State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China.
Cancer. 2012 Apr 15;118(8):2085-95. doi: 10.1002/cncr.26502. Epub 2011 Sep 1.
Dysfunction of molecules that regulate both apoptosis and proliferation is involved in tumorigenesis. A common insertional polymorphism in promoter of MCL1, a member of BCL2 family gene with the dual regulatory functions, has been shown to be functional in leukemia, but its association with cancer predisposition and prognosis has not been well established. We hypothesized that MCL1 promoter variants may modify risk of solid cancer.
We genotyped -190 insertional polymorphism and 3 linked single nucleotide polymorphisms (SNPs) (-627A>C, -298G>C, and -235C>A) in 320 lung cancer patients and 362 controls, and analyzed their functional significance.
We confirmed that these regulatory variants correlated with enhanced promoter activity and elevated expression of both mRNA and protein in solid cancer cells and tissues. We further demonstrated that heightened expression of MCL1 resulted in decreased proliferation ability of lung cancer cells. We found a reduced cancer risk (adjusted odds ratio [OR] = 0.47; 95% confidence interval [CI] = 0.25-0.88) associated with -190 insertional genotype. Stratification analysis further showed pronounced associations in nonsmokers (OR, 0.25; 95% CI, 0.09-0.70), in females (OR, 0.22; 95% CI, 0.07-0.74), and in the histological type of adenocarcinoma (OR, 0.18; 95% CI, 0.05-0.62). Likewise, homologous diplotype of these polymorhpisms that positively affected gene expression was associated with reduced risk in nonsmokers (OR, 0.19; 95% CI, 0.06-0.58).
The present study demonstrated that common variants in MCL1 promoter correlated with increased transactivation in solid cancer cells and were associated with reduced risk of lung cancer in nonsmokers, suggesting a dominant antiproliferative function of MCL1 against its antiapoptosis effect in development of solid cancer in nonsmokers.
调节细胞凋亡和增殖的分子功能障碍与肿瘤发生有关。BCL2 家族基因成员 MCL1 的启动子中的常见插入多态性具有双重调节功能，已被证明在白血病中具有功能，但与癌症易感性和预后的关系尚未得到很好的确定。我们假设 MCL1 启动子变异可能会改变实体癌的风险。
我们对 320 名肺癌患者和 362 名对照者的 -190 插入多态性和 3 个连锁单核苷酸多态性（-627A>C、-298G>C 和 -235C>A）进行了基因分型，并分析了它们的功能意义。
我们证实这些调节变异与实体癌细胞和组织中增强的启动子活性和 MCL1 mRNA 和蛋白的高表达相关。我们进一步证明 MCL1 的高表达导致肺癌细胞增殖能力降低。我们发现癌症风险降低（调整后的比值比[OR] = 0.47；95%置信区间[CI] = 0.25-0.88）与 -190 插入基因型相关。分层分析进一步显示，在不吸烟者（OR，0.25；95%CI，0.09-0.70）、女性（OR，0.22；95%CI，0.07-0.74）和腺癌组织学类型（OR，0.18；95%CI，0.05-0.62）中，关联更为显著。同样，这些多态性的同源二倍型对基因表达有积极影响，与不吸烟者的低风险相关（OR，0.19；95%CI，0.06-0.58）。
本研究表明，MCL1 启动子中的常见变异与实体癌细胞中的转录激活增强相关，与不吸烟者肺癌风险降低相关，提示 MCL1 在不吸烟者实体癌发生过程中的抗增殖作用可能超过其抗凋亡作用。
