WNT5A exhibits tumor-suppressive activity through antagonizing the Wnt/β-catenin signaling, and is frequently methylated in colorectal cancer
WNT5A exhibits tumor-suppressive activity through antagonizing the Wnt/β-catenin signaling, and is frequently methylated in colorectal cancer
复制标题
DOI：
10.1158/1078-0432.ccr-07-1644
复制
发表时间：
2008-01-01
影响因子：
11.5
通讯作者：
Tao, Qian
中科院分区：
文献类型：
--
作者：
Ying, Jianming;Li, Hongyu;Tao, Qian
目的：Wnt/β-catenin信号通路的异常激活与包括结直肠癌(CRC)在内的多种肿瘤有关。Wnt5A是非转化性Wnt蛋白家族的一员，其在肿瘤发生中的作用尚不明确。实验设计：我们检测了它在正常结肠、结直肠癌细胞系和肿瘤中的表达和甲基化。结果：由于启动子甲基化，Wnt5A在大多数大肠癌细胞系中被沉默，但在包括结肠在内的大多数正常组织中表达，在正常结肠上皮细胞中未发生甲基化。WNT5A的表达可以通过药物或基因去甲基化重新激活，这表明甲基化直接介导了它的沉默。WNT5A甲基化在结直肠癌中常见(14/29，48%)，但在配对的正常结肠组织中仅偶见(2/15，13%；P=0.025)。在沉默的结直肠癌细胞中异位表达Wnt5A，而不是WNT结构域缺失的无功能短异构体，可显著抑制肿瘤细胞的克隆性，这与细胞内β-连环蛋白水平下调和p-连环蛋白活性降低有关。结论：Wnt5A在结直肠癌中经常通过肿瘤特异性甲基化而失活，因此是一个潜在的生物标志物。Wnt5A可能通过拮抗Wnt/β-catenin信号而发挥肿瘤抑制作用。
Purpose: Aberrant activation of theWnt/beta-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 beta-catenin protein level and concomitant decrease in p-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 theWnt/beta-catenin signaling.