Lin Jia, Zhang Yanyan, Wang Hongge, Chang Jiang, Wei Lixuan, Cao Lei, Zhang Zhi, Zhang Xuemei
Department of Molecular Genetics, College of Life Science, North China University of Science and Technology, Tangshan, China.
Department of Epidemiology, School of Public Health, North China University of Science and Technology, Tangshan, China.
PLoS One. 2016 Oct 10;11(10):e0164358. doi: 10.1371/journal.pone.0164358. eCollection 2016.
Caspase-3 (CASP3) plays a central role in executing cell apoptosis and thus in carcinogenesis. We previously investigated the relationship between functional polymorphisms in CAPS3 829 A>C and 20541 C>T and risk of esophageal squamous cell carcinoma. However little is known about the role of CASP3 variants in susceptibility to lung cancer. To figure out the contribution of CASP3 polymorphisms to lung cancer risk, genotypes of 1000 lung cancer patients and 1000 controls were conducted by RFLP-PCR (restriction fragment length polymorphism PCR). The transcriptional activity of CASP3 829 A>C was examined by dual luciferase reporter assay. Logistic regression was applied to calculate Odds ratios (OR) and 95% confidence intervals (95%CI). Compared with CASP3 829 AA genotype, AC and CC genotype had significantly increased risk of lung cancer with OR (95% CI) of 1.33 (1.09-1.63) and 1.55 (1.19-2.01), respectively. To further explore the possible impact of 829 A>C SNP on CASP3 transcriptional activity, we detected the dual luciferase activity of PGL3-promoter vectors containing 829A or 829C alleles in lung cancer cell lines and found that report gene expressions driven by 829A containing CASP3 promoter were 1.64-fold, 1.94-fold greater than those driven by CASP3 829C containing counterparts in A549 and NCI-H1975 cells (P<0.001). When stratified by sex, the significantly increased risk associated with CASP3 829 AC or CC genotype was obviousl in males with OR (95% CI) of 1.42 (1.11-1.81) and 1.51 (1.11-2.05), but not in females. When stratified by age, we found that CASP3 829 AC or CC genotype contributed to the risk of lung cancer in youngers with OR (95% CI) of 2.73 (1.71-4.34) and 4.02 (2.20-7.32), but not in elder group. We also found that 829AC or 829CC genotype increased adenocarcinoma risk compared with the AA genotype with OR (95%CI) of 1.33 (1.04-1.70) and 1.51(1.09-2.07). CASP3 polymorphism and smoking interaction was demonstrated related with higher risk of lung cancer. We achieved that the CASP3 829AC or 829CC genotypes was associated with increased risk of lung cancer in both non-smoker and smoker group, with OR (95%CI) of 1.48 (1.08-2.02) and OR (95%CI) of 1.64 (1.09-2.48) among non-smokers and OR (95%CI) of 2.68 (1.89-3.81) and OR (95%CI) of 3.23 (2.21-4.92) among smokers, respectively. Among carriers with 20541CT genotype, the ORs (95%CI) of risk with lung cancer for smoking <16, 16-28, or > 28 pack-years were 1.16(0.65-2.07), 1.66(0.98-2.82) and 5.01(3.31-7.58) compared with the 20541CC carriers. And among carriers with 20541CT genotype, the ORs (95%CI) were 0.86(0.33-2.20), 2.12(0.83-5.41) and 5.71(2.68-12.16). These results highlight apoptosis-related CASP3 as an important gene in human carcinogenesis and further support the CASP3 polymorphisms confer to the lung cancer susceptibility.
半胱天冬酶 -3（CASP3）在执行细胞凋亡从而在致癌过程中发挥核心作用。我们之前研究了CASP3 829 A>C和20541 C>T功能多态性与食管鳞状细胞癌风险之间的关系。然而，关于CASP3变体在肺癌易感性中的作用知之甚少。为了弄清楚CASP3多态性对肺癌风险的影响，采用限制性片段长度多态性聚合酶链反应（RFLP-PCR）对1000例肺癌患者和1000例对照进行基因分型。通过双荧光素酶报告基因检测法检测CASP3 829 A>C的转录活性。应用逻辑回归计算比值比（OR）和95%置信区间（95%CI）。与CASP3 829 AA基因型相比，AC和CC基因型患肺癌的风险显著增加，OR（95%CI）分别为1.33（1.09 - 1.63）和1.55（1.19 - 2.01）。为了进一步探究829 A>C单核苷酸多态性（SNP）对CASP3转录活性的可能影响，我们在肺癌细胞系中检测了含有829A或829C等位基因的PGL3 - 启动子载体的双荧光素酶活性，发现含有829A的CASP3启动子驱动的报告基因表达在A549和NCI - H1975细胞中比含有829C的对应物驱动的表达分别高1.64倍和1.94倍（P<0.001）。按性别分层时，与CASP3 829 AC或CC基因型相关的显著增加的风险在男性中明显，OR（95%CI）为1.42（1.11 - 1.81）和1.51（1.11 - 2.05），而在女性中不明显。按年龄分层时，我们发现CASP3 829 AC或CC基因型在年轻人中增加了患肺癌的风险，OR（95%CI）为2.73（1.71 - 4.34）和4.02（2.20 - 7.32），而在老年组中不增加。我们还发现与AA基因型相比，829AC或829CC基因型增加了腺癌风险，OR（95%CI）为1.33（1.04 - 1.70）和1.51（1.09 - 2.07）。CASP3多态性与吸烟的相互作用被证明与较高的肺癌风险相关。我们发现，在非吸烟者和吸烟者组中，CASP3 829AC或829CC基因型均与肺癌风险增加相关，非吸烟者中的OR（95%CI）为1.48（1.08 - 2.02），吸烟者中的OR（95%CI）为1.64（1.09 - 2.48）；在吸烟者中，OR（95%CI）分别为2.68（1.89 - 3.81）和3.23（2.21 - 4.92）。在携带20541CT基因型的人群中，与20541CC携带者相比，吸烟<16、16 - 28或>28包年的肺癌风险OR（95%CI）分别为1.16（0.65 - 2.07）、1.66（0.98 - 2.82）和5.01（3.31 - 7.58）。在携带20541CT基因型的人群中，OR（95%CI）分别为0.86（0.33 - 2.20）、2.12（0.83 - 5.41）和5.71（2.68 - 12.16）。这些结果突出了与凋亡相关的CASP3作为人类致癌过程中的一个重要基因，并进一步支持CASP3多态性赋予肺癌易感性。
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