Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China.
Mol Carcinog. 2012 Feb;51(2):196-205. doi: 10.1002/mc.20801. Epub 2011 May 18.
Cyclin D1, with a common G/A polymorphism in rs9344, is an essential regulator of the G1 phase in cell cycles and plays an important role in several tumor types, and the homology of cyclin D1 with human papillomavirus (HPV)-16 E7 brought our attention to CCND1 gene in cervical cancer. A total of 738 native Chinese subjects consist of 327 cases and 411 controls were enrolled in this study. CCND1 genotyping was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and partially verified by sequencing of genomic DNA and cDNA. The transcription of cyclin D1 mRNA isoforms was analyzed by quantitative PCR; expression of protein isoforms by immunohistochemistry and Western blotting. We observed that the AA genotype had decreased risk of developing cervical cancer (odds ratio [OR] = 0.332; 95% confidence interval [CI] = 0.113-0.978; P = 0.045). The two mRNA isoforms were both transcripted from A and G allele. Transcript b decreased in squamous cell carcinoma of the uterine cervix (SCCUC) group (P = 0.004), especially poorly differentiated group (P = 0.004), and in G allele group of normal subjects (P = 0.001). In immunohistochemistry analysis, cyclins D1, D1a, and D1b failed to correlate with cervical cancer (P = 0.808, 0.445, and 0.095). However, cyclin D1b was downregulated in SCCUC group analyzed by Western blotting (P = 0.039). This study indicates that CCND1 rs9344 polymorphisms confer host susceptibility to cervical cancer. A allele possesses a relative protective effect probably through the cyclin D1b's inhibition on HPV carcinogenesis.
Cyclin D1 是细胞周期 G1 期的重要调节因子，其基因（CCND1）上存在一个常见的 G/A 多态性（rs9344），在多种肿瘤类型中发挥着重要作用。Cyclin D1 与人类乳头瘤病毒（HPV）-16 E7 的同源性引起了我们对宫颈癌中 CCND1 基因的关注。本研究共纳入 738 名中国本地受试者，包括 327 例病例和 411 例对照。通过聚合酶链反应-限制性片段长度多态性（PCR-RFLP）分析 CCND1 基因分型，并通过基因组 DNA 和 cDNA 测序部分验证。通过定量 PCR 分析 cyclin D1 mRNA 同工型的转录；通过免疫组织化学和 Western blot 分析蛋白同工型的表达。我们观察到 AA 基因型发生宫颈癌的风险降低（比值比 [OR] = 0.332；95%置信区间 [CI] = 0.113-0.978；P = 0.045）。两种 mRNA 同工型均由 A 和 G 等位基因转录。在子宫颈鳞状细胞癌（SCCUC）组中，b 转录本减少（P = 0.004），特别是低分化组（P = 0.004）和正常受试者的 G 等位基因组（P = 0.001）。在免疫组织化学分析中，cyclin D1、D1a 和 D1b 与宫颈癌无相关性（P = 0.808、0.445 和 0.095）。然而，Western blot 分析显示，SCCUC 组 cyclin D1b 下调（P = 0.039）。本研究表明，CCND1 rs9344 多态性赋予宿主对宫颈癌的易感性。A 等位基因可能具有相对保护作用，可能是通过 cyclin D1b 抑制 HPV 致癌作用。
