAZ in pre-tumor NASH-hepatocytes, via induction of Cybb and NOX2-mediated DNA damage, contributes to subsequent HCC tumor development. These findings illustrate how NASH provides a unique window into the early molecular events that can lead to tumor formation and suggest that NASH therapies targeting TAZ might also prevent NASH-HCC.

LAY SUMMARY: Nonalcoholic steatohepatitis (NASH) is emerging as the leading cause of a type of liver cancer called hepatocellular carcinoma (HCC), but molecular events in pre-tumor NASH hepatocytes leading to HCC remain largely unknown. Our study shows that a protein called TAZ in pre-tumor NASH-hepatocytes promotes damage to the DNA of hepatocytes and thereby contributes to eventual HCC. This study reveals a very early event in HCC that is induced in pre-tumor NASH, and the findings suggest that NASH therapies targeting TAZ might also prevent NASH-HCC.

Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Keywords: NOX2/Cybb; TAZ/WWTR1; hepatocellular carcinoma (HCC); nonalcoholic steatohepatitis (NASH); oxidative DNA damage

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