SFRP1 and SFRP2 suppress the transformation and invasion abilities of cervical cancer cells through Wnt signal pathway
SFRP1 and SFRP2 suppress the transformation and invasion abilities of cervical cancer cells through Wnt signal pathway
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DOI：
10.1016/j.ygyno.2008.10.026
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发表时间：
2009-03-01
影响因子：
4.7
通讯作者：
Lin, Ya-Wen
中科院分区：
文献类型：
--
作者：
Chung, Ming-Tzeung;Lai, Hung-Cheng;Lin, Ya-Wen
目标. Wnt/β-连环蛋白信号通路的异常激活在包括宫颈癌在内的人类癌症中很常见。分泌型卷曲相关蛋白（SFRPs）作为Wnt拮抗剂在肿瘤发生中发挥重要作用。最近，我们发现SFRP 1和SFRP 2经常通过启动子超甲基化下调。然而，SFRP 1和SFRP 2在宫颈癌中的作用尚不清楚。为了提高我们对SFRP 1和SFRP 2在宫颈癌细胞中作用的了解，我们在宫颈癌细胞系中使用过表达或shRNA方法。结果。SFRP 1和SFRP 2表达的恢复减弱了CaSki细胞中的Writ信号传导，减少了细胞核中游离β-连环蛋白的异常积累，并抑制了癌细胞生长。此外，观察到CaSki或HeLa 3rd细胞的细胞质中β-连环蛋白积累的不同状态，表明执行不同的Wnt途径。此外，我们证明了SFRP 1和SFRP 2通过抑制SLUG、TWIST和SNAIL（参与上皮间质转化（EMT）程序的三种转录因子）的表达来增强上皮标记物E-cadherin的表达。最后，在异种移植动物模型中，我们发现SFRP 1抑制体内癌细胞的致瘤性。总之，这些数据强烈表明，SFRP基因的表观遗传沉默导致Wnt通路的致癌激活，并通过EMT程序促进宫颈癌进展。(C)2008年爱思唯尔公司All rights reserved.
Objectives. Aberrant activation of the Wnt/beta-catenin signaling pathway is common in human cancers, including cervical cancer. The secreted frizzled-related proteins (SFRPs) function as Wnt antagonists and play important implications in carcinogenesis. Recently, we have shown that SFRP1 and SFRP2 are frequently downregulated through promoter hypermethylation. However, the function of SFRP1 and SFRP2 in cervical cancer remains unclear.Methods. To improve our understanding of the role of SFRP1 and SFRP2 in cervical cancer cells, we use overexpression or shRNA approach in cervical cancer cell lines.Results. Restoration of the expression of SFRP1 and SFRP2 attenuated Writ signaling in CaSki cells, decreased abnormal accumulation of free beta-catenin in the nucleus, and suppressed cancer cell growth. In addition, different statuses of beta-catenin accumulation in the cytoplasm of CaSki or HeLa3rd cells were observed, suggesting that different Wnt pathways are executed. Furthermore, we demonstrated that SFRP1 and SFRP2 enhance the expression of the epithelial marker E-cadherin, through inhibition of the expression of SLUG, TWIST and SNAIL, three transcription factors involved in the epithelial mesenchymal transition (EMT) program. Finally, in a xenograft animal model, we showed that SFRP1 suppresses tumorigenicity of cancer cells in vivo.Conclusions. Taken together, these data strongly suggest that epigenetic silencing of SFRP genes leads to oncogenic activation of the Wnt pathway and contributes to cervical cancer progression through the EMT program. (C) 2008 Elsevier Inc. All rights reserved.