WNT5A exhibits tumor-suppressive activity through antagonizing the Wnt/β-catenin signaling, and is frequently methylated in colorectal cancer

Jianming Ying, Hongyu Li, Jun Yu, Man Ng Ka, Fong Poon Fan, Sze Chuen Cesar Wong, Anthony T.C. Chan, Joseph J.Y. Sung, Qian Tao

Research output: Journal article publicationJournal articleAcademic researchpeer-review

157 Citations (Scopus)

Abstract

Purpose: Aberrant activationof the Wnt/β-catenin signaling pathway is associated with multiple tumors including colorectal cancer (CRC). WNT5A is a member of the nontransforming Wnt protein family, whose role in tumorigenesis is still ambiguous. We investigated its epigenetic alteration in CRCs. Experimental Design: We examined its expression and methylation in normal colon, CRC cell lines, and tumors. We also evaluated its tumor-suppressive function and its modulation to Wnt signaling in CRC cells. Results: WNT5A is silenced in most CRC cell lines due to promoter methylation, but is expressed in most normal tissues including the colon, and is unmethylated in normal colon epithelial cells. WNT5A expression could be reactivated by pharmacologic or genetic demethylation, indicating that methylation directly mediates its silencing. WNT5A methylation was frequently detected in CRC tumors (14 of 29, 48%), but only occasionally in paired normal colon tissues (2 of 15, 13%; P = 0.025). Ectopic expression of WNT5A, but not its nonfunctional short-isoform with the WNT domain deleted, in silenced CRC cells resulted in substantial inhibition of tumor cell clonogenicity, which is associated with down-regulated intracellular β-catenin protein level and concomitant decrease in β-catenin activity. Conclusions: WNT5A is frequently inactivated in CRC by tumor-specific methylation, and thus, is a potential biomarker. WNT5A could act as a tumor suppressor for CRC by antagonizing the Wnt/β-catenin signaling.
Original languageEnglish
Pages (from-to)55-61
Number of pages7
JournalClinical Cancer Research
Volume14
Issue number1
DOIs
Publication statusPublished - 1 Jan 2008
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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