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Correspondence: aumemura@koto.kpu-m.ac.jp, Tel.: +81-75-251-5519; Fax: +81-75-251-0710

Author contributions: Conceptualization, K.O., A.U., S.K., H.T., Y.K., J.L.A., T.S., T.O., M.K., and Y.I.; Data curation, K.O., A.U., S.U., and M.K.; Formal analysis, K.O. and A.U.; Funding acquisition, A.U., T.O., and Y.I.; Project administration, A.U.;

Resources, Y.K., J.L.A., T.S., and T.O.; Supervision, S.U., Y.S., T.N., K.Y., M.M., J.L.A., T.O., M.K., and Y.I.; Writing–original draft, K.O. and A.U.; Writing–review and editing, M.K. and Y.I. All authors have read and agreed to the published version of the manuscript.

Acknowledgements: We thank Yamamoto, Tochiki, Goi, Iizumi, Sakai (KPUM), Mitsumoto, Matsuyama, and other staffs (Saiseikai Suita Hospital), Nakagawa (The University of Tokyo), Yamachika, Ito, and all the collaborators for their kind help and support.

Disclosures: A.U. received commercial research funding from Bristol–Myers Squibb Company, AbbVie Inc, and Merck Sharp and Dohme Corp. M.M. received lecture fees from Bayer AG and Eisai Co., Ltd.

Y.I. received lecture fees from Bristol-Myers Squibb Company and Merck Sharp and Dohme, as well as commercial research funding from Bayer AG, Eisai Co., Ltd., Bristol–Myers Squibb Company, and Merck Sharp and Dohme. All other authors declare no competing interest.

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Research Funding:

We thank Yamamoto, Tochiki, Goi, Iizumi, Sakai (KPUM), Mitsumoto, Matsuyama, and other staffs (Saiseikai Suita Hospital), Nakagawa (The University of Tokyo), Yamachika, Ito, and all the collaborators for their kind help and support.

This research was supported by research grants from JSPS KAKENHI #19K08377 (A.U.), AMED #JP19fk0210059 (A.U.), #JP18fk0210027 (K.Y. and Y.I.), #JP19fk0210040 (T.O.),

#JP18fk0210040 (Y.I.), The Ministry of Education, Culture, Sports, Science and Technology (MEXT) Grant-in-Aid for Scientific Research (S) #16H06389 (T.O.), the National Cancer Institute (NCI) #CA211794 (M.K.),

Superfund Basic Research Program #P42ES010337(M.K.), Bristol-Myers Squibb (A.U.), AbbVie Inc (A.U.), and Bayer (Y.I.);

M.K. is an American Cancer Society Research Professor and the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • liver cancer
  • glucocorticoid receptor
  • MIG-6
  • ERRFI1
  • epidermal growth factor receptor (EGFR)
  • honokiol
  • Growth-factor receptor
  • Fatty liver
  • Hepatocellular carcinoma
  • Negative regulation
  • Expression
  • Tumorigenesis
  • Inflammation
  • Inhibition
  • Erlotinib
  • Disease

Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor-MIG6 Axis

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Journal Title:

Cancers

Volume:

Volume 13, Number 7

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Type of Work:

Article | Final Publisher PDF

Abstract:

Non-alcoholic steatohepatitis (NASH) has become a serious public health problem associated with metabolic syndrome. The mechanisms by which NASH induces hepatocellular carcinoma (HCC) remain unknown. There are no approved drugs for treating NASH or preventing NASH-induced HCC. We used a genetic mouse model in which HCC was induced via high-fat diet feeding. This mouse model strongly resembles human NASH-induced HCC. The natural product honokiol (HNK) was tested for its preventative effects against NASH progression to HCC. Then, to clarify the mechanisms underlying HCC development, human HCC cells were treated with HNK. Human clinical specimens were also analyzed to explore this study’s clinical relevance. We found that epidermal growth factor receptor (EGFR) signaling was hyperactivated in the livers of mice with NASH and human HCC specimens. Inhibition of EGFR signaling by HNK drastically attenuated HCC development in the mouse model. Mechanistically, HNK accelerated the nuclear translocation of glu-cocorticoid receptor (GR) and promoted mitogen-inducible gene 6 (MIG6)/ERBB receptor feedback inhibitor 1 (ERRFI1) expression, leading to EGFR degradation and thereby resulting in robust tumor suppression. In human samples, EGFR-positive HCC tissues and their corresponding non-tumor tissues exhibited decreased ERRFI1 mRNA expression. Additionally, GR-positive non-tumor liver tissues displayed lower EGFR expression. Livers from patients with advanced NASH exhibited decreased ERRFI1 expression. EGFR degradation or inactivation represents a novel approach for NASH–HCC treatment and prevention, and the GR–MIG6 axis is a newly defined target that can be activated by HNK and related compounds.

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© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/rdf).
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