Functional genetic variants of c-Jun and their interaction with smoking and drinking increase the susceptibility to lung cancer in southern and eastern Chinese
Functional genetic variants of c-Jun and their interaction with smoking and drinking increase the susceptibility to lung cancer in southern and eastern Chinese
复制标题
c-Jun的功能性遗传变异及其与吸烟和饮酒的相互作用增加了中国南部和东部地区肺癌的易感性
DOI：
10.1002/ijc.27407
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发表时间：
2012-09-01
影响因子：
6.4
通讯作者：
Lu, Jiachun
中科院分区：
文献类型：
--
作者：
Huang, Binfang;Liu, Bin;Lu, Jiachun
人原癌基因c-Jun和c-Fos组成激活蛋白-1复合物，是一种应答环境因子的关键转录因子，促进肿瘤的发生。我们假设这两个基因的遗传变异可能会改变携带者对肺癌的易感性。在两项独立的病例对照研究中，我们对中国南方人群中的三个假定的功能多态性（c-Jun的-1318T>G和-673T>C; c-Fos的-60C>T）进行了基因分型，然后验证了中国东部人群中的相关性。我们发现，与-1318TT基因型相比，-1318GT/GG变异基因型具有更高的肺癌风险（OR = 1.46，95%CI = 1.26 ± 1.69），且-673CC基因型较-673TT/CT基因型有更高的肺癌风险（OR = 1.35，95%CI = 1.17 ± 1.56）。将这两个基因座组合后，风险基因型的数量与癌症风险的增加呈剂量-反应关系（p趋势= 2.21 × 10（-11））;此外，风险基因型与吸烟或饮酒状态在增加癌症风险方面相互作用（p值分别为0.009和0.007）。进一步研究发现，c-Jun-1318 GT/GG基因型、-673 CC基因型或两种基因型同时存在的突变体在体内的mRNA和蛋白表达水平较高，在体外的报告基因转录活性较高，特别是在烟草提取物或酒精混合物的刺激下，荧光素酶检测结果显示。然而，对于c-Fos的-60 C>T，未观察到与肺癌风险的显著关联。我们的数据表明，c-Jun的遗传变异（-1318T>G和-673T>C）通过与吸烟或饮酒相互作用增加c-Jun的表达而增加携带者对肺癌的易感性。
Human proto-oncogene c-Jun and c-Fos assemble the activator protein-1 complex which is a crucial transcription factor responding to environmental factors and promotes tumorgenesis. We hypothesized that genetic variants in these two genes may alter the carriers' susceptibility to lung cancer. In two independent casecontrol studies, we genotyped three putative functional polymorphisms (-1318T>G and -673T>C of c-Jun; -60C>T of c-Fos) in southern Chinese and then validated the association in eastern Chinese. We found that compared to -1318TT genotype, the -1318GT/GG variant genotypes had an increased lung cancer risk (OR = 1.46, 95% CI = 1.261.69), and the -673CC genotype had an increased lung cancer risk compared to -673TT/CT genotypes (OR = 1.35, 95% CI = 1.171.56) in the total 1,559 cases versus 1,679 controls. After combining these two loci, the number of the risk genotypes was associated with increased cancer risk in a dose-response manner (ptrend = 2.21 x 10(-11)); moreover, the risk genotypes interacted with smoking or drinking status on increasing cancer risk (p values of interaction were 0.009 and 0.007, respectively). Further, we found that those with -1318GT/GG genotypes, -673CC genotypes or both genotypes in c-Jun had higher mRNA and protein expression levels in vivo, and those variants had higher transcription activities in reporter genes in vitro, especially under the stimuli with tobacco extract or alcohol mixture as luciferase assay shown. However, for -60C>T of c-Fos, no significant association was observed for lung cancer risk. Our data suggested that the genetic variants in c-Jun (-1318T>G and -673T>C) increase the carriers' susceptibility to lung cancer via interaction with smoking or drinking on increasing the c-Jun's expression.