Downregulation of WIF-1 and Wnt5a in patients with colorectal carcinoma: clinical significance
Downregulation of WIF-1 and Wnt5a in patients with colorectal carcinoma: clinical significance
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DOI：
10.1007/s13277-014-2015-9
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发表时间：
2014-08-01
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影响因子：
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通讯作者：
Mokdad-Gargouri, Raja
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作者：
Abdelmaksoud-Dammak, Rania;Miladi-Abdennadher, Imen;Mokdad-Gargouri, Raja
无翅型（Wnt）信号通路的激活在包括结直肠癌（CRC）在内的各种人类癌症中是常见的。Wnt抑制因子-1（WIF-1）是一种分泌型拮抗剂，可与Wnt配体结合，从而抑制Wnt信号通路。在这项研究中，我们的目的是分析两个成员的Wnt信号（WIF-1和Wnt 5a）在突尼斯散发性大肠癌患者的表达。WIF-1在肿瘤组织中的甲基化率为87.95%，而在正常粘膜中的甲基化率为39.54%，且与远处转移和血管浸润相关（P分别为0.001和0.037）。WIF-1启动子的非甲基化特征在总生存期方面为患者带来益处（P log rank = 0.024）。此外，在WIF-1启动子甲基化的患者组中，肿瘤尺寸小（< 5 cm）且无远处转移的患者的总体生存率显著延长（P log rank分别为0.007和0.036）。WIF-1启动子的异常CpG甲基化导致肿瘤组织中该肿瘤抑制基因的转录沉默（P = 0.001）。此外，我们还发现，与正常组织相比，肿瘤组织中Wnt 5a mRNA的水平显著降低（P = 0.031），并且在表现出更多侵袭性行为（存在淋巴结和晚期TNM分期）的组织中更低。我们的发现支持WIF-1经常甲基化，Wnt 5a在CRC中作为肿瘤抑制基因。WIF-1和Wnt 5a功能的丧失导致疾病的更具侵略性的行为。
Activation of the wingless-type (Wnt) signaling pathway is common in various human cancers including colorectal cancer (CRC). Wnt inhibitory factor-1 (WIF-1) is a secreted antagonist that can bind Wnt ligands and therefore inhibits the Wnt signaling pathway. In this study, we aimed to analyze the expression of two members of Wnt signaling (WIF-1 and Wnt5a) in Tunisian patients with sporadic CRC. WIF-1 was frequently methylated in tumor tissues (87.95 %) compared to normal mucosa (39.54 %) and correlated with distant metastasis and vascular invasion (P = 0.001 and 0.037, respectively). The unmethylated profile of the WIF-1 promoter conferred a benefit to patients in terms of overall survival (P log rank = 0.024). In addition, in the group of patients with methylated WIF-1 promoter, the overall survival rate was significantly prolonged for those with small tumor size (< 5 cm) and absence of distant metastasis (P log rank = 0.007 and 0.036, respectively). Aberrant CpG methylation of the WIF-1 promoter leads to transcriptional silencing of this tumor suppressor gene in tumor tissues (P = 0.001). Furthermore, we showed that the level of Wnt5a mRNA was significantly lower in tumor compared to normal tissues (P = 0.031) and lower still in those showing more aggressive behavior (presence of lymph nodes and advanced TNM stage). Our finding supports that WIF-1 is frequently methylated and that Wnt5a acts as a tumor suppressor gene in CRC. Loss of WIF-1 and Wnt5a functions results in more aggressive behavior of the disease.