Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Song, Guangyuan, Zhu, Xingxin, Xuan, Zefeng, Zhao, Long, Dong, Haijiang, Chen, Jian, Li, Zequn, Song, Wenfeng, Jin, Cheng, Zhou, Mengqiao, Xie, Haiyang, Zheng, Shusen, Song, Penghong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797690/
https://www.ncbi.nlm.nih.gov/pubmed/33500727
http://dx.doi.org/10.7150/thno.48739
_version_ 1783634925395640320
author Song, Guangyuan
Zhu, Xingxin
Xuan, Zefeng
Zhao, Long
Dong, Haijiang
Chen, Jian
Li, Zequn
Song, Wenfeng
Jin, Cheng
Zhou, Mengqiao
Xie, Haiyang
Zheng, Shusen
Song, Penghong
author_facet Song, Guangyuan
Zhu, Xingxin
Xuan, Zefeng
Zhao, Long
Dong, Haijiang
Chen, Jian
Li, Zequn
Song, Wenfeng
Jin, Cheng
Zhou, Mengqiao
Xie, Haiyang
Zheng, Shusen
Song, Penghong
author_sort Song, Guangyuan
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7797690
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Ivyspring International Publisher
record_format MEDLINE/PubMed
spelling pubmed-77976902021-01-25 Hypermethylation of GNA14 and its tumor-suppressive role in hepatitis B virus-related hepatocellular carcinoma Song, Guangyuan Zhu, Xingxin Xuan, Zefeng Zhao, Long Dong, Haijiang Chen, Jian Li, Zequn Song, Wenfeng Jin, Cheng Zhou, Mengqiao Xie, Haiyang Zheng, Shusen Song, Penghong Theranostics Research Paper 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. Ivyspring International Publisher 2021-01-01 /pmc/articles/PMC7797690/ /pubmed/33500727 http://dx.doi.org/10.7150/thno.48739 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Song, Guangyuan
Zhu, Xingxin
Xuan, Zefeng
Zhao, Long
Dong, Haijiang
Chen, Jian
Li, Zequn
Song, Wenfeng
Jin, Cheng
Zhou, Mengqiao
Xie, Haiyang
Zheng, Shusen
Song, Penghong
Hypermethylation of GNA14 and its tumor-suppressive role in hepatitis B virus-related hepatocellular carcinoma
title Hypermethylation of GNA14 and its tumor-suppressive role in hepatitis B virus-related hepatocellular carcinoma
title_full Hypermethylation of GNA14 and its tumor-suppressive role in hepatitis B virus-related hepatocellular carcinoma
title_fullStr Hypermethylation of GNA14 and its tumor-suppressive role in hepatitis B virus-related hepatocellular carcinoma
title_full_unstemmed Hypermethylation of GNA14 and its tumor-suppressive role in hepatitis B virus-related hepatocellular carcinoma
title_short Hypermethylation of GNA14 and its tumor-suppressive role in hepatitis B virus-related hepatocellular carcinoma
title_sort hypermethylation of gna14 and its tumor-suppressive role in hepatitis b virus-related hepatocellular carcinoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797690/
https://www.ncbi.nlm.nih.gov/pubmed/33500727
http://dx.doi.org/10.7150/thno.48739
work_keys_str_mv AT songguangyuan hypermethylationofgna14anditstumorsuppressiveroleinhepatitisbvirusrelatedhepatocellularcarcinoma
AT zhuxingxin hypermethylationofgna14anditstumorsuppressiveroleinhepatitisbvirusrelatedhepatocellularcarcinoma
AT xuanzefeng hypermethylationofgna14anditstumorsuppressiveroleinhepatitisbvirusrelatedhepatocellularcarcinoma
AT zhaolong hypermethylationofgna14anditstumorsuppressiveroleinhepatitisbvirusrelatedhepatocellularcarcinoma
AT donghaijiang hypermethylationofgna14anditstumorsuppressiveroleinhepatitisbvirusrelatedhepatocellularcarcinoma
AT chenjian hypermethylationofgna14anditstumorsuppressiveroleinhepatitisbvirusrelatedhepatocellularcarcinoma
AT lizequn hypermethylationofgna14anditstumorsuppressiveroleinhepatitisbvirusrelatedhepatocellularcarcinoma
AT songwenfeng hypermethylationofgna14anditstumorsuppressiveroleinhepatitisbvirusrelatedhepatocellularcarcinoma
AT jincheng hypermethylationofgna14anditstumorsuppressiveroleinhepatitisbvirusrelatedhepatocellularcarcinoma
AT zhoumengqiao hypermethylationofgna14anditstumorsuppressiveroleinhepatitisbvirusrelatedhepatocellularcarcinoma
AT xiehaiyang hypermethylationofgna14anditstumorsuppressiveroleinhepatitisbvirusrelatedhepatocellularcarcinoma
AT zhengshusen hypermethylationofgna14anditstumorsuppressiveroleinhepatitisbvirusrelatedhepatocellularcarcinoma
AT songpenghong hypermethylationofgna14anditstumorsuppressiveroleinhepatitisbvirusrelatedhepatocellularcarcinoma