Functional regulatory variants of MCL1 contribute to enhanced promoter activity and reduced risk of lung cancer in nonsmokers: Implications for context-dependent phenotype of an antiapoptotic and antiproliferative gene in solid tumor

摘要

Background: 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. Methods: 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. Results: 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). Conclusions: 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.