Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
PLoS Genet. 2013;9(12):e1003937. doi: 10.1371/journal.pgen.1003937. Epub 2013 Dec 19.
Viral hepatitis, obesity, and alcoholism all represent major risk factors for hepatocellular carcinoma (HCC). Although these conditions also lead to integrated stress response (ISR) or unfolded protein response (UPR) activation, the extent to which these stress pathways influence the pathogenesis of HCC has not been tested. Here we provide multiple lines of evidence demonstrating that the ISR-regulated transcription factor CHOP promotes liver cancer. We show that CHOP expression is up-regulated in liver tumors in human HCC and two mouse models thereof. Chop-null mice are resistant to chemical hepatocarcinogenesis, and these mice exhibit attenuation of both apoptosis and cellular proliferation. Chop-null mice are also resistant to fibrosis, which is a key risk factor for HCC. Global gene expression profiling suggests that deletion of CHOP reduces the levels of basal inflammatory signaling in the liver. Our results are consistent with a model whereby CHOP contributes to hepatic carcinogenesis by promoting inflammation, fibrosis, cell death, and compensatory proliferation. They implicate CHOP as a common contributing factor in the development of HCC in a variety of chronic liver diseases.
病毒性肝炎、肥胖症和酗酒均为肝细胞癌（HCC）的主要危险因素。尽管这些情况也会导致整合应激反应（ISR）或未折叠蛋白反应（UPR）激活，但这些应激途径对 HCC 发病机制的影响程度尚未得到检验。在这里，我们提供了多条证据表明，ISR 调节的转录因子 CHOP 促进肝癌的发生。我们发现，CHOP 的表达在人类 HCC 及其两种小鼠模型的肝肿瘤中上调。Chop 基因敲除小鼠对化学性肝癌发生具有抗性，并且这些小鼠的细胞凋亡和细胞增殖均减弱。Chop 基因敲除小鼠对纤维化也具有抗性，而纤维化是 HCC 的一个关键危险因素。全基因表达谱分析表明，CHOP 的缺失降低了肝脏中基础炎症信号的水平。我们的结果与以下模型一致，即 CHOP 通过促进炎症、纤维化、细胞死亡和代偿性增殖而促进肝发生癌变。该模型提示 CHOP 是多种慢性肝病中 HCC 发展的共同致病因素。
