Hepatitis B virus X protein induces hepatic stem cell-like features in hepatocellular carcinoma by activating KDM5B.
Hepatitis B virus X protein induces hepatic stem cell-like features in hepatocellular carcinoma by activating KDM5B.
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DOI：
10.3748/wjg.v23.i18.3252
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发表时间：
2017-05-14
影响因子：
4.3
通讯作者：
Kaneko S
中科院分区：
文献类型：
--
作者：
Wang X;Oishi N;Shimakami T;Yamashita T;Honda M;Murakami S;Kaneko S
探讨B型肝炎病毒X蛋白（HBx）在肝细胞癌（HCC）中对肝祖细胞（HPC）样特征的调控作用及其分子机制。我们使用逆转录病毒载体将野生型HBx或空载体引入HepG 2细胞中。然后，我们使用这些细胞来分析细胞增殖，衰老，转化和干细胞样特征。根据制造商的方案，在Affyssin GeneChip Human U133A2.0 ver.2阵列上进行基因表达谱分析。通过BRB-Array Tools软件版本4.2.2进行无监督分层聚类分析和类别比较分析。对238例乙型肝炎病毒（B virus，HBV）相关肝癌患者的基因芯片资料进行临床分析。组蛋白去甲基化酶KDM 5 B在HBV相关性肝癌中的表达明显增高（P < 0.01）。在HBV蛋白中，只有HBx通过激活c-myc上调KDM 5 B。肝干细胞（HpSC）标志物（EpCAM、AFP、PROM 1和NANOG）在KDM 5 B高的HCC病例中显著高表达（P < 0.01）。KDM 5 B在维持HpSC样特征中起重要作用，并与预后不良相关。此外，抑制KDM 5 B抑制球体形成和细胞侵袭在体外。HBx激活组蛋白去甲基化酶KDM 5 B并诱导HCC中的HPC样特征。组蛋白去甲基化酶KDM 5 B可能是治疗HBV相关HCC的重要靶点。
To determine the role of hepatitis B virus X protein (HBx), HBx in regulating hepatic progenitor cell (HPC)-like features in hepatocellular carcinoma (HCC) and the underlying molecular mechanisms. We used a retrovirus vector to introduce wild type HBx or empty vector into HepG2 cells. We then used these cells to analyze cell proliferation, senescence, transformation, and stem-like features. Gene expression profiling was carried out on Affymetrix GeneChip Human U133A2.0 ver.2 arrays according to the manufacturer’s protocol. Unsupervised hierarchical clustering analysis and Class Comparison analysis were performed by BRB-Array Tools software Version 4.2.2. A total of 238 hepatitis B virus (HBV)-related HCC patients’ array data were used for analyzing clinical features. The histone demethylase KDM5B was significantly highly expressed in HBV-related HCC cases (P < 0.01). In HBV proteins, only HBx up-regulated KDM5B by activating c-myc. Hepatic stem cell (HpSC) markers (EpCAM, AFP, PROM1, and NANOG) were significantly highly expressed in KDM5B-high HCC cases (P < 0.01). KDM5B played an important role in maintaining HpSC-like features and was associated with a poor prognosis. Moreover, inhibition of KDM5B suppressed spheroid formation and cell invasion in vitro. HBx activates the histone demethylase KDM5B and induces HPC-like features in HCC. Histone demethylases KDM5B may be an important therapeutic target against HBV-related HCC cases.