叶酸与p16蛋白在宫颈癌变中的作用及其相互效应

贾吴琳; 丁玲; 任志英; 吴婷婷; 赵维敏; 樊石磊; 王金桃

Abstract

贾吴琳,丁玲,任志英,吴婷婷,赵维敏,樊石磊,王金桃.叶酸与p16蛋白在宫颈癌变中的作用及其相互效应[J].Chinese journal of Epidemiology,2016,37(12):1647-1652

叶酸与p16蛋白在宫颈癌变中的作用及其相互效应

Effects of both folic acid, p16 protein expression and their interaction on progression of cervical cancerization

Received:June 07, 2016

DOI：10.3760/cma.j.issn.0254-6450.2016.12.018

KeyWord: 叶酸 p16蛋白宫颈癌变交互作用

English Key Word: Folate p16 protein Cervical carcinoma Interaction

FundProject:国家自然科学基金（30872166，81273157，81473060）；国家卫生和计划生育委员会公益性行业科研专项（201402010）；山西省优势和特色重点学科建设项目

Author Name	Affiliation	E-mail
Jia Wulin	Department of Epidemiology, School of Public Health, Shanxi Medical University, Taiyuan 030001, China
Ding Ling	Department of Epidemiology, School of Public Health, Shanxi Medical University, Taiyuan 030001, China
Ren Zhiying	Community Health Center, Shanxi Cardiovascular Hospital, Taiyuan 030001, China
Wu Tingting	Department of Epidemiology, School of Public Health, Shanxi Medical University, Taiyuan 030001, China
Zhao Weimin	Department of Epidemiology, School of Public Health, Shanxi Medical University, Taiyuan 030001, China
Fan Shilei	Department of Epidemiology, School of Public Health, Shanxi Medical University, Taiyuan 030001, China
Wang Jintao	Department of Epidemiology, School of Public Health, Shanxi Medical University, Taiyuan 030001, China	wangjt59@163.com

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Abstract:

目的探讨叶酸与p16蛋白在宫颈癌变中的作用及其相互效应。方法选取经病理学确诊的80例正常宫颈（NC）妇女、55例低度宫颈上皮内瘤样变（CINⅠ）患者、55例高度宫颈上皮内瘤样变（CINⅡ/Ⅲ）患者、64例宫颈鳞状细胞癌（SCC）患者为研究对象。分别采用微生物法和Western-blot方法检测其血清叶酸水平和p16蛋白的表达量。同时采用体外细胞实验研究方法，对HPV阴性的宫颈癌细胞C33A和HPV16阳性的宫颈癌细胞Caski进行不同浓度叶酸干预，检测两种宫颈癌细胞的增殖和凋亡情况，以及p16蛋白的表达。结果 NC组、CINⅠ组、CINⅡ/Ⅲ组和SCC组血清叶酸含量分别为（5.96±3.93） ng/ml、（5.08±3.43） ng/ml、（3.92±2.59） ng/ml、（3.18±2.71） ng/ml，p16蛋白表达水平分别为0.80±0.32、1.33±0.52、1.91±0.77、2.09±0.72；随着宫颈病变的进展，血清叶酸含量逐渐降低（趋势检验 χ²=32.71，P<0.001），p16蛋白表达量逐渐升高（趋势检验 χ²=56.06，P<0.001）。在CINⅠ、CINⅡ/Ⅲ、SCC组中血清叶酸缺乏与p16蛋白高表达均存在正相加交互作用。体外实验结果显示，随着叶酸浓度的增加，宫颈癌细胞的增殖抑制率（C33A：r=0.928，P=0.003；Caski：r=0.962，P=0.001）和凋亡率（C33A：r=0.984，P<0.001；Caski：r=0.986，P<0.001）均上升，p16蛋白表达量逐渐降低（C33A：r=-0.817，P=0.025；Caski：r=-0.871，P=0.011），且p16蛋白表达量与宫颈癌细胞的增殖抑制率（C33A：r=-0.935，P=0.002；Caski：r=-0.963，P=0.001）和凋亡率（C33A：r=-0.844，P=0.017；Caski：r=-0.898，P=0.006）均呈负相关关系。结论血清叶酸缺乏与p16蛋白高表达均可增加宫颈癌和癌前病变的发病风险，两者在宫颈癌和癌前病变中存在正相加交互作用。补充叶酸可逆转p16蛋白的异常表达，有效抑制宫颈癌细胞的增殖，促进凋亡。

English Abstract:

Objective To explore the effects of both folic acid, p16 protein expression and their interaction on progression of cervical cancerization. Methods Participants were pathologically diagnosed new cases, including 80 women with normal cervical (NC), 55 patients with low-grade cervical intraepithelial neoplasia (CINⅠ), 55 patients with high-grade cervical intraepithelial neoplasia (CINⅡ/Ⅲ) and 64 patients with cervical squamous cell carcinoma (SCC). Serum folate levels were detected by microbiological assay method while p16 protein expression levels were measured by Western-blot. In vitro, cervical cancer cell lines C33A (HPV negative) and Caski (HPV16 positive) were treated with different concentrations of folate. Proliferation and apoptosis of cells and the levels of p16 protein expression were measured in groups with different folic acid concentrations. Results Results showed that the levels of serum folate were (5.96±3.93) ng/ml, (5.08±3.43) ng/ml, (3.92±2.59) ng/ml and (3.18±2.71) ng/ml, and the levels of p16 protein were 0.80±0.32, 1.33±0.52, 1.91±0.77, and 2.09±0.72 in the group of NC, CINⅠ, CINⅡ/Ⅲ and SCC, respectively. However, the levels of serum folate decreased (trend χ²=32.71, P<0.001) and p16 protein expression increased (trend χ²=56.06, P<0.001) gradually along with the severity of cervix lesions. An additive interaction was seen between serum folate deficiency and high expression of p16 protein in the CINⅠ, CINⅡ/Ⅲ and SCC group. Results in vitro showed that, with the increase of folate concentration, the inhibition rate of cell proliferation (C33A:r=0.928, P=0.003; Caski:r=0.962, P=0.001) and the rate on cell apoptosis (C33A:r=0.984, P<0.001; Caski:r=0.986, P<0.001) all increased but the levels of p16 protein expression (C33A:r=-0.817, P=0.025; Caski:r=-0.871, P=0.011) reduced. The proliferation inhibition rate (C33A:r=-0.935, P=0.002; Caski:r=-0.963, P=0.001) and apoptosis rate of cells (C33A:r=-0.844, P=0.017; Caski:r=-0.898, P=0.006) were negatively correlated with the levels of p16 protein expression. Conclusions Our findings indicated that both serum folate deficiency and high expression of p16 protein could increase the risk of cervical cancer and cervix precancerous lesion, and there was an additive interaction between them. Our findings suggested that folic acid supplementation could reverse the abnormal expression of p16 protein, and effectively promote apoptosis and inhibit proliferation in cervical carcinoma cells.

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