Wei Yisheng, Wang Lei, Lan Ping, Zhao Hongjun, Pan Zhizhong, Huang Jun, Lu Jiachun, Wang Jianping
Department of Colorectal Surgery, Gastrointestinal Institute of Sun Yat-Sen University, The Sixth Affiliated Hospital (Gastrointestinal and Anal Hospital) of Sun Yat-Sen University, Guangzhou City 510655, People's Republic of China.
Int J Cancer. 2009 Oct 15;125(8):1876-83. doi: 10.1002/ijc.24575.
MKK4 (mitogen-activated protein kinase kinase 4, NM_003010.2), which belongs to the mitogen-activated protein kinase pathways, possesses functions in tumorigenesis. We hypothesized the genetic variants in MKK4 gene may alter its functions and thus cancer risk. In current hospital-based case-control study of 706 patients with sporadic colorectal cancer (CRC) and 723 sex-age-frequency-matched control subjects in a southern Chinese population, we genotyped two polymorphisms of MKK4 promoter (i.e., -1304T>G, rs3826392 and -1044A>T, rs3809728) and assessed their associations with the risk of sporadic CRC. Compared with -1304TT genotypes, -1304TG had a significantly decreased risk of CRC (adjusted odds ratios [OR] = 0.56; 95% CI = 0.44-0.72; p = 3.53 x 10(-6)), the -1304GG carriers had a further decreased risk of CRC (OR = 0.40; 95% CI = 0.23-0.70; p = 1.32 x 10(-3)), and there was a significant trend for an allele dose effect on risk of CRC (p(trend) = 2.64 x 10(-7)). The decreased risk associated with -1304G variant genotypes (i.e., TG+GG) was more pronounced in the subjects older than 60 years (adjusted OR = 0.41; 95% CI = 0.29-0.57; p = 2.25 x 10(-7)), in ever drinkers (adjusted OR = 0.41; 95% CI = 0.28-0.59; p = 2.42 x 10(-6)). The age and alcohol drinking status interacted with -1304G variant genotypes on reducing cancer risk (p values for interaction were 0.015 and 0.043, respectively). Western blotting analysis showed that the levels of Mkk4 protein in sporadic CRC neoplastic tissues were significantly higher in the carriers of -1304G variant genotypes than that in those with -1304TT genotypes. However, no significant association was observed between -1044A>T polymorphism and risk of CRC. To the best of our knowledge, this is the first study of genetic variants in MKK4 and cancer susceptibility. Larger studies are needed to validate our findings.
MKK4（丝裂原活化蛋白激酶激酶4，NM_003010.2）属于丝裂原活化蛋白激酶信号通路，在肿瘤发生过程中发挥作用。我们推测MKK4基因中的遗传变异可能会改变其功能，进而影响癌症风险。在一项基于医院的病例对照研究中，我们纳入了706例散发性结直肠癌（CRC）患者和723名年龄、性别、频率匹配的对照者，这些人均来自中国南方人群。我们对MKK4启动子的两个多态性位点（即-1304T>G，rs3826392和-1044A>T，rs3809728）进行基因分型，并评估它们与散发性CRC风险的关联。与-1304TT基因型相比，-1304TG基因型的CRC风险显著降低（校正比值比[OR]=0.56；95%可信区间[CI]=0.44 - 0.72；p = 3.53×10⁻⁶），-1304GG携带者的CRC风险进一步降低（OR = 0.40；95%CI = 0.23 - 0.70；p = 1.32×10⁻³），并且在CRC风险上存在显著的等位基因剂量效应趋势（p趋势 = 2.64×10⁻⁷）。与-1304G变异基因型（即TG + GG）相关的风险降低在60岁以上的受试者中更为明显（校正OR = 0.41；95%CI = 0.29 - 0.57；p = 2.25×10⁻⁷），在曾经饮酒者中也更为明显（校正OR = 0.41；95%CI = 0.28 - 0.59；p = 2.42×10⁻⁶）。年龄和饮酒状态与-1304G变异基因型在降低癌症风险方面存在相互作用（相互作用的p值分别为0.015和0.043）。蛋白质印迹分析表明，-1304G变异基因型携带者的散发性CRC肿瘤组织中Mkk4蛋白水平显著高于-1304TT基因型者。然而，未观察到-1044A>T多态性与CRC风险之间存在显著关联。据我们所知，这是首次关于MKK4基因变异与癌症易感性的研究。需要更大规模的研究来验证我们的发现。
