WNT5AExhibits Tumor-Suppressive Activity through Antagonizing the Wnt/β-Catenin Signaling, and Is Frequently Methylated in Colorectal Cancer

Abstract

Purpose: Aberrant activation of theWnt/h-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 h-catenin protein level and concomitant decrease in h-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/h-catenin signaling.Wingless-type mouse mammary tumor virus integration site family (Wnt) proteins are a large family of cysteine-rich, secreted signaling glycoproteins that control essential developmental and normal physiologic processes (reviewed in refs. 1, 2). Vertebrate Wnts are divided into canonical signaling and noncanonical members (3,4). Activation of the canonical Wnt signaling pathway (Wnt/h-catenin/TCF) leads to the tumorigenesis of multiple carcinomas including colorectal cancer (CRC; refs. 5,6).WNT5A is located at 3p14, a commonly deleted tumor suppressor locus in multiple tumors. WNT5A has been classified as a noncanonical and nontransforming Wnt protein (3), with its role in tumorigenesis still ambiguous. There is evidence indicating that increased WNT5A expression is important for cancer progression, and that WNT5A was initially proposed as a proto-oncogene (7). WNT5A has been shown as a potent enhancer of cell motility and invasiveness of melanoma (8), up-regulated in cancers of the lung, breast, stomach, and prostate (9 -12). On the other hand, in other tumor models, including hematopoietic tissues, brain, breast, thyroid, and uroepithelial cancers, WNT5A has been shown to inhibit tumor cell proliferation (13 -17), with its expression as a good prognostic marker for patients with breast and colon cancer (18,19). These results suggest that dysregulation of WNT5A expression is involved in tumor pathogenesis, although its exact role is still controversial.Epigenetic silencing of tumor suppressor genes by promoter methylati...

Wnt/Planar cell polarity signaling: A new paradigm for cancer therapy

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The Metalloprotease ADAMTS8 Displays Antitumor Properties through Antagonizing EGFR–MEK–ERK Signaling and Is Silenced in Carcinomas by CpG Methylation

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Dysregulation of WNT5A/ROR2 Signaling Characterizes the Progression of Barrett-Associated Esophageal Adenocarcinoma

“…This notion was further supported in vitro, as rhWNT5A significantly inhibited OE33 cell proliferation, migration, and invasion. Indeed, loss or low expression of WNT5A is associated with increased invasion and aggressiveness of many solid tumors, such as thyroid cancer (16), breast cancer (18), neuroblastoma, (17) and colon cancer (19,28). Furthermore, loss of WNT5A expression has been shown to correlate with cell transformation (33), whereas ectopic expression of human WNT5A reversed the phenotype of a mouse epithelial cell line from tumorigenic to (34).…”