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HBx‐mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis
Tumor metastasis is responsible for the high mortality rates in patients with hepatocellular carcinoma (HCC). Absent in melanoma 2 (AIM2) has been implicated in inflammation and carcinogenesis, although its role in HCC metastasis remains unknown. In the present study, we show that AIM2 protein expre...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579341/ https://www.ncbi.nlm.nih.gov/pubmed/28580773 http://dx.doi.org/10.1002/1878-0261.12090 |
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author | Chen, Shi‐Lu Liu, Li‐Li Lu, Shi‐Xun Luo, Rong‐Zhen Wang, Chun‐Hua Wang, Hong Cai, Shao‐Hang Yang, Xia Xie, Dan Zhang, Chris Zhiyi Yun, Jing‐Ping |
author_facet | Chen, Shi‐Lu Liu, Li‐Li Lu, Shi‐Xun Luo, Rong‐Zhen Wang, Chun‐Hua Wang, Hong Cai, Shao‐Hang Yang, Xia Xie, Dan Zhang, Chris Zhiyi Yun, Jing‐Ping |
author_sort | Chen, Shi‐Lu |
collection | PubMed |
description | Tumor metastasis is responsible for the high mortality rates in patients with hepatocellular carcinoma (HCC). Absent in melanoma 2 (AIM2) has been implicated in inflammation and carcinogenesis, although its role in HCC metastasis remains unknown. In the present study, we show that AIM2 protein expression was noticeably reduced in HCC cell lines and clinical samples. A reduction in AIM2 was closely associated with higher serum AFP levels, vascular invasion, poor tumor differentiation, an incomplete tumor capsule and unfavorable postsurgical survival odds. In vitro studies demonstrated that AIM2 expression was modulated by hepatitis B virus X protein (HBx) at transcriptional and post‐translational levels. HBx overexpression markedly blocked the expression of AIM2 at mRNA and protein levels by enhancing the stability of Enhancer of zeste homolog 2 (EZH2). Furthermore, HBx interacted with AIM2, resulting in an increase of AIM2 degradation via ubiquitination induction. Functionally, knockdown of AIM2 enhanced cell migration, formation of cell pseudopodium, wound healing and tumor metastasis, whereas reintroduction of AIM2 attenuated these functions. The loss of AIM2 induced the activation of epithelial‐mesenchymal transition (EMT). Fibronectin 1 (FN1) was found to be a downstream effector of AIM2, with its expression reversely modulated by AIM2. Silencing of FN1 significantly halted cell migration induced by AIM2 depletion. These data demonstrate that HBx‐induced loss of AIM2 is associated with poor outcomes and facilitates HCC metastasis by triggering the EMT process. The results of the present study therefore suggest that AIM2 is a potential prognostic biomarker in hepatitis B virus‐related HCC, as well as a possible therapeutic target for tumor metastasis. |
format | Online Article Text |
id | pubmed-5579341 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-55793412017-09-06 HBx‐mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis Chen, Shi‐Lu Liu, Li‐Li Lu, Shi‐Xun Luo, Rong‐Zhen Wang, Chun‐Hua Wang, Hong Cai, Shao‐Hang Yang, Xia Xie, Dan Zhang, Chris Zhiyi Yun, Jing‐Ping Mol Oncol Research Articles Tumor metastasis is responsible for the high mortality rates in patients with hepatocellular carcinoma (HCC). Absent in melanoma 2 (AIM2) has been implicated in inflammation and carcinogenesis, although its role in HCC metastasis remains unknown. In the present study, we show that AIM2 protein expression was noticeably reduced in HCC cell lines and clinical samples. A reduction in AIM2 was closely associated with higher serum AFP levels, vascular invasion, poor tumor differentiation, an incomplete tumor capsule and unfavorable postsurgical survival odds. In vitro studies demonstrated that AIM2 expression was modulated by hepatitis B virus X protein (HBx) at transcriptional and post‐translational levels. HBx overexpression markedly blocked the expression of AIM2 at mRNA and protein levels by enhancing the stability of Enhancer of zeste homolog 2 (EZH2). Furthermore, HBx interacted with AIM2, resulting in an increase of AIM2 degradation via ubiquitination induction. Functionally, knockdown of AIM2 enhanced cell migration, formation of cell pseudopodium, wound healing and tumor metastasis, whereas reintroduction of AIM2 attenuated these functions. The loss of AIM2 induced the activation of epithelial‐mesenchymal transition (EMT). Fibronectin 1 (FN1) was found to be a downstream effector of AIM2, with its expression reversely modulated by AIM2. Silencing of FN1 significantly halted cell migration induced by AIM2 depletion. These data demonstrate that HBx‐induced loss of AIM2 is associated with poor outcomes and facilitates HCC metastasis by triggering the EMT process. The results of the present study therefore suggest that AIM2 is a potential prognostic biomarker in hepatitis B virus‐related HCC, as well as a possible therapeutic target for tumor metastasis. John Wiley and Sons Inc. 2017-07-11 2017-09 /pmc/articles/PMC5579341/ /pubmed/28580773 http://dx.doi.org/10.1002/1878-0261.12090 Text en © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Chen, Shi‐Lu Liu, Li‐Li Lu, Shi‐Xun Luo, Rong‐Zhen Wang, Chun‐Hua Wang, Hong Cai, Shao‐Hang Yang, Xia Xie, Dan Zhang, Chris Zhiyi Yun, Jing‐Ping HBx‐mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis |
title |
HBx‐mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis |
title_full |
HBx‐mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis |
title_fullStr |
HBx‐mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis |
title_full_unstemmed |
HBx‐mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis |
title_short |
HBx‐mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis |
title_sort | hbx‐mediated decrease of aim2 contributes to hepatocellular carcinoma metastasis |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579341/ https://www.ncbi.nlm.nih.gov/pubmed/28580773 http://dx.doi.org/10.1002/1878-0261.12090 |
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