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Abstract：
Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). Although HCV clearance has been improved by the advent of direct-acting antiviral agents (DAA), retrospective studies have shown that the risk of subsequent HCC, while considerably decreased compared with active HCV infection, persists after DAA regimens. However, either the mechanisms of how chronic HCV infection causes HCC or the factors responsible for HCC development after viral eradication in patients with DAA treatments remain elusive. We reported an in vitro model of chronic HCV infection and determined Wnt/β-catenin signaling activation due to the inhibition of GSK-3β activity via serine 9 phosphorylation (p-ser9-GSK-3β) leading to stable non-phosphorylated β-catenin. Immunohistochemical staining demonstrated the upregulation of both β-catenin and p-Ser9-GSK-3β in HCV-induced HCC tissues. Chronic HCV infection increased proliferation and colony-forming ability, but knockdown of β-catenin decreased proliferation and increased apoptosis. Unexpectedly, Wnt/β-catenin signaling remained activated in chronic HCV-infected cells after HCV eradication by DAA, but metformin reversed it through PKA/GSK-3β-mediated β-catenin degradation, inhibited colony-forming ability and proliferation, and increased apoptosis, suggesting that DAA therapy in combination with metformin may be a novel therapy to treat HCV-associated HCC where metformin suppresses Wnt/β-catenin signaling for HCV-infected patients.
摘要：
慢性丙型肝炎病毒（HCV）感染导致肝细胞癌（HCC）。尽管直接作用抗病毒剂（DAA）的出现改善了HCV的清除，回顾性研究表明，后续HCC的风险，虽然与活动性HCV感染相比显着下降，在DAA方案后仍然存在。然而,在DAA治疗的患者中，慢性HCV感染如何导致HCC的机制或导致HCC发展的因素仍然难以捉摸。我们报道了慢性HCV感染的体外模型，并确定了Wnt/β-catenin信号激活，这是由于通过丝氨酸9磷酸化（p-ser9-GSK-3β）抑制GSK-3β活性导致稳定的非磷酸化β-catenin。免疫组织化学染色显示HCV诱导的HCC组织中β-catenin和p-Ser9-GSK-3β的上调。慢性HCV感染增加增殖和集落形成能力，但是β-catenin的敲除减少增殖和增加凋亡。出乎意料的是,通过DAA根除HCV后，Wnt/β-catenin信号在慢性HCV感染细胞中保持激活，但二甲双胍通过PKA/GSK-3β介导的β-连环蛋白降解逆转，抑制集落形成能力和增殖，和增加细胞凋亡，提示DAA联合二甲双胍治疗可能是治疗HCV感染患者的HCV相关HCC的新疗法，其中二甲双胍抑制Wnt/β-catenin信号传导。
