Hypermethylation of GNA14 and its tumor-suppressive role in hepatitis B virus-related hepatocellular carcinoma

被引:27
作者
Song, Guangyuan [1 ,2 ,3 ,4 ]
Zhu, Xingxin [1 ,2 ,3 ,4 ]
Xuan, Zefeng [1 ,2 ,3 ,4 ]
Zhao, Long [1 ,2 ,3 ,4 ]
Dong, Haijiang [1 ,2 ,3 ,4 ]
Chen, Jian [1 ,2 ,3 ,4 ]
Li, Zequn [1 ,2 ,3 ,4 ]
Song, Wenfeng [1 ,2 ,3 ,4 ]
Jin, Cheng [1 ,2 ,3 ,4 ]
Zhou, Mengqiao [1 ,2 ,3 ,4 ]
Xie, Haiyang [1 ,2 ,3 ,4 ]
Zheng, Shusen [1 ,2 ,3 ,4 ]
Song, Penghong [1 ,2 ,3 ,4 ]
机构
[1] Zhejiang Univ, Affiliated Hosp 1, Sch Med, Div Hepatobiliary & Pancreat Surg,Dept Surg, Hangzhou 310003, Zhejiang, Peoples R China
[2] NHC Key Lab Combined Multiorgan Transplantat, Hangzhou 310003, Zhejiang, Peoples R China
[3] Chinese Acad Med Sci 2019RU019, Res Unit Collaborat Diag & Treatment Hepatobiliar, Key Lab Diag & Treatment Organ Transplantat, Hangzhou 310003, Zhejiang, Peoples R China
[4] Res Ctr Diag & Treatment Hepatobiliary Dis, Key Lab Organ Transplantat, Hangzhou 310003, Zhejiang, Peoples R China
来源
THERANOSTICS | 2021年 / 11卷 / 05期
基金
中国国家自然科学基金;
关键词
HCC; DNA methylation; GNA14; HBV; HBx; X PROTEIN PROMOTES; DNA METHYLATION; SIGNALING PROMOTES; CELL METABOLISM; NOTCH; ACTIVATION; CANCER; INDUCTION; GENES;
D O I
10.7150/thno.48739
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:2318 / 2333
页数:16
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