Activation of IL6/IGFIR Confers Poor Prognosis of HBV-Related Hepatocellular Carcinoma through Induction of OCT4/NANOG Expression
Activation of IL6/IGFIR Confers Poor Prognosis of HBV-Related Hepatocellular Carcinoma through Induction of OCT4/NANOG Expression
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DOI：
10.1158/1078-0432.ccr-13-3274
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发表时间：
2015-01-01
影响因子：
11.5
通讯作者：
Huang, Yen-Hua
中科院分区：
文献类型：
--
作者：
Chang, Te-Sheng;Wu, Yu-Chih;Huang, Yen-Hua
目的：揭示白细胞介素 (IL)-6 和胰岛素样生长因子 (IGF)-I 受体 (IGFIR) 在表达干性相关特性中的作用，并评估多能转录因子 OCT4/NANOG 和 IGFIR 在肝细胞癌 (HCC) 中的预后价值。 实验设计：使用 ELISA 检测 (n = 120) 检测血清 IL6 水平。使用 OCT4/NANOG 启动子荧光素酶报告基因、RNA 干扰、次级球体形成、侧群和异种移植动物模型检查 IL6/IGFI 对 HCC 干性表达的影响。采用Western blotting（n=8）和免疫组化染色（n=85）检测组织中OCT4/NANOG蛋白和磷酸IGFI受体（p-IGFIR）。通过实时 qRT-PCR 分析组织 (n=191) 中的 OCT4、NANOG 和 IGFIR 表达水平，并使用 Kaplan-Meier 生存分析与早期肿瘤复发相关。结果：在人类 HCC 组织中观察到 OCT4/NANOG 和 IGFIR/p-IGFIR 的表达水平之间存在高度正相关。 OCT4/NANOG/IGFIR的同时表达主要局限于乙型肝炎病毒（HBV）相关的肝癌（HBV-HCC），并且与早期肿瘤复发显着相关。高血清水平的 IL6 与高 OCT4/NANOG 表达显着相关。 IL6 依赖于 STAT3 刺激自分泌 IGFI/IGFIR 表达，从而刺激细胞系和异种移植小鼠肿瘤中的干性相关特性。通过 RNA 干扰或用抑制剂鬼臼苦素 (PPP) 治疗来抑制 IGFIR 激活，在体外和体内均显着抑制了 IL6 诱导的干性相关特性。结论：多能性相关基因的表达与早期肿瘤复发相关，并受到 IL6 诱导的 IGF/IGFIR 激活的调节，特别是在 HBV-HCC 中。 (C) 2014 年 AACR。
Purpose: To unravel the role of interleukin (IL)-6 and insulinlike growth factor (IGF)-I receptor (IGFIR) in expressing stemness-related properties and to evaluate the prognostic values of pluripotent transcription factor OCT4/NANOG, and IGFIR in hepatocellular carcinoma (HCC).Experimental Design: Serum levels of IL6 were detected using ELISA assays (n = 120). The effects of IL6/IGFI on stemness expression in HCC were examined using OCT4/NANOG promoter luciferase reporter, RNA interference, secondary sphere formation, side population, and xenograft animal models. The OCT4/NANOG protein and phospho-IGFI receptor (p-IGFIR) in tissues were detected by Western blotting (n=8) and immunohistochemical staining (n=85). OCT4, NANOG, and IGFIR expression levels in tissues (n=191) were analyzed by real-time qRT-PCR and was correlated with early tumor recurrence using the Kaplan-Meier survival analysis.Results: A high positive correlation between the expression levels of OCT4/NANOG and IGFIR/p-IGFIR in human HCC tissues was observed. The concurrent expression of OCT4/NANOG/IGFIR was mostly confined to hepatitis B virus (HBV)-related HCC (HBV-HCC) and was significantly correlated with early tumor recurrence. High serum levels of IL6 were significantly correlated with high OCT4/NANOG expression. IL6 stimulated an autocrine IGFI/IGFIR expression STAT3 dependently, which stimulated stemness-related properties in both the cell lines and the xenografted mouse tumors. The inhibition of IGFIR activation by either RNA interference or by treatment with the inhibitor picropodophyllin (PPP) significantly suppressed the IL6-induced stemness-related properties both in vitro and in vivo.Conclusions: The expression of pluripotency-related genes is associated with early tumor recurrence and is regulated by IL6-induced IGF/IGFIR activation, particularly in HBV-HCC. (C) 2014 AACR.