Article Publish Status: FREE
Abstract Title:

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

Abstract Source:

Cancers (Basel). 2021 Mar 25 ;13(7). Epub 2021 Mar 25. PMID: 33806040

Abstract Author(s):

Keiichiro Okuda, Atsushi Umemura, Shiori Umemura, Seita Kataoka, Hiroyoshi Taketani, Yuya Seko, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Yoshihiro Kanbara, Jack L Arbiser, Toshihide Shima, Takeshi Okanoue, Michael Karin, Yoshito Itoh

Article Affiliation:

Keiichiro Okuda


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 glucocorticoid 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 decreasedmRNA expression. Additionally, GR-positive non-tumor liver tissues displayed lower EGFR expression. Livers from patients with advanced NASH exhibited decreasedexpression. 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.

Study Type : Animal Study

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