WNT5A antagonizes WNT/β-catenin signaling and is frequently silenced by promoter CpG methylation in esophageal squamous cell carcinoma
WNT5A antagonizes WNT/β-catenin signaling and is frequently silenced by promoter CpG methylation in esophageal squamous cell carcinoma
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DOI：
10.4161/cbt.10.6.12609
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发表时间：
2010-09-15
影响因子：
3.6
通讯作者：
Tao, Qian
中科院分区：
文献类型：
--
作者：
Li, Jisheng;Ying, Jianming;Tao, Qian
WNT5A被归类为非转化性WNT家族成员，其在肿瘤发生中的作用尚不明确。它在某些癌症(甲状腺、脑、乳腺癌和结直肠癌)中表现出肿瘤抑制活性，但在肺癌、胃癌和前列腺癌中异常上调。我们研究了它在食管鳞癌(ESCC)中的表观遗传学改变和功能。半定量逆转录聚合酶链式反应分析发现，Wnt5A在18个食管鳞癌细胞系中有5个表达沉默或下调，而在正常食道组织和永生化的正常食道上皮细胞系中表达。在5个下调的ESCC细胞系中有4个检测到Wnt5A的启动子CpG甲基化，而5-氮-2‘-脱氧胞苷处理诱导了Wnt5A的表达并使其启动子去甲基化。WNT5A启动子甲基化在食管鳞癌组织中的表达频率较高(24/36，67%)，而在配对的手术切缘组织中表达较少(22%，P<0.01)，而在7例正常食管壁组织中均未检测到甲基化。异位表达Wnt5A可显著抑制ESC细胞的克隆形成和运动能力，并显著降低细胞内β-连环蛋白水平和转录活性。综上所述，我们发现Wnt5A在ESCC中经常被启动子甲基化沉默，并通过拮抗WNT/β-连环蛋白途径而显示出肿瘤抑制特性。因此，Wnt5A的表观遗传干扰将直接导致WNT/β-catenin信号在ESCC发病过程中的异常激活。
WNT5A is classified as a non-transforming WNT family member whose role in carcinogenesis is still ambiguous. It exhibits tumor suppressor activities in some cancers (thyroid, brain, breast and colorectum), but is aberrantly upregulated in cancers of lung, stomach and prostate. We investigated its epigenetic alterations and functions in esophageal squamous cell carcinoma (ESCC). With semi-quantitative reverse transcription PC R, we found that WNT5A was silenced or downregulated in 5 of 18 ESCC cell lines, but expressed in normal esophagus tissue and immortalized normal esophageal epithelial cell lines. Promoter CpG methylation of WNT5A was detected in 4 of the 5 downregulated ESCC cell lines, while 5-aza-2'-deoxycytidine treatment induced WNT5A expression and demethylated its promoter in silenced cell lines. WNT5A promoter methylation was frequently detected in primary ESCC (24/36, 67%), but less frequently and weakly in paired surgical marginal esophageal tissues (8/36, 22%; p < 0.01), while no methylation was detected in seven normal esophageal epithelial tissues from healthy donors. Ectopic expression of WNT5A resulted in significant inhibition of clonogenicity and motility of ESC cells, accompanied by a dramatic decrease of intracellular beta-catenin protein level and beta-catenin transcriptional activity. In summary, we show that WNT5A is frequently silenced in ESCC by promoter methylation and exhibits tumor suppressor properties through antagonizing the WNT/beta-catenin pathway. The epigenetic disruption of WNT5A would thus contribute directly to the aberrant activation of WNT/beta-catenin signaling during ESCC pathogenesis.