Growth differentiation factor 15 is induced by hepatitis C virus infection and regulates hepatocellular carcinoma-related genes.
Growth differentiation factor 15 is induced by hepatitis C virus infection and regulates hepatocellular carcinoma-related genes.
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丙型肝炎病毒感染诱导生长分化因子15并调节肝细胞癌相关基因
DOI：
10.1371/journal.pone.0019967
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Yang W
中科院分区：
文献类型：
--
作者：
Si Y;Liu X;Cheng M;Wang M;Gong Q;Yang Y;Wang T;Yang W
慢性丙型肝炎病毒感染可导致肝纤维化、肝硬变和肝细胞癌。我们的目的是鉴定和表征先前筛选的细胞因子GDF15在丙型肝炎病毒发病机制中的作用。我们在体外和体内检测了丙型肝炎病毒感染后GDF15的表达。用培养的JFH-1丙型肝炎病毒检测GDF15对病毒增殖的影响。应用GDF15过表达和RNA干扰技术分析GDF15调控的基因、信号通路和细胞生物学表型。在丙型肝炎病毒感染的肝癌细胞中，GDF15的mRNA表达和蛋白分泌显著增加，这可能是宿主对病毒蛋白或感染诱导的细胞应激的反应。感染丙型肝炎病毒的患者的血液GDF15水平平均是健康志愿者的15倍。丙型肝炎病毒队列中的三名肝癌患者显示出极高的GDF15浓度。转染组或外源性GDF15组可促进丙型肝炎病毒的增殖，而内源性GDF15组可抑制病毒复制。过表达的GDF15导致Akt的激活和Akt下游靶向GSK-3、β和Raf的磷酸化。肝癌相关分子如E-钙粘蛋白、β-连环蛋白、细胞周期蛋白A2/B1/D1在体外均有上调。GDF15在肝癌细胞中的过表达导致DNA合成增加，促进细胞增殖，显著增强细胞的侵袭性。这些结果提示，血清GDF15水平升高可能是病毒性肝炎的潜在诊断指标，GDF15可能通过改变宿主细胞的信号和生长而参与丙型肝炎的发病。
Liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) are commonly induced by chronic hepatitis C virus (HCV) infection. We aimed to identify and characterize the involvement of previously screened cytokine GDF15 in HCV pathogenesis. We examined the GDF15 expression after HCV infection both in vitro and in vivo. Cultured JFH-1 HCV was used to determine the GDF15 function on virus propagation. GDF15 overexpression and RNA interference were employed to profile the GDF15-regulated genes, signaling pathways and cell biology phenotypes. The mRNA expression and protein secretion of GDF15 was dramatically increased in HCV-infected hepatoma cells, which maybe a host response to viral proteins or infection-induced cell stress. Patients infected with HCV had an average 15-fold higher blood GDF15 level than that of healthy volunteers. Three HCC individuals in the HCV cohort showed extremely high GDF15 concentrations. Transfection or exogenously supplied GDF15 enhanced HCV propagation, whereas knockdown of endogenous GDF15 resulted in inhibition of virus replication. Overexpressed GDF15 led to Akt activation and the phosphorylation of Akt downstream targeted GSK-3β and Raf. Several HCC-related molecules, such as E-cadherin, β-catenin, Cyclin A2/B1/D1, were up-regulated by GDF15 stimulation in vitro. Overexpression of GDF15 in hepatoma cells resulted in increased DNA synthesis, promoted cell proliferation, and importantly enhanced invasiveness of the cells. In conclusion, these results suggest that an elevated serum GDF15 level is a potential diagnostic marker for viral hepatitis, and GDF15 may contribute to HCV pathogenesis by altering the signaling and growth of host cells.
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影响因子：
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