Objective: To explore the relationship between abnormal expression of fragile histidine triad (FHIT) gene and methyl-CpG-binding protein 2 (MeCP2) as well as their interaction on cervical cancerization. Methods: A total of 73 patients with cervical squamous cell carcinoma (SCC), 113 patients with cervical intraepithelial neoplasia (CIN Ⅰ, n=45; CINⅡ/Ⅲ, n=68) and 60 women with normal cervix (NC) were included in the study. Real time PCR and Western blot were performed to detect the expression levels of mRNA and protein about FHIT and MeCP2, respectively. The methylation status of FHIT gene CpG island was tested by methylation-specifc PCR (MSP). Kruskal-Wallis H test, χ(2) test, trend χ(2) test and Spearman correlation analysis were conducted with software SPSS 20.0. The interaction was evaluated by generalized multifactor dimensionality reduction (GMDR) model. Results: With the deterioration of cervical lesion, the methylation rates of FHIT gene CpG island (χ(2)=18.64, P<0.001; trend χ(2)=18.08, P<0.001) increased gradually, while the expression levels of FHIT mRNA (H=27.32, P<0.001; trend χ(2)=12.65, P<0.001) and protein (H=47.10, P<0.001; trend χ(2)=29.79, P<0.001) decreased gradually. There was a negative correlation between the methylation rates of FHIT gene CpG island and the expression level of FHIT protein (r=-0.226, P<0.001). The levels of MeCP2 mRNA (H=26.19, P<0.001; trend χ(2)=11.81, P=0.001) and protein (H=69.02, P<0.001; trend χ(2)=47.44, P<0.001) increased gradually with the aggravation of cervical lesions. There was a positive correlation between the expression level of MeCP2 protein and the FHIT mRNA Ct ratio (r=0.254, P<0.001). Expression of proteins were negatively correlated between MeCP2 and FHIT (r=-0.213, P=0.001). The results analyzed by GMDR model showed that there were interactions among high MeCP2 protein expression, the CpG island methylation of FHIT and mRNA and protein expression in CINⅡ/Ⅲ group, and among high MeCP2 mRNA and protein expression, the CpG island methylation of FHIT and low mRNA and protein expression in SCC group. Conclusion: High expression of MeCP2 mRNA and protein, the CpG island methylation and low mRNA and protein expression of FHIT could increase the risk of cervical carcinogenesis, and there might be a synergistic effect on cervical carcinogenesis.
目的： 探讨脆性组氨酸三联体（FHIT）与甲基-CpG-结合蛋白2（MeCP2）异常表达在宫颈癌变中的交互作用。 方法： 选择经病理学确诊的宫颈鳞状细胞癌（SCC）患者73例，宫颈上皮内瘤样变（CIN）患者113例（CINⅠ45例；CINⅡ/Ⅲ68例）和宫颈正常（NC）妇女60人作为研究对象，分别采用荧光定量PCR和Western blot检测宫颈组织中FHIT及MeCP2 mRNA和蛋白的表达量，甲基化特异性PCR（MSP）检测FHIT基因CpG岛甲基化状态。利用SPSS 20.0软件进行相关资料的Kruskal-Wallis H检验、χ(2)检验、χ(2)趋势检验和Spearman秩相关分析，应用广义多因子降维模型（GMDR）评价交互作用。 结果： 随着宫颈癌变的进展，FHIT基因CpG岛甲基化率（χ(2)=18.64，P<0.001，趋势检验χ(2)=18.08，P<0.001）逐渐升高，FHIT mRNA（H=27.32，P<0.001；趋势检验χ(2)=12.65，P<0.001）与蛋白（H=47.10，P<0.001；趋势检验χ(2)=29.79，P<0.001）表达量逐渐降低，且FHIT基因CpG岛甲基化率与FHIT蛋白表达量呈负相关（r=-0.226，P<0.001）。MeCP2 mRNA（H=26.19，P<0.001；趋势检验χ(2)=11.81，P=0.001）与蛋白（H=69.02，P<0.001；趋势检验χ(2)=47.44，P<0.001）表达量均逐渐升高。MeCP2蛋白表达量与FHIT mRNA Ct比值呈正相关（r=0.254，P<0.001），与FHIT蛋白表达量呈负相关（r=-0.213，P=0.001）。GMDR交互作用分析表明，在CINⅡ/Ⅲ组，MeCP2蛋白高表达、FHIT基因CpG岛甲基化及mRNA和蛋白低表达存在交互作用；在SCC组，MeCP2 mRNA和蛋白高表达、FHIT基因CpG岛甲基化及mRNA和蛋白低表达存在交互作用。 结论： MeCP2 mRNA和蛋白高表达、FHIT基因CpG岛甲基化及mRNA和蛋白低表达，均可增加宫颈癌变的风险，且在宫颈癌变中具有协同作用。.
Keywords: Cervical carcinogenesis; Fragile histidine triad; Methyl-CpG-binding protein 2.