Department of Gastroenterology and Hepatology, University Hospital, Essen, Germany.
PLoS One. 2012;7(9):e44474. doi: 10.1371/journal.pone.0044474. Epub 2012 Sep 11.
Overwhelming lines of epidemiological evidence have indicated that persistent infection with hepatitis C virus (HCV) is a major risk for the development of hepatocellular carcinoma (HCC). We have recently shown that HCV core protein mediates functional inactivation of the promyelocytic leukemia (PML) tumor suppressor pathway. However, the role of PML in HCC development yet remains unclear. To clarify the function of PML in liver carcinogenesis and HCV-associated pathogenesis we crossed PML-deficient mice with HCV transgene (HCV-Tg) expressing mice and treated the resulting animals with DEN/Phenobarbital, an established protocol for liver carcinogenesis. Seven months after treatment, livers were examined macroscopically and histologically. Genetic depletion of the tumor suppressor PML coincided with an increase in hepatocyte proliferation, resulting in development of multiple dysplastic nodules in 100% of the PML-deficient livers and of HCCs in 53%, establishing a tumor suppressive function of PML in the liver. In animals expressing the HCV-transgene in PML-deficient background, HCC development occurred even in 73%, while only 7% of their wildtype littermates developed HCC. The neoplastic nature of the tumors was confirmed by histology and expression of the HCC marker glutamine synthetase. Several pro- and antiapoptotic factors were tested for differential expression and liver carcinogenesis was associated with impaired expression of the proapoptotic molecule TRAIL in PML-deficient mice. In conclusion, this study provides first in vivo evidence that the tumor suppressor PML acts as an important barrier in liver carcinogenesis and HCV-dependent liver pathology.
大量的流行病学证据表明，丙型肝炎病毒（HCV）的持续感染是肝细胞癌（HCC）发展的主要风险因素。我们最近表明，HCV 核心蛋白介导早幼粒细胞白血病（PML）肿瘤抑制途径的功能失活。然而，PML 在 HCC 发展中的作用尚不清楚。为了阐明 PML 在肝癌发生和 HCV 相关发病机制中的作用，我们将 PML 缺陷型小鼠与表达 HCV 转基因（HCV-Tg）的小鼠进行了杂交，并使用 DEN/Phenobarbital 对这些动物进行了处理，这是一种用于肝癌发生的既定方案。治疗 7 个月后，对肝脏进行了宏观和组织学检查。肿瘤抑制基因 PML 的遗传缺失与肝细胞增殖增加相一致，导致 PML 缺陷型肝脏中 100%出现多个异型增生结节，并发展为 53%的 HCC，从而确立了 PML 在肝脏中的肿瘤抑制功能。在 PML 缺陷型背景下表达 HCV 转基因的动物中，即使在 73%的动物中也发生了 HCC 发展，而其野生型同窝仔中只有 7%发生 HCC。肿瘤的性质通过组织学和 HCC 标志物谷氨酰胺合成酶的表达得到证实。对几种促凋亡和抗凋亡因子进行了差异表达测试，并且在 PML 缺陷型小鼠中，肝致癌作用与促凋亡分子 TRAIL 的表达受损相关。总之，这项研究提供了体内证据，表明肿瘤抑制基因 PML 作为肝脏致癌作用和 HCV 依赖性肝脏病理学的重要屏障。
