Hypermethylation of GNA14 and its tumor-suppressive role in hepatitis B virus-related hepatocellular carcinoma.
Hypermethylation of GNA14 and its tumor-suppressive role in hepatitis B virus-related hepatocellular carcinoma.
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GNA14的高甲基化及其在乙型肝炎病毒相关肝细胞癌中的抑癌作用
作者：
Song G;Zhu X;Xuan Z;Zhao L;Dong H;Chen J;Li Z;Song W;Jin C;Zhou M;Xie H;Zheng S;Song P
肝细胞癌（Hepatocellular carcinoma，HCC）是世界范围内致死率最高的恶性肿瘤之一，其发病机制尚未完全阐明。肿瘤抑制因子的失活可能有助于HCC的发生、进展和复发。DNA甲基化是参与调控HCC发生的重要机制。在此，我们的目的是确定关键的甲基化相关的肿瘤抑制因子，以及潜在的生物标志物和治疗肝癌的目标。方法：联合分析TCGA和GEO数据库，获得HCC中潜在的甲基化相关抑癌基因。进行甲基靶测序以分析GNA14启动子的甲基化水平。在HCC肿瘤样品中评估GNA14作为HCC预测因子的诊断价值，并与正常组织进行比较。通过体外功能获得和功能丧失试验研究GNA14及其上游和下游调节因子的功能作用。进行皮下肿瘤发生、肺定植和原位肝肿瘤模型以分析GNA14在体内的作用。结果如下：GNA 14在HCC中表达下调，且与B型肝炎病毒（Hepatitisvirus，HBV）感染、血管浸润及预后呈负相关。DNA甲基化被证明是导致GNA14表达改变的原因，并受到HBV编码的X蛋白（HBx）的调节。GNA14通过促进Notch1的切割来调节RB通路以抑制肿瘤增殖，并可能通过抑制JMJD6的表达来抑制肿瘤转移。结论：HBx可能通过调控GNA14基因启动子甲基化状态来调控GNA14的表达。我们将GNA14确定为HCC的潜在生物标志物和治疗靶点。
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and its specific mechanism has not been fully elucidated. Inactivation of tumor suppressors may contribute to the occurrence, progression, and recurrence of HCC. DNA methylation is a crucial mechanism involved in regulating the occurrence of HCC. Herein, we aimed to identify the key methylation-related tumor suppressors as well as potential biomarkers and therapeutic targets in HCC. Methods: Combined analysis of TCGA and GEO databases was performed to obtain potential methylation-related tumor suppressors in HCC. Methyl-target sequencing was performed to analyze the methylation level of the GNA14 promoter. The diagnostic value of GNA14 as a predictor of HCC was evaluated in HCC tumor samples and compared with normal tissues. The functional role of GNA14 and its upstream and downstream regulatory factors were investigated by gain-of-function and loss-of-function assays in vitro. Subcutaneous tumorigenesis, lung colonization, and orthotopic liver tumor model were performed to analyze the role of GNA14 in vivo. Results: The expression of GNA14 was found to be downregulated in HCC and it was negatively correlated with hepatitis B virus (HBV) infection, vascular invasion, and prognosis of HCC. DNA methylation was demonstrated to be responsible for the altered expression of GNA14 and was regulated by HBV-encoded X protein (HBx). GNA14 regulated the RB pathway by promoting Notch1 cleavage to inhibit tumor proliferation, and might inhibit tumor metastasis by inhibiting the expression of JMJD6. Conclusion: GNA14 could be regulated by HBx by modulating the methylation status of its promoter. We identified GNA14 as a potential biomarker and therapeutic target for HCC.
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DOI：
10.1200/jco.2016.67.5264
发表时间：
2017-01-20
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Ferrarotto R;Mitani Y;Diao L;Guijarro I;Wang J;Zweidler-McKay P;Bell D;William WN Jr;Glisson BS;Wick MJ;Kapoun AM;Patnaik A;Eckhardt G;Munster P;Faoro L;Dupont J;Lee JJ;Futreal A;El-Naggar AK;Heymach JV
通讯作者：
Heymach JV
HBx 诱导的 S100A9 以 NF-κB 依赖性方式促进肝细胞癌细胞的生长和转移。
影响因子：
9
作者：
Duan L;Wu R;Zhang X;Wang D;You Y;Zhang Y;Zhou L;Chen W
通讯作者：
Chen W
影响因子：
9.8
作者：
Lim, Young H.;Bacchiocchi, Antonella;Choate, Keith A.
通讯作者：
Choate, Keith A.
JMJD6 通过新型酪氨酸激酶活性调节组蛋白 H2A.X 磷酸化并促进三阴性乳腺癌细胞自噬
影响因子：
8
作者：
Liu, Yan;Long, Yue-Hong;Zhang, Xiao-Jun
通讯作者：
Zhang, Xiao-Jun
影响因子：
2.7
作者：
Pan, XiaoPing;Li, JianZhou;Li, LanJuan
通讯作者：
Li, LanJuan