Klopstock Naama, Katzenellenbogen Mark, Pappo Orit, Sklair-Levy Miriam, Olam Devorah, Mizrahi Lina, Potikha Tamara, Galun Eithan, Goldenberg Daniel
Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
PLoS One. 2009;4(4):e5025. doi: 10.1371/journal.pone.0005025. Epub 2009 Apr 2.
The hepatitis C virus (HCV) is one of the major risk factors for the development of hepatocellular carcinoma (HCC). Nevertheless, transgenic mice which express the whole HCV polyprotein (HCV-Tg) do not develop HCC. Whereas chronic HCV infection causes inflammation in patients, in HCV-Tg mice, the host immune reaction against viral proteins is lacking. We aimed to test the role of HCV proteins in HCC development on the background of chronic inflammation in vivo.
METHODOLOGY/PRINCIPAL FINDINGS: We crossed HCV-Tg mice that do not develop HCC with the Mdr2-knockout (Mdr2-KO) mice which develop inflammation-associated HCC, to generate Mdr2-KO/HCV-Tg mice. We studied the effect of the HCV transgene on tumor incidence, hepatocyte mitosis and apoptosis, and investigated the potential contributing factors for the generated phenotype by gene expression and protein analyses. The Mdr2-KO/HCV-Tg females from the N2 generation of this breeding (having 75% of the FVB/N genome and 25% of the C57BL/6 genome) produced significantly larger tumors in comparison with Mdr2-KO mice. In parallel, the Mdr2-KO/HCV-Tg females had an enhanced inflammatory gene expression signature. However, in the N7 generation (having 99.2% of the FVB/N genome and 0.8% of the C57BL/6 genome) there was no difference in tumor development between Mdr2-KO/HCV-Tg and Mdr2-KO animals of both sexes. The HCV transgene was similarly expressed in the livers of Mdr2-KO/HCV-Tg females of both generations, as revealed by detection of the HCV transcript and the core protein.
These findings suggest that the HCV transgene accelerated inflammation-associated hepatocarcinogenesis in a host genetic background-dependent manner.
丙型肝炎病毒（HCV）是肝细胞癌（HCC）发生的主要危险因素之一。然而，表达完整HCV多聚蛋白的转基因小鼠（HCV-Tg）并不会发生HCC。慢性HCV感染会导致患者出现炎症，而在HCV-Tg小鼠中，缺乏针对病毒蛋白的宿主免疫反应。我们旨在测试HCV蛋白在体内慢性炎症背景下对HCC发生发展的作用。
方法/主要发现：我们将不会发生HCC的HCV-Tg小鼠与会发生炎症相关HCC的多药耐药蛋白2基因敲除（Mdr2-KO）小鼠进行杂交，以产生Mdr2-KO/HCV-Tg小鼠。我们研究了HCV转基因对肿瘤发生率、肝细胞有丝分裂和凋亡的影响，并通过基因表达和蛋白质分析研究了产生该表型的潜在影响因素。该杂交N2代的Mdr2-KO/HCV-Tg雌性小鼠（具有75%的FVB/N基因组和25%的C57BL/6基因组）与Mdr2-KO小鼠相比，产生的肿瘤明显更大。同时，Mdr2-KO/HCV-Tg雌性小鼠具有增强的炎症基因表达特征。然而，在N7代（具有99.2%的FVB/N基因组和0.8%的C57BL/6基因组），Mdr2-KO/HCV-Tg和Mdr2-KO两性动物在肿瘤发生方面没有差异。通过检测HCV转录本和核心蛋白发现，两代Mdr2-KO/HCV-Tg雌性小鼠肝脏中HCV转基因的表达相似。
这些发现表明，HCV转基因以宿主遗传背景依赖的方式加速了炎症相关的肝癌发生。
