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Published on: September 26, 2014
Hepatocyte nuclear factor 4α suppresses the aggravation of colon carcinoma
Hou Shan Yao1, Juan Wang1, Xiao Ping Zhang2
1Department of General Surgery, Shanghai Chang Zheng Hospital, Second Military Medical University, 415 Feng Yang Road, Shanghai, China.
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.
Insights
Hepatocyte nuclear factor 4-α (HNF4α) is downregulated in colon cancer, correlating with worse survival. Restoring HNF4α inhibits tumor growth, metastasis, and promotes apoptosis by affecting EMT and cell cycle progression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Hepatocyte nuclear factor 4-α (HNF4α) is a nuclear receptor.
- HNF4α is expressed at lower levels in colon carcinoma tissues.
- The role of HNF4α in colon cancer progression is unclear.
Purpose of the Study:
- To investigate the role of HNF4α in colon carcinoma progression.
- To elucidate the molecular mechanisms underlying HNF4α's function in colon cancer.
Main Methods:
- Analysis of HNF4α expression in colon carcinoma specimens.
- Correlation of HNF4α expression with clinical parameters and patient survival.
- In vitro studies using colon carcinoma cell lines (HT29, LoVo, SW480) with ectopic HNF4α expression.
- In vivo studies using xenograft models.
- Analysis of epithelial-mesenchymal transition (EMT) markers and signaling pathways (Wnt/β-catenin).
Main Results:
- HNF4α mRNA and protein were significantly downregulated in colon carcinoma tissues.
- Low HNF4α expression correlated with advanced pT classification, lymph node metastasis, distant metastasis, and clinical stage.
- Patients with low HNF4α expression had significantly worse progression-free survival (PFS) and overall survival (OS).
- Ectopic HNF4α expression inhibited colon cancer cell proliferation, migration, invasion, induced G2/M phase arrest, promoted apoptosis, and upregulated E-cadherin while downregulating vimentin.
- HNF4α overexpression suppressed tumor growth and liver metastasis in vivo, downregulated snail, slug, and twist, and inhibited EMT via the Wnt/β-catenin pathway.
- HNF4α downregulation may be mediated by promoter methylation.
Conclusions:
- Downregulation of HNF4α plays a critical role in colon carcinoma progression.
- HNF4α acts as a tumor suppressor in colon cancer.
- HNF4α inhibits EMT, apoptosis, and cell cycle progression, potentially through the Wnt/β-catenin pathway.
- HNF4α may serve as a prognostic biomarker for colon cancer.
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