Chung Ming-Tzeung, Lai Hung-Cheng, Sytwu Huey-Kang, Yan Ming-De, Shih Yu-Lueng, Chang Cheng-Chang, Yu Mu-Hsien, Liu Hang-Seng, Chu Da-Wei, Lin Ya-Wen
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
Gynecol Oncol. 2009 Mar;112(3):646-53. doi: 10.1016/j.ygyno.2008.10.026. Epub 2008 Dec 18.
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.
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.
Restoration of the expression of SFRP1 and SFRP2 attenuated Wnt 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.
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.
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（SFRP）作为Wnt拮抗剂发挥作用，并在致癌过程中具有重要意义。最近，我们发现SFRP1和SFRP2经常通过启动子高甲基化而下调。然而，SFRP1和SFRP2在宫颈癌中的功能仍不清楚。
为了更好地理解SFRP1和SFRP2在宫颈癌细胞中的作用，我们在宫颈癌细胞系中采用过表达或短发夹RNA（shRNA）方法。
SFRP1和SFRP2表达的恢复减弱了CaSki细胞中的Wnt信号，减少了细胞核中游离β-连环蛋白的异常积累，并抑制了癌细胞的生长。此外，在CaSki或HeLa3rd细胞的细胞质中观察到β-连环蛋白积累的不同状态，这表明执行了不同的Wnt信号通路。此外，我们证明SFRP1和SFRP2通过抑制参与上皮-间质转化（EMT）程序的三种转录因子SLUG、TWIST和SNAIL的表达，增强了上皮标志物E-钙黏蛋白的表达。最后，在异种移植动物模型中，我们表明SFRP1在体内抑制癌细胞的致瘤性。
综上所述，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。
