Chung Ming-Tzeung, Sytwu Huey-Kang, Yan Ming-De, Shih Yu-Lueng, Chang Cheng-Chang, Yu Mu-Hsien, Chu Tang-Yuan, Lai Hung-Cheng, Lin Ya-Wen
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
Gynecol Oncol. 2009 Feb;112(2):301-6. doi: 10.1016/j.ygyno.2008.10.004. Epub 2008 Nov 26.
Oncogenic activation of the Wnt/beta-catenin signaling pathway is common in human cancers, including cervical cancer. The secreted frizzled-related proteins (SFRPs) function as negative regulators of Wnt signaling and play an important role in carcinogenesis. Frequent promoter hypermethylation of SFRPs has been identified in human cancers; however, the precise role of SFRPs in cervical cancer is not clear.
The methylation status of SFRPs gene family was analyzed in two cervical cancer cell lines and a full spectrum of cervical neoplasia, including 45 low-grade squamous intraepithelial lesions (LSIL), 49 high-grade squamous intraepithelial lesions (HSIL), 109 squamous cell carcinomas (SCC), and 45 normal controls.
The SFRP1 promoter was hypermethylated in 33.9% of SCC, 8.2% of HSIL, 2.2% of LSIL, but not in normal tissues. The SFRP2 promoter was hypermethylated in 80.7% of SCC, 16.3% of HSIL, 15.6% LSIL and 4.4% normal tissues. The SFRP4 promoter was hypermethylated in 67.9% of SCC, 36.7% of HSIL, 4.4% of LSIL, but not in normal tissues. The SFRP5 promoter was hypermethylated in 10.1% of SCC, 4.1% of HSIL, 13.3% of LSIL and 4.4% normal tissues. The frequency of SFRP1, SFRP2 and SFRP4 promoter methylation in tumors was significantly higher than in normal, LSIL, and HSIL samples (P<0.0001). SFRP5 methylation was significantly different in patients with or without lymph-node metastases (0% vs 15.2%, respectively, P<0.05).
Our data suggest that promoter hypermethylation of SFRP1, SFRP2 and SFRP4 is associated with cervical carcinogenesis, which could be used for molecular screening of cervical neoplasias in future.
Wnt/β-连环蛋白信号通路的致癌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信号的负调节因子，在致癌过程中起重要作用。在人类癌症中已发现SFRPs启动子频繁发生高甲基化；然而，SFRPs在宫颈癌中的具体作用尚不清楚。
分析了两种宫颈癌细胞系以及一系列宫颈肿瘤（包括45例低级别鳞状上皮内病变（LSIL）、49例高级别鳞状上皮内病变（HSIL）、109例鳞状细胞癌（SCC）和45例正常对照）中SFRPs基因家族的甲基化状态。
SFRP1启动子在33.9%的SCC、8.2%的HSIL、2.2%的LSIL中发生高甲基化，但在正常组织中未发生。SFRP2启动子在80.7%的SCC、16.3%的HSIL、15.6%的LSIL和4.4%的正常组织中发生高甲基化。SFRP4启动子在67.9%的SCC、36.7%的HSIL、4.4%的LSIL中发生高甲基化，但在正常组织中未发生。SFRP5启动子在10.1%的SCC、4.1%的HSIL、13.3%的LSIL和4.4%的正常组织中发生高甲基化。肿瘤中SFRP1、SFRP2和SFRP4启动子甲基化的频率显著高于正常、LSIL和HSIL样本（P<0.0001）。SFRP5甲基化在有或无淋巴结转移的患者中存在显著差异（分别为0%和15.2%，P<0.05）。
我们的数据表明，SFRP1、SFRP2和SFRP4启动子的高甲基化与宫颈癌发生相关，未来可用于宫颈肿瘤的分子筛查。
