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.

Phosphoprotein enriched in diabetes (PED/PEA15) promotes migration in hepatocellular carcinoma and confers resistance to sorafenib

“…After reducing HNF4 α , protein ( Figure 4e ) and mRNA levels ( Figure 4f ) of PED increased in both cell lines. Next, we wanted to test if HNF4 α regulates cell migration 23 , 24 through PED. Therefore, we performed a rescue experiment and silenced PED and HNF4 α simultaneously in SNU-449 cells ( Figure 4g ).…”

Role of conventional immunomarkers, HNF4‐α and SATB2, in the differential diagnosis of pulmonary and colorectal adenocarcinomas

“…This gene has been shown to cause maturity-onset diabetes of the young 15 and has implications in liver and intestinal development. 16,17 Besides its physiological functions in normal colorectal tissue, expression of HNF4-a has been demonstrated in CRC, 18,19 intestinal-type ampullary cancer, 20 gastric cancer, [21][22][23][24] ovarian mucinous neoplasms 25 and IMA. 9 In our study we confirm that CRC metastases also exhibit HNF4-a expression frequently (96%).…”

“…1 (3) 25 (3) 1 (5) 25 (2) 10 (3) 16 (3) 1 (1) 25 (3) 15 (3) 10 (2) ADC, adenocarcinoma; mADC, mucinous adenocarcinoma; ASC, adenosquamous carcinoma; CDX-2, caudal type homeobox transcription factor 2; CK, cytokeratin; HNF4-a, hepatocyte nuclear factor 4 alpha; IMA, invasive mucinous adenocarcinoma; LC, large cell carcinoma; PC, pleomorphic carcinoma; SATB2, special AT-rich sequence-binding protein 2; TTF-1, thyroid transcription factor-1. (15) 42 (12) 29 (23) 7 (20) 65 (15) 55 (13) 16 (27) pT3 68 (14) 1 (11) 67 (14) 4 (19) 64 (14) 3 (18) 65 (14) 44 (13) 24 (19) 2 (6) 66 (15) 54 (13) 84 (19) 1 (6) 84 (18) 59 (17) 26 (21) 5 (14) 80 (18) 70 (17) 13 (3) 1 (6) 13 (3) 10 (3) 4 (3) 1 (3) 13 (3) 12 (3) 1 (2) Stage IA (17) 3 (18) 74…”

Berberine Attenuated Proliferation, Invasion and Migration by Targeting the AMPK/HNF4α/WNT5A Pathway in Gastric Carcinoma

“…But studies have illustrated, in small intestine and colon cancer, loss of HNF4α activated the WNT/β-catenin signaling pathway. In these cancer tissues, HNF4α was low expressed compared with adjacent normal tissues ( Cattin et al, 2009 ; Yao et al, 2016 ).…”

“…The results showed that knockdown of HNF4α decreased significantly the protein and mRNA expression levels of WNT5A, cytoplasmic β-catenin and cyclinD1 in vitro , and increased significantly the expression of E-cadherin comparing with control cells. HNF4α was reported to compete with β-catenin for binding to TCF4, regulating Epithelial-to-mesenchymal transition (EMT) ( Yao et al, 2016 ). Loss of E-cadherin is regarded as a major conventional marker of the EMT ( Alotaibi et al, 2015 ; Yamashita et al, 2018 ).…”