The Institute for Chemical Carcinogenesis, The State Key Lab of Respiratory Disease, Guangzhou Medical University, Guangzhou, PR China.
Hum Mutat. 2011 Nov;32(11):1299-308. doi: 10.1002/humu.21574. Epub 2011 Sep 19.
Peptidyl-prolyl cis/trans isomerase (PPIase), PIN1, has been found to be a critical catalyst that involves in multiple oncogenic signaling pathways. Recently, several putative functional polymorphisms of the PIN1 gene have been identified to be associated with cancer risk. In this study, we tested the hypothesis that two common polymorphisms, c.-842G>C (rs2233678) and c.-667C>T (rs2233679), in the PIN1 promoter are associated with risk of lung cancer. In two independent case-control studies of 1,559 lung cancer cases and 1,679 controls conducted in Southern and Eastern Chinese population, we found that compared with the most common c.-842GG genotype, the carriers of c.-842C variant genotypes (GC + CC) had a decreased risk of lung cancer (odds ratio [OR] = 0.63, 95% confidence interval [CI] = 0.51-0.78, p = 1.13 × 10(-5) ). Although no association was observed between the c.-667C>T polymorphism and cancer risk, we found that the haplotype "C-C" had a greater protective effect (OR = 0.39, 95% CI = 0.23-0.67, p = 5.03 × 10(-4) ). The stratification analysis showed that the protective role of c.-842C variants was more pronounced in current smokers (p = 4.45 × 10(-5) ), especially in male smokers (p = 6.71 × 10(-6) ) and in those who smoked more than 20 pack-years (p = 2.30 × 10(-5) ) and the c.-842C variant genotypes interacted with smoking status (P(interaction) = 0.019) or pack-years smoked (P(interaction) = 0.008) on reducing cancer risk. Further functional assay revealed that the c.-842C variant allele had a lower transcription activity in luciferase assay and a lower DNA-binding ability with nuclear proteins, and low transcription activity in western blot assay. In conclusions, our data suggest that functional c.-842C variants and haplotype "C-C" in the PIN1 promoter contribute to decreased risk of lung cancer by diminishing the promoter activity, which may be susceptibility biomarkers for lung cancer.
肽基脯氨酰顺/反式异构酶（PPIase）、PIN1 已被发现是一种关键的催化剂，涉及多种致癌信号通路。最近，已经鉴定出 PIN1 基因的几个假定功能多态性与癌症风险相关。在这项研究中，我们检验了假设，即 PIN1 启动子中的两个常见多态性 c.-842G>C（rs2233678）和 c.-667C>T（rs2233679）与肺癌风险相关。在在中国南方和东部进行的两项独立的 1559 例肺癌病例和 1679 例对照的病例对照研究中，我们发现与最常见的 c.-842GG 基因型相比，c.-842 变异基因型（GC + CC）的携带者患肺癌的风险降低（比值比[OR] = 0.63，95%置信区间[CI] = 0.51-0.78，p = 1.13×10(-5)）。尽管 c.-667C>T 多态性与癌症风险之间没有关联，但我们发现“C-C”单倍型具有更大的保护作用（OR = 0.39，95%CI = 0.23-0.67，p = 5.03×10(-4)）。分层分析表明，c.-842C 变体的保护作用在当前吸烟者中更为明显（p = 4.45×10(-5)），尤其是在男性吸烟者（p = 6.71×10(-6)）和吸烟超过 20 包年的吸烟者中（p = 2.30×10(-5)），c.-842C 变体基因型与吸烟状态（P(交互) = 0.019）或吸烟包年数（P(交互) = 0.008）相互作用降低癌症风险。进一步的功能测定显示，c.-842C 变体等位基因在荧光素酶测定中的转录活性较低，与核蛋白的 DNA 结合能力较低，在 Western blot 测定中的转录活性较低。总之，我们的数据表明，PIN1 启动子中的功能性 c.-842C 变体和“C-C”单倍型降低了肺癌的风险，降低了启动子活性，这可能是肺癌的易感性生物标志物。
