HINT2 downregulation promotes colorectal carcinoma migration and metastasis

Histidine triad nucleotide-binding 2 (HINT2), a member of the histidine triad proteins family, sensitizes cells to apoptosis in hepatocellular carcinoma. Here, we showed that HINT2 expression is lower in primary colorectal cancer (CRC) and metastasis tissues than in normal colorectal tissues, and th...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Weihua, Cai, Shaoxin, Wang, Le, Yang, Changshun, Zhou, Biaohuan, Wang, Huan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355117/
https://www.ncbi.nlm.nih.gov/pubmed/28088787
http://dx.doi.org/10.18632/oncotarget.14587
_version_ 1782515470776139776
author Li, Weihua
Cai, Shaoxin
Wang, Le
Yang, Changshun
Zhou, Biaohuan
Wang, Huan
author_facet Li, Weihua
Cai, Shaoxin
Wang, Le
Yang, Changshun
Zhou, Biaohuan
Wang, Huan
author_sort Li, Weihua
collection PubMed
description Histidine triad nucleotide-binding 2 (HINT2), a member of the histidine triad proteins family, sensitizes cells to apoptosis in hepatocellular carcinoma. Here, we showed that HINT2 expression is lower in primary colorectal cancer (CRC) and metastasis tissues than in normal colorectal tissues, and that HINT2 abundance is inversely correlated with CRC tumor stage. Treating CRC cells with 5-aza-2′-deoxycytidine, a demethylating agent, upregulated HINT2, suggesting HINT2 downregulation is caused by methylation of the gene promoter. HINT2 downregulation increased tumor migration and invasion in vitro, promoted CRC cell metastasis in vivo, and increased expression of epithelial-to-mesenchymal transition (EMT) markers. Furthermore, HINT2 downregulation depended on hypoxia inducible factor (HIF)-2α-mediated transcriptional activation of zinc finger E-box-binding homeobox 1 (ZEB1). These results suggest that HINT2 downregulation promotes HIF-2α expression, which induces EMT and enhances CRC cell migration and invasion. HINT2 may thus a useful clinical indicator of CRC progression and metastasis risk.
format Online
Article
Text
id pubmed-5355117
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-53551172017-04-15 HINT2 downregulation promotes colorectal carcinoma migration and metastasis Li, Weihua Cai, Shaoxin Wang, Le Yang, Changshun Zhou, Biaohuan Wang, Huan Oncotarget Research Paper Histidine triad nucleotide-binding 2 (HINT2), a member of the histidine triad proteins family, sensitizes cells to apoptosis in hepatocellular carcinoma. Here, we showed that HINT2 expression is lower in primary colorectal cancer (CRC) and metastasis tissues than in normal colorectal tissues, and that HINT2 abundance is inversely correlated with CRC tumor stage. Treating CRC cells with 5-aza-2′-deoxycytidine, a demethylating agent, upregulated HINT2, suggesting HINT2 downregulation is caused by methylation of the gene promoter. HINT2 downregulation increased tumor migration and invasion in vitro, promoted CRC cell metastasis in vivo, and increased expression of epithelial-to-mesenchymal transition (EMT) markers. Furthermore, HINT2 downregulation depended on hypoxia inducible factor (HIF)-2α-mediated transcriptional activation of zinc finger E-box-binding homeobox 1 (ZEB1). These results suggest that HINT2 downregulation promotes HIF-2α expression, which induces EMT and enhances CRC cell migration and invasion. HINT2 may thus a useful clinical indicator of CRC progression and metastasis risk. Impact Journals LLC 2017-01-10 /pmc/articles/PMC5355117/ /pubmed/28088787 http://dx.doi.org/10.18632/oncotarget.14587 Text en Copyright: © 2017 Li et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Li, Weihua
Cai, Shaoxin
Wang, Le
Yang, Changshun
Zhou, Biaohuan
Wang, Huan
HINT2 downregulation promotes colorectal carcinoma migration and metastasis
title HINT2 downregulation promotes colorectal carcinoma migration and metastasis
title_full HINT2 downregulation promotes colorectal carcinoma migration and metastasis
title_fullStr HINT2 downregulation promotes colorectal carcinoma migration and metastasis
title_full_unstemmed HINT2 downregulation promotes colorectal carcinoma migration and metastasis
title_short HINT2 downregulation promotes colorectal carcinoma migration and metastasis
title_sort hint2 downregulation promotes colorectal carcinoma migration and metastasis
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355117/
https://www.ncbi.nlm.nih.gov/pubmed/28088787
http://dx.doi.org/10.18632/oncotarget.14587
work_keys_str_mv AT liweihua hint2downregulationpromotescolorectalcarcinomamigrationandmetastasis
AT caishaoxin hint2downregulationpromotescolorectalcarcinomamigrationandmetastasis
AT wangle hint2downregulationpromotescolorectalcarcinomamigrationandmetastasis
AT yangchangshun hint2downregulationpromotescolorectalcarcinomamigrationandmetastasis
AT zhoubiaohuan hint2downregulationpromotescolorectalcarcinomamigrationandmetastasis
AT wanghuan hint2downregulationpromotescolorectalcarcinomamigrationandmetastasis