Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou 215123, China.
Int J Cancer. 2012 May 1;130(9):1981-90. doi: 10.1002/ijc.26253. Epub 2011 Aug 25.
MKK4 is a candidate tumor suppressor, which acts as a critical mediator of Epstein-Barr Virus (EBV)-induced c-Jun N-terminal kinase (JNK) activation. Functional polymorphism MKK4 -1304T>G has been showed to be protective in colorectal cancer or lung cancer. We hypothesized that genetic variants in the MKK4 promoter were associated with the risk of nasopharyngeal carcinoma (NPC). Two common polymorphisms in MKK4, -1304T>G and -1044A>T were genotyped in two independent case-control panels of Eastern and Southern Chinese populations, totally containing 1237 NPC and 1328 controls. We found that compared to the most common -1304TT genotype, carriers of variant genotypes (-1304TG+GG) were associated with a significantly reduced risk for NPC in total subjects (adjusted OR = 0.78; 95%CI = 0.67-0.94). Further stratification analysis showed that the protective effect was more pronounced in EBV negative status (adjusted OR = 0.51; 95%CI = 0.41-0.68) but restrained in those with EBV infection (adjusted OR = 1.05; 95%CI = 0.88-1.26), and that the -1304GG variant genotypes interacted with EBV negative status on reducing cancer risk (p = 0.011). However, no significant association was observed between the -1044A>T polymorphism and risk of NPC. Our data suggest that the protective role of genetic variant MKK4 -1304T>G is restrained in NPC with EBV infection. These findings implicate the role of EBV and MKK4 -1304 T>G interaction as a causative factor for the NPC.
MKK4 是一种候选肿瘤抑制因子，作为 Epstein-Barr 病毒（EBV）诱导的 c-Jun N 末端激酶（JNK）激活的关键介质。已显示功能性多态性 MKK4-1304T>G 在结直肠癌或肺癌中具有保护作用。我们假设 MKK4 启动子中的遗传变异与鼻咽癌（NPC）的风险相关。在两个独立的中国东部和南部人群病例对照研究中，对 MKK4 的两个常见多态性，-1304T>G 和-1044A>T 进行了基因分型，总共包含 1237 例 NPC 和 1328 例对照。我们发现，与最常见的-1304TT 基因型相比，变异基因型（-1304TG+GG）的携带者患 NPC 的风险显著降低（调整后的 OR=0.78；95%CI=0.67-0.94）。进一步的分层分析表明，在 EBV 阴性状态下，保护作用更为明显（调整后的 OR=0.51；95%CI=0.41-0.68），但在 EBV 感染患者中受到限制（调整后的 OR=1.05；95%CI=0.88-1.26），并且-1304GG 变异基因型与 EBV 阴性状态相互作用可降低癌症风险（p=0.011）。然而，-1044A>T 多态性与 NPC 风险之间没有观察到显著相关性。我们的数据表明，遗传变异 MKK4-1304T>G 的保护作用在 EBV 感染的 NPC 中受到限制。这些发现表明 EBV 和 MKK4-1304T>G 相互作用的作用是 NPC 的一个致病因素。
