title: HINT2 downregulation promotes colorectal carcinoma migration and metastasis.
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.
authors.affiliation: Department of Surgical Oncology, Fujian Provincial Clinical College, Fujian Medical University, Fuzhou 350001, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Surgical Oncology, Fujian Provincial Clinical College, Fujian Medical University, Fuzhou 350001, China.
authors.forename: Shaoxin
authors.initials: S
authors.lastname: Cai
authors.affiliation: Department of Surgical Oncology, Fujian Provincial Clinical College, Fujian Medical University, Fuzhou 350001, China.
authors.forename: Le
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Surgical Oncology, Fujian Provincial Clinical College, Fujian Medical University, Fuzhou 350001, China.
authors.forename: Changshun
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Surgical Oncology, Fujian Provincial Clinical College, Fujian Medical University, Fuzhou 350001, China.
authors.forename: Biaohuan
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Surgical Oncology, Fujian Provincial Clinical College, Fujian Medical University, Fuzhou 350001, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D015398:Signal Transduction; D014162:Transfection; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D024101:Mitochondrial Proteins; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000099162:Endothelial PAS Domain-Containing Protein 1; C533603:Hint2 protein, human; C486307:ZEB1 protein, human
keywords: HIF-2α; HINT2; ZEB1; colorectal cancer; epithelial–mesenchymal transition