Dual role for inositol-requiring enzyme 1 in promoting the development of hepatocellular carcinoma during diet-induced obesity in mice
Dual role for inositol-requiring enzyme 1 in promoting the development of hepatocellular carcinoma during diet-induced obesity in mice
复制标题
肌醇需求酶 1α 在饮食诱导的肥胖小鼠中促进肝细胞癌发展的双重作用。
DOI：
10.1002/hep.29871
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发表时间：
2018-08-01
期刊：
影响因子：
13.5
通讯作者：
Liu, Yong
中科院分区：
文献类型：
--
作者：
Wu, Ying;Shan, Bo;Liu, Yong
肥胖与内质网应激和慢性代谢性炎症有关。内质网应激激活未折叠蛋白反应（UPR），并与包括肝细胞癌（HCC）在内的多种癌症有关。然而，目前尚不清楚单个UPR通路是否与HCC的发展有机制联系。在这里，我们报道了肌醇需要酶1 (IRE1)， er定位的UPR信号传感器，在肥胖促进的HCC发展中的双重作用。我们发现肝细胞中IRE1的基因消融不仅可以显著减少肝脏特异性IRE1敲除（LKO）小鼠在正常饲料（NC）喂养时二乙基亚硝胺（DEN）诱导的HCC的发生，而且还可以防止高脂肪饲料（HFD）喂养时HCC的加速进展。无论其肥胖状态如何，LKO小鼠的肝细胞增殖和信号传导及转录激活因子3 （STAT3）激活均下降，即使肝细胞凋亡增加。此外，IRE1的废除减弱了肥胖相关的核因子κ B激酶亚单位β (IKK)-核因子κ B （NF-B）途径的肝脏抑制剂的激活，导致促肿瘤炎症细胞因子肿瘤坏死因子（TNF）和白细胞介素6 （IL-6）的产生减少。重要的是，在人类HCC患者的肿瘤组织中也观察到较高的IRE1表达和升高的STAT3磷酸化，这与他们较差的生存率相关。结论：IRE1在肥胖诱导的代谢性炎症中参与前馈循环，通过stat3介导的肝细胞增殖促进HCC的发展。(肝脏病学2018)。
Obesity is associated with both endoplasmic reticulum (ER) stress and chronic metabolic inflammation. ER stress activates the unfolded protein response (UPR) and has been implicated in a variety of cancers, including hepatocellular carcinoma (HCC). It is unclear whether individual UPR pathways are mechanistically linked to HCC development, however. Here we report a dual role for inositol-requiring enzyme 1 (IRE1), the ER-localized UPR signal transducer, in obesity-promoted HCC development. We found that genetic ablation of IRE1 in hepatocytes not only markedly reduced the occurrence of diethylnitrosamine (DEN)-induced HCC in liver-specific IRE1 knockout (LKO) mice when fed a normal chow (NC) diet, but also protected against the acceleration of HCC progression during high-fat diet (HFD) feeding. Irrespective of their adiposity states, LKO mice showed decreased hepatocyte proliferation and signal transducer and activator of transcription 3 (STAT3) activation, even in the face of increased hepatic apoptosis. Furthermore, IRE1 abrogation blunted obesity-associated activation of hepatic inhibitor of nuclear factor kappa B kinase subunit beta (IKK)-nuclear factor kappa B (NF-B) pathway, leading to reduced production of the tumor-promoting inflammatory cytokines tumor necrosis factor (TNF) and interleukin 6 (IL-6). Importantly, higher IRE1 expression along with elevated STAT3 phosphorylation was also observed in the tumor tissues from human HCC patients, correlating with their poorer survival rate. Conclusion: IRE1 acts in a feed-forward loop during obesity-induced metabolic inflammation to promote HCC development through STAT3-mediated hepatocyte proliferation. (Hepatology 2018).