Hepatocyte nuclear factor 4 suppresses the aggravation of colon carcinoma

Hepatocyte nuclear factor 4- (HNF4), a nuclear receptor, is expressed at lower levels in colon carcinoma tissues than in adjacent normal tissues. However, the relation between HNF4 and colon cancer progression and the underlying molecular mechanisms remain unclear. Here, we investigated the role of HNF4 in the progression of colon carcinoma. We showed that HNF4 mRNA and protein were downregulated in colon carcinoma specimens. HNF4 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 HNF4 expression had worse 3-year progression-free survival (PFS, P=0.006) and overall survival (OS, P=0.005) than patients with high HNF4 expression. Low HNF4 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 HNF4 inhibited colon carcinoma cell (HT29, LoVo, and SW480) proliferation, migration, and invasion, induced G2/M phase arrest and promoted apoptosis. Ectopic expression of HNF4 upregulated E-cadherin and downregulated vimentin in vitro, and suppressed SW480 xenograft tumor growth and liver metastasis in vivo. Furthermore, HNF4 overexpression downregulated the expression of snail, slug and twist. HNF4 inhibited EMT through its effect on the Wnt/-catenin signaling pathway, and HNF4 downregulation may be mediated by promoter methylation in cancer tissues. Our results suggest that downregulation of HNF4 plays a critical role in the aggravation of colon carcinoma possibly by promoting EMT via the Wnt/-catenin signaling pathway and by affecting apoptosis and cell cycle progression. (c) 2015 Wiley Periodicals, Inc.