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

Stephen L. Chan, Yan Cui, Andrew Van Hasselt, Hongyu Li, Gopesh Srivastava, Hongchuan Jin, Ka M. Ng, Yajun Wang, Kwan Y. Lee, George S.W. Tsao, Sheng Zhong, Keith D. Robertson, SunYoung Rha, Anthony T.C. Chan, Qian Tao

Research output: Contribution to journalArticle

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Abstract

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 β-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.

Original languageEnglish
Pages (from-to)644-650
Number of pages7
JournalLaboratory Investigation
Volume87
Issue number7
DOIs
Publication statusPublished - 2007 Jul 5

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Wnt Proteins
Methylation
Epigenomics
Neoplasms
decitabine
Cell Line
Down-Regulation
Nasopharyngeal Neoplasms
Catenins
Polymerase Chain Reaction
Southeastern Asia
Nasopharyngeal carcinoma
Tumor Biomarkers
Reverse Transcription
China

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

Cite this

Chan, Stephen L. ; Cui, Yan ; Van Hasselt, Andrew ; Li, Hongyu ; Srivastava, Gopesh ; Jin, Hongchuan ; Ng, Ka M. ; Wang, Yajun ; Lee, Kwan Y. ; Tsao, George S.W. ; Zhong, Sheng ; Robertson, Keith D. ; Rha, SunYoung ; Chan, Anthony T.C. ; Tao, Qian. / The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas. In: Laboratory Investigation. 2007 ; Vol. 87, No. 7. pp. 644-650.
@article{451dee1566e145b7b8a9f3614e1f1442,
title = "The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas",
abstract = "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 β-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.",
author = "Chan, {Stephen L.} and Yan Cui and {Van Hasselt}, Andrew and Hongyu Li and Gopesh Srivastava and Hongchuan Jin and Ng, {Ka M.} and Yajun Wang and Lee, {Kwan Y.} and Tsao, {George S.W.} and Sheng Zhong and Robertson, {Keith D.} and SunYoung Rha and Chan, {Anthony T.C.} and Qian Tao",
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Chan, SL, Cui, Y, Van Hasselt, A, Li, H, Srivastava, G, Jin, H, Ng, KM, Wang, Y, Lee, KY, Tsao, GSW, Zhong, S, Robertson, KD, Rha, S, Chan, ATC & Tao, Q 2007, 'The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas', Laboratory Investigation, vol. 87, no. 7, pp. 644-650. https://doi.org/10.1038/labinvest.3700547

The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas. / Chan, Stephen L.; Cui, Yan; Van Hasselt, Andrew; Li, Hongyu; Srivastava, Gopesh; Jin, Hongchuan; Ng, Ka M.; Wang, Yajun; Lee, Kwan Y.; Tsao, George S.W.; Zhong, Sheng; Robertson, Keith D.; Rha, SunYoung; Chan, Anthony T.C.; Tao, Qian.

In: Laboratory Investigation, Vol. 87, No. 7, 05.07.2007, p. 644-650.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas

AU - Chan, Stephen L.

AU - Cui, Yan

AU - Van Hasselt, Andrew

AU - Li, Hongyu

AU - Srivastava, Gopesh

AU - Jin, Hongchuan

AU - Ng, Ka M.

AU - Wang, Yajun

AU - Lee, Kwan Y.

AU - Tsao, George S.W.

AU - Zhong, Sheng

AU - Robertson, Keith D.

AU - Rha, SunYoung

AU - Chan, Anthony T.C.

AU - Tao, Qian

PY - 2007/7/5

Y1 - 2007/7/5

N2 - 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 β-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.

AB - 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 β-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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