The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas

Published Mar 27, 2007Laboratory investigation; a journal of technical methods and pathology

The tumor-suppressing protein Wnt inhibitory factor 1 is often inactivated by DNA changes in nasopharyngeal and esophageal cancers

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Abstract

WIF1 was found to be downregulated or silenced in 100% of nasopharyngeal carcinoma (NPC) cell lines and 63% of esophageal squamous cell carcinoma (ESCC) cell lines tested.

WIF1 is a secreted antagonist of the Wnt-signaling pathway, commonly inactivated in various cancers.
Methylation of the WIF1 gene was detected in 85% of primary NPC tumors and 27% of primary ESCC tumors.
Normal NPC and esophageal cell lines showed WIF1 expression and no methylation, suggesting a tumor-specific silencing mechanism.
Treatment with a demethylating agent restored WIF1 expression in cancer cell lines, indicating its epigenetic inactivation.
Ectopic expression of WIF1 in tumor cells led to reduced colony formation and lower levels of beta-catenin protein in NPC cells.
WIF1 methylation may serve as a specific biomarker for nasopharyngeal carcinoma and esophageal squamous cell carcinoma.

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Aberrant activation of the wingless-type- (Wnt)-signaling pathway is common in many cancers including nasopharyngeal (NPC) and esophageal squamous cell (ESCC) carcinomas, both prevalent in Southern China and Southeast Asia. However, the molecular mechanism leading to this abnormality is still obscure. Wnt inhibitory factor-1 (WIF1) is a secreted antagonist of the Wnt pathway, and is recently shown to be inactivated by epigenetic mechanism in some tumors. Here, we examined whether WIF1 is also inactivated epigenetically in NPC and ESCC. With semiquantitative reverse transcription-PCR and methylation-specific PCR, we detected WIF1 downregulation or silencing in 6/6 of NPC and 12/19 of ESCC cell lines, which is well correlated with its methylation status. Methylation was further confirmed by high-resolution bisulfite genomic sequencing. Methylation was also frequently observed in a large collection of primary tumors of NPC (85%, 55/65) and ESCC (27%, 25/92), with WIF1 expressed and unmethylated in normal NPC and esophageal cell lines and normal tissues. Treatment of 5-aza-2'-deoxycytidine demethylated WIF1 and induced its expression in NPC and ESCC cell lines, highlighting a direct role of epigenetic inactivation. Ectopic expression of WIF1 in NPC and ESCC tumor cells resulted in significant inhibition of tumor cell colony formation, similar to TP53, and also significant downregulation of beta-catenin protein level in NPC cells. Thus, WIF1 functions as a tumor suppressor for both NPC and ESCC through suppressing the Wnt-signaling pathway, but is frequently silenced by epigenetic mechanism in a tumor-specific way. Our study indicates that epigenetic inactivation of WIF1 contributes to the aberrant activation of Wnt pathway and is involved in the pathogenesis of both tumors. WIF1 methylation could also serve as a specific biomarker for these tumors.

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The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas

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