Epigenetic Inactivation of Wnt Inhibitory Factor-1 in Human Esophageal Squamous Cell Carcinoma

Published Dec 1, 2012Oncology research

Turning off a Wnt pathway blocker by epigenetic changes in human esophageal squamous cell cancer

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Abstract

WIF1 promoter methylation was frequently observed in ESCC tissues (46%, 23/50) and cell lines (50%, 2/4).

WIF1 is often silenced in esophageal squamous cell carcinoma (ESCC) due to promoter hypermethylation.
Restoring WIF1 expression in EC109 cells significantly inhibited both cell proliferation and migration.
Treatment with the demethylating agent 5-aza-2'-deoxycytidine increased or restored WIF1 expression in ESCC cell lines.
Reexpression of WIF1 led to a significant decrease in beta-catenin/T-cell factor-dependent transcription activity.
WIF1 silencing is associated with the carcinogenesis of ESCC.

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Wnt inhibitory factor-1 (WIF1), as one of most important Wnt antagonists, has been detected frequently silenced by promoter hypermethylation in various types of cancer. In this study, we aimed to investigate the promoter methylation profiles of WIF1 in human esophageal squamous cell carcinoma (ESCC) tissues and cell lines, as well as the functional roles of WIF1 in the human ESCC metastatic behavior. WIF1 mRNA levels and promoter methylation status in ESCC tissues and cell lines were detected using RT-PCR and methylation-specific PCR (MS-PCR), respectively. WIF1 protein levels were assessed by Western blot. Stable ESCC cell line with restoration of WIF1 was generated in EC109 cells, which naturally do not express detectable WIF1 mRNA. The effects of reexpressed WIF1 on EC109 cell proliferation and migration were investigated using crystal violet and wound healing assay, respectively. Also the effects of WIF1 reexpression on the beta-catenin/T-cell factor-dependent transcription activity was measured by luciferase assay. WIF1 promoter methylation was frequently observed in ESCC tissues (46%, 23/50) and cell lines (50%, 2/4). Treatment with demethylating agent, 5-aza-2'-deoxycytidine (5-aza-dC), increased or restored WIF1 expression in these ESCC cell lines. Restoration of the WIF1 in EC109 cells resulted in a significant inhibition on both cell proliferation and migration. Moreover, reexpression of WIF1 caused significant decrease of beta-catenin/T-cell factor-dependent transcription activity. These findings demonstrated that WIF1 silencing due to promoter hypermethylation is a major mechanism during carcinogenesis of ESCC. This would be an opportunity to prevent the development and progression of HCC through modulation of WIF1.

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Epigenetic Inactivation of Wnt Inhibitory Factor-1 in Human Esophageal Squamous Cell Carcinoma

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