Li Qiaoling, Ding Ling, Jing Nan, Liu Chunliang, Yang Zuokai, Chen Fang, Hou Lifang, Wang Jintao
Department of Epidemiology, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China.
Department of Preventive Medicine, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Oncol Lett. 2018 Feb;15(2):1963-1972. doi: 10.3892/ol.2017.7471. Epub 2017 Nov 22.
Aberrant DNA methylation is a recognized feature in various types of human cancer, and folate has a vital role in the epigenetics of mammalian cells by supplying methyl groups for DNA methylation reactions. Fragile histidine triad (FHIT) is a tumor suppressor gene that is frequently silenced in cervical cancer (CC) and preneoplastic lesions. Promoter hypermethylation was previously observed in CC, and its epigenetic silencing has been observed at mRNA or protein levels. Changes in folate intake to modulate DNA methylation may be a mechanistic link to cancer, but this remains to be elucidated. The aim of the present study was to evaluate the influences of folate on FHIT gene methylation and expression in the progression of cervical cancerization. In the present study, red blood cell (RBC) folate levels, FHIT gene methylation status, and mRNA and protein expression levels were detected in 254 women, including normal cervix (NC, n=80), cervical intraepithelial neoplasm grade 1 (CIN1, n=55; CIN2/3, n=55) and cervical squamous cell carcinoma (SCC, n=64) samples. The methylation status of FHIT gene and its mRNA and protein expression levels were measured in CaSki (HPV16 positive) and C33A (HPV16 negative) CC cells treated with different concentrations of folate. The results indicated that FHIT gene methylation rate increased with the severity of cervix lesions, however, RBC folate levels, FHIT mRNA and protein expression levels were reduced. The proliferation inhibition rate, apoptosis rate, and FHIT protein and mRNA expression levels increased along with rising concentrations of folate, whereas the degree of FHIT gene methylation gradually weakened in CaSki or C33A cell lines. The present findings indicated that folate deficiency, FHIT gene promoter hypermethylation and reduced expression were significantly associated with cervical carcinogenesis. The results indicated that folate was able to enhance apoptosis and inhibit the cervical cell proliferation while regulating FHIT gene methylation and expression. Adequate intake of folate to maintain normal DNA methylation status is an effective way for cervical lesions prevention, and demethylation treatment may offer a new strategy for therapy of CC.
异常的DNA甲基化是各类人类癌症的一个公认特征，而叶酸通过为DNA甲基化反应提供甲基基团，在哺乳动物细胞的表观遗传学中发挥着至关重要的作用。脆性组氨酸三联体（FHIT）是一种肿瘤抑制基因，在宫颈癌（CC）及癌前病变中常发生沉默。此前在CC中观察到启动子高甲基化，并且在mRNA或蛋白质水平上也观察到其表观遗传沉默。通过改变叶酸摄入量来调节DNA甲基化可能是与癌症相关的一种机制联系，但这一点仍有待阐明。本研究的目的是评估叶酸对宫颈癌发生发展过程中FHIT基因甲基化和表达的影响。在本研究中，检测了254名女性的红细胞（RBC）叶酸水平、FHIT基因甲基化状态以及mRNA和蛋白质表达水平，这些女性的样本包括正常宫颈（NC，n = 80）、宫颈上皮内瘤变1级（CIN1，n = 55；CIN2/3，n = 55）以及宫颈鳞状细胞癌（SCC，n = 64）。在用不同浓度叶酸处理的CaSki（HPV16阳性）和C33A（HPV16阴性）CC细胞中，检测了FHIT基因的甲基化状态及其mRNA和蛋白质表达水平。结果表明，FHIT基因甲基化率随宫颈病变严重程度增加而升高，然而，RBC叶酸水平、FHIT mRNA和蛋白质表达水平却降低。随着叶酸浓度升高，CaSki或C33A细胞系中的增殖抑制率、凋亡率以及FHIT蛋白质和mRNA表达水平均升高，而FHIT基因甲基化程度逐渐减弱。本研究结果表明，叶酸缺乏、FHIT基因启动子高甲基化以及表达降低与宫颈癌发生显著相关。结果表明，叶酸能够增强凋亡并抑制宫颈细胞增殖，同时调节FHIT基因甲基化和表达。摄入足够的叶酸以维持正常的DNA甲基化状态是预防宫颈病变的有效方法，而去甲基化治疗可能为CC的治疗提供一种新策略。
