HINT2 downregulation promotes colorectal carcinoma migration and metastasis

Weihua Li; Shaoxin Cai; Le Wang; Changshun Yang; Biaohuan Zhou; Huan Wang

doi:10.18632/oncotarget.14587

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Research Papers:

HINT2 downregulation promotes colorectal carcinoma migration and metastasis

Weihua Li _, Shaoxin Cai, Le Wang, Changshun Yang, Biaohuan Zhou and Huan Wang

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Oncotarget. 2017; 8:13521-13531. https://doi.org/10.18632/oncotarget.14587

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Abstract

Weihua Li1,*, Shaoxin Cai1,*, Le Wang1, Changshun Yang1, Biaohuan Zhou1, Huan Wang1

1Department of Surgical Oncology, Fujian Provincial Clinical College, Fujian Medical University, Fuzhou 350001, China

*These authors contributed equally to this work

Correspondence to:

Weihua Li, email: [email protected]

Keywords: colorectal cancer, HINT2, epithelial–mesenchymal transition, HIF-2α, ZEB1

Received: June 30, 2016 Accepted: January 03, 2017 Published: January 10, 2017

ABSTRACT

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.

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Research Papers:

HINT2 downregulation promotes colorectal carcinoma migration and metastasis

Abstract