Shi Meng, Xia Jianhong, Xing Huaixin, Yang Wenjun, Xiong Xiangyu, Pan Wenting, Han Sichong, Shang Jinhua, Zhou Changchun, Zhou Liqing, Yang Ming
Shandong Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.
Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China.
Sci Rep. 2016 Jun 1;6:27013. doi: 10.1038/srep27013.
Metallopeptidase 13 (MMP13), a well-known and highly regulated zinc-dependent MMP collagenase, plays a crucial part in development and progression of esophageal squamous cell carcinoma (ESCC). Therefore, we examined associations between ESCC susceptibility and four haplotype-tagging single nucleotide polymorphisms (htSNPs) using a two stage case-control strategy. Odds ratios (OR) and 95% confidence intervals (95% CI) were computed by logistic regression model. After analyzing 1588 ESCC patients and frequency-matched 1600 unaffected controls, we found that MMP13 rs2252070 G > A genetic polymorphism is significantly associated with ESCC risk in Chinese Han populations (GA: OR = 0.63, 95% CI = 0.54-0.74, P = 1.7 × 10(-6), AA: OR = 0.73, 95% CI = 0.66-0.81, P = 1.8 × 10(-6)). Interestingly, the rs2252070 G-to-A change was shown to diminish a Sp1-binding site in ESCC cells. Reporter gene assays indicated that the rs2252070 A allele locating in a potential MMP13 promoter has low promoter activities. After measuring MMP13 gene expression in sixty-six pairs of esophageal cancer and normal tissues, we observed that the rs2252070 A protective allele carriers showed decreased oncogene MMP13 expression. Results of these analyses underline the support of the notion that MMP13 might function as a key oncogene in esophageal carcinogenesis.
金属蛋白酶13（MMP13）是一种广为人知且受到高度调控的锌依赖性MMP胶原酶，在食管鳞状细胞癌（ESCC）的发生和发展中起着关键作用。因此，我们采用两阶段病例对照策略，研究了ESCC易感性与四个单倍型标签单核苷酸多态性（htSNP）之间的关联。通过逻辑回归模型计算比值比（OR）和95%置信区间（95%CI）。在分析了1588例ESCC患者和频率匹配的1600例未受影响的对照后，我们发现MMP13 rs2252070 G＞A基因多态性与中国汉族人群的ESCC风险显著相关（GA：OR = 0.63，95%CI = 0.54 - 0.74，P = 1.7×10⁻⁶；AA：OR = 0.73，95%CI = 0.66 - 0.81，P = 1.8×10⁻⁶）。有趣的是，rs2252070的G到A的变化显示会减少ESCC细胞中的一个Sp1结合位点。报告基因分析表明，位于潜在MMP13启动子中的rs2252070 A等位基因具有低启动子活性。在测量了66对食管癌组织和正常组织中的MMP13基因表达后，我们观察到rs2252070 A保护性等位基因携带者的癌基因MMP13表达降低。这些分析结果支持了MMP13可能在食管癌发生过程中作为关键癌基因发挥作用这一观点。
