Laboratory of Virology and Experimental Chemotherapy, Rega Institute for Medical Research, University of Leuven (KU Leuven), Belgium.
Division Animal and Human Health Engineering, Department of Biosystems (BIOSYST), University of Leuven (KU Leuven), Belgium.
Biochem Pharmacol. 2018 Sep;155:305-315. doi: 10.1016/j.bcp.2018.07.011. Epub 2018 Jul 21.
HCV is a major risk factor for hepatocellular carcinoma (HCC). HCC development in chronically infected HCV patients has until now been attributed to persistent inflammation and interference of viral proteins with host cell signaling. Since activation of the epidermal growth factor receptor (EGFR) presents a crucial step in HCV entry, we aimed at investigating whether EGFR signaling may contribute to the pathogenesis of HCV-related HCC. By applying microarray analysis, we generated a gene expression signature for secreted proteins in HCV-infected hepatoma cells. This gene signature was enriched for inflammatory and angiogenic processes; both crucially involved in HCC development. RT-qPCR analysis, conducted on the entire list of upregulated genes, confirmed induction of 11 genes (AREG, IL8, CCL20, CSF1, GDF15, IGFBP1, VNN3, THBS1 and PAI-1) in a virus titer- and replication-dependent manner. EGFR activation in hepatoma cells largely mimicked the gene signature seen in the infectious HCV model. Further, the EGFR-ERK pathway, but not Akt signaling, was responsible for this gene expression profile. Finally, microarray analysis conducted on clinical data from the GEO database, revealed that our validated gene expression profile is significantly represented in livers of patients with HCV-related liver pathogenesis (cirrhosis and HCC) compared to healthy livers. Taken together, our data indicate that persistent activation of EGFR-ERK signaling in chronically infected HCV patients may induce a specific pro-inflammatory and pro-angiogenic signature that presents a new mechanism by which HCV can promote liver cancer pathogenesis. A better understanding of the key factors in HCV-related oncogenesis, may efficiently direct HCC drug development.
丙型肝炎病毒 (HCV) 是肝细胞癌 (HCC) 的主要危险因素。慢性 HCV 感染患者的 HCC 发展迄今为止归因于持续的炎症和病毒蛋白对宿主细胞信号的干扰。由于表皮生长因子受体 (EGFR) 的激活是 HCV 进入的关键步骤，我们旨在研究 EGFR 信号是否可能有助于 HCV 相关 HCC 的发病机制。通过应用微阵列分析，我们生成了 HCV 感染肝癌细胞中分泌蛋白的基因表达谱。该基因特征富含炎症和血管生成过程；这两者都与 HCC 的发展密切相关。对整个上调基因列表进行的 RT-qPCR 分析证实了 11 个基因 (AREG、IL8、CCL20、CSF1、GDF15、IGFBP1、VNN3、THBS1 和 PAI-1) 在病毒滴度和复制依赖性方式下的诱导。肝癌细胞中的 EGFR 激活在很大程度上模拟了传染性 HCV 模型中观察到的基因特征。此外，EGFR-ERK 途径而不是 Akt 信号负责该基因表达谱。最后，对 GEO 数据库中临床数据进行的微阵列分析表明，与健康肝脏相比，我们验证的基因表达谱在 HCV 相关肝发病机制（肝硬化和 HCC）患者的肝脏中显著存在。总之，我们的数据表明，慢性 HCV 感染患者中持续激活的 EGFR-ERK 信号可能诱导一种特定的促炎和促血管生成特征，这代表了 HCV 促进肝癌发病机制的新机制。更好地了解 HCV 相关致癌作用中的关键因素，可能有效地指导 HCC 药物开发。
