title: Hepatocyte nuclear factor 4α suppresses the aggravation of colon carcinoma.
abstract: Hepatocyte nuclear factor 4-α (HNF4α), a nuclear receptor, is expressed at lower levels in colon carcinoma tissues than in adjacent normal tissues. However, the relation between HNF4α and colon cancer progression and the underlying molecular mechanisms remain unclear. Here, we investigated the role of HNF4α in the progression of colon carcinoma. We showed that HNF4α mRNA and protein were downregulated in colon carcinoma specimens. HNF4α expression was related to pT classification (P < 0.001), lymph node metastasis (P = 0.002), distant metastasis (P < 0.001) and clinical stage (P < 0.001) in colon carcinoma patients. Patients with low or negative HNF4α expression had worse 3-year progression-free survival (PFS, P = 0.006) and overall survival (OS, P = 0.005) than patients with high HNF4α expression. Low HNF4α expression was an independent prognostic factor for 3-year PFS (hazard ratio 2.94; 95% confidence interval 1.047-8.250; P = 0.041). Ectopic expression of HNF4α inhibited colon carcinoma cell (HT29, LoVo, and SW480) proliferation, migration, and invasion, induced G2/M phase arrest and promoted apoptosis. Ectopic expression of HNF4α upregulated E-cadherin and downregulated vimentin in vitro, and suppressed SW480 xenograft tumor growth and liver metastasis in vivo. Furthermore, HNF4α overexpression downregulated the expression of snail, slug and twist. HNF4α inhibited EMT through its effect on the Wnt/β-catenin signaling pathway, and HNF4α downregulation may be mediated by promoter methylation in cancer tissues. Our results suggest that downregulation of HNF4α plays a critical role in the aggravation of colon carcinoma possibly by promoting EMT via the Wnt/β-catenin signaling pathway and by affecting apoptosis and cell cycle progression.
authors: Department of General Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, 415 Feng Yang Road, Shanghai, China.
authors: Hou Shan
authors: HS
authors: Yao
authors: Department of General Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, 415 Feng Yang Road, Shanghai, China.
authors: Juan
authors: J
authors: Wang
authors: Medical Intervention Engineering, Tongji University, North Zhongshan Road, Shanghai, China.
authors: Xiao Ping
authors: XP
authors: Zhang
authors: Department of pathology, Shanghai Chang Zheng Hospital, Second Military Medical University, 415 Feng Yang Road, Shanghai, China.
authors: Liang Zhe
authors: LZ
authors: Wang
authors: Department of General Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, 415 Feng Yang Road, Shanghai, China.
authors: Yi
authors: Y
authors: Wang
authors: Department of General Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, 415 Feng Yang Road, Shanghai, China.
authors: Xin Xing
authors: XX
authors: Li
authors: Department of General Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, 415 Feng Yang Road, Shanghai, China.
authors: Kai Zhou
authors: KZ
authors: Jin
authors: Department of General Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, 415 Feng Yang Road, Shanghai, China.
authors: Zhi Qian
authors: ZQ
authors: Hu
authors: Department of General Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, 415 Feng Yang Road, Shanghai, China.
authors: Wei Jun
authors: WJ
authors: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D016019:Survival Analysis; D051176:beta Catenin / Q000378:metabolism
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D051176:beta Catenin
keywords: Hepatocyte nuclear factor 4α; colon carcinoma; epithelial-mesenchymal transition; wnt/β-catenin signaling pathway