Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor—MIG6 Axis
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 mous...
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MDPI AG
2021-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/7/1515 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Keiichiro Okuda |
| collection | DOAJ |
| description | 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 decreased <i>ERRFI1</i> mRNA expression. Additionally, GR-positive non-tumor liver tissues displayed lower EGFR expression. Livers from patients with advanced NASH exhibited decreased <i>ERRFI1</i> 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. |
| first_indexed | 2024-03-10T12:55:15Z |
| format | Article |
| id | doaj.art-874412f360624bfabc9ce804bbddba94 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T12:55:15Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-874412f360624bfabc9ce804bbddba942023-11-21T11:59:56ZengMDPI AGCancers2072-66942021-03-01137151510.3390/cancers13071515Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor—MIG6 AxisKeiichiro Okuda0Atsushi Umemura1Shiori Umemura2Seita Kataoka3Hiroyoshi Taketani4Yuya Seko5Taichiro Nishikawa6Kanji Yamaguchi7Michihisa Moriguchi8Yoshihiro Kanbara9Jack L. Arbiser10Toshihide Shima11Takeshi Okanoue12Michael Karin13Yoshito Itoh14Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita 564-0013, JapanDepartment of Dermatology, Emory University School of Medicine, Atlanta, GA 30322, USADepartment of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita 564-0013, JapanDepartment of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Suita 564-0013, JapanLaboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, San Diego, CA 92093, USADepartment of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, JapanNon-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 decreased <i>ERRFI1</i> mRNA expression. Additionally, GR-positive non-tumor liver tissues displayed lower EGFR expression. Livers from patients with advanced NASH exhibited decreased <i>ERRFI1</i> 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.https://www.mdpi.com/2072-6694/13/7/1515liver cancerglucocorticoid receptorMIG-6/ERRFI1epidermal growth factor receptor (EGFR)honokiol |
| spellingShingle | 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 Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor—MIG6 Axis Cancers liver cancer glucocorticoid receptor MIG-6/ERRFI1 epidermal growth factor receptor (EGFR) honokiol |
| title | Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor—MIG6 Axis |
| title_full | Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor—MIG6 Axis |
| title_fullStr | Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor—MIG6 Axis |
| title_full_unstemmed | Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor—MIG6 Axis |
| title_short | Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor—MIG6 Axis |
| title_sort | honokiol prevents non alcoholic steatohepatitis induced liver cancer via egfr degradation through the glucocorticoid receptor mig6 axis |
| topic | liver cancer glucocorticoid receptor MIG-6/ERRFI1 epidermal growth factor receptor (EGFR) honokiol |
| url | https://www.mdpi.com/2072-6694/13/7/1515 |
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