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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
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.
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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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