Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor-MIG6 Axis.
Honokiol Prevents Non-Alcoholic Steatohepatitis-Induced Liver Cancer via EGFR Degradation through the Glucocorticoid Receptor-MIG6 Axis.
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DOI：
10.3390/cancers13071515
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发表时间：
2021-03-25
期刊：
影响因子：
5.2
通讯作者：
Itoh Y
中科院分区：
文献类型：
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作者：
Okuda K;Umemura A;Umemura S;Kataoka S;Taketani H;Seko Y;Nishikawa T;Yamaguchi K;Moriguchi M;Kanbara Y;Arbiser JL;Shima T;Okanoue T;Karin M;Itoh Y
非酒精性脂肪性肝病(NAFLD)是全球范围内的一个主要健康问题，与代谢综合征的日益流行有关。NAFLD患者的一部分进展为非酒精性脂肪性肝炎(NASH)，这增加了肝细胞癌(HCC)的风险。然而，导致肝细胞癌进展的机制尚不清楚，也没有开发出预防方法。为了解决这一问题，本研究使用天然化合物和厚朴酚来阐明这一过程的机制。结果表明，NASH小鼠表皮生长因子受体(EGFR)表达上调，和厚朴酚治疗可抑制EGFR和肝细胞癌的进展。进一步分析表明和厚朴酚增加了糖皮质激素受体(GR)核转位和丝裂原诱导基因6(MIG6)/ERBB受体反馈抑制物1(ERRFI1)的表达，从而促进了EGFR的降解。这些发现在NASH和肝癌患者的组织中得到了证实。非酒精性脂肪性肝炎(NASH)已成为与代谢综合征相关的严重公共卫生问题。NASH诱导肝细胞癌的机制尚不清楚。目前还没有被批准的治疗NASH或预防NASH诱导的肝细胞癌的药物。我们使用了一种遗传小鼠模型，在该模型中，肝细胞癌是通过高脂饮食诱导的。这种小鼠模型非常类似于人类NASH诱导的肝细胞癌。测试了天然产物和厚朴酚(HNK)对Nash进展为肝细胞癌的预防作用。然后，为了阐明肝癌发生的机制，我们用HNK处理人肝癌细胞。我们还对人类临床标本进行了分析，以探讨该研究的临床相关性。我们发现，表皮生长因子受体(EGFR)信号在NASH和人肝细胞癌小鼠的肝脏中被过度激活。HNK抑制EGFR信号可显著抑制小鼠模型中肝细胞癌的发展。在机制上，HNK加速糖皮质激素受体(GR)的核转位，促进丝裂原诱导基因6(MIG6)/ERBB受体反馈抑制物1(ERRFI1)的表达，导致EGFR降解，从而产生强大的肿瘤抑制作用。在人类样本中，EGFR阳性的肝癌组织及其相应的非肿瘤组织中ERRFI1mRNA的表达降低。此外，GR阳性的非肿瘤肝组织中EGFR表达较低。晚期NASH患者的肝脏中ERRFI1表达降低。EGFR的降解或失活为NASH-HCC的治疗和预防提供了新的途径，而GR-MIG6轴是一个新定义的靶点，可以被HNK及其相关化合物激活。
Non-alcoholic fatty liver disease (NAFLD) is a major health problem globally linked with the growing prevalence of metabolic syndrome. A subset of patients with NAFLD progress to non-alcoholic steatohepatitis (NASH), which increases the risk of hepatocellular carcinoma (HCC). However, the mechanisms responsible for the progression to HCC are unclear, and no preventative modalities have been developed. To address this issue, the present study used the natural compound honokiol to clarify the mechanism of this process. The results illustrated that epidermal growth factor receptor (EGFR) was upregulated in mice with NASH, and treatment with honokiol inhibited EGFR and the progression to HCC. Further analysis illustrated that honokiol increased glucocorticoid receptor (GR) nuclear translocation and mitogen-inducible gene 6 (MIG6)/ERBB receptor feedback inhibitor 1 (ERRFI1) expression, thereby promoting EGFR degradation. These findings were confirmed in tissues from patients with NASH and HCC. 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 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.