微小RNAlet-7a及其靶基因K-ras多态性与局部晚期食管鳞癌放化疗疗效的相关性研究  

Effects of miRNA let-7a and K-ras polymorphisms on chemoradio therapy efficiency in patients with locally advanced esophageal squamous cell carcinoma

作　　者：张建清[1] 汤旭山[2] 杨媚[1] 白鸽[1] 马晓丽[3] 张莉[3] 

机构地区：[1]新疆医科大学第一附属医院肿瘤中心,乌鲁木齐830054 [2]新疆医科大学附属肿瘤医院消化内科,乌鲁木齐830011 [3]新疆医科大学第一附属医院VIP内科,乌鲁木齐830054

出　　处：《新疆医科大学学报》2016年第12期1547-1553,共7页Journal of Xinjiang Medical University

基　　金：新疆维吾尔自治区自然科学基金(2013211B61)

摘　　要：目的探讨微小RNA let-7a及其靶基因K-ras多态性与食管鳞癌患者放化疗疗效的关系。方法收集局部晚期食管鳞癌患者(病例组,92例)和正常体检者(正常组,92例)血液标本。进行微小RNA let-7a rs10877887位点、rs13293512位点及靶基因K-ras rs712位点单核苷酸多态性检测。分析两组间各位点多态性的分型与分布特点及与放化疗疗效、预后及中位PFS的相关性,并运用荧光素酶报告基因实验K-ras是否为微小RNA let-7 a的直接靶基因。结果放化疗疗效与食管鳞癌分期及有无淋巴结转移有关(P<0.05)。两组基因多态性分析显示,rs10877887位点多态性无明显差异(P>0.05),rs13293512携带CC基因型的个体以及非TT基因型的个体食管鳞癌的发病风险增加(P<0.05),rs712位点携带TT基因型和非GG基因型的个体食管鳞癌的发病风险明显增加(P<0.05)。同时荧光索酶报告实验证明K-ras是微小RNA let-7a的直接靶基因。预后分析发现,rs10877887位点对疗效和预后无影响(P>0.05);rs13293512携带CC基因型的个体,rs712位点携带TT基因型和非GG基因型的个体,有效率明显降低,中位PFS生存时间明显减少(P<0.05)。COX回归分析,显示淋巴有效治疗转移、临床分期Ⅳ期、rs13293512位点CC基因型、rs712位点TT基因型是食管鳞癌预后的独立危险因素。结论rs13293512位点CC基因型与rs712位点TT基因型增加局部晚期食管鳞癌术后放化疗抵抗性和患病风险,降低放化疗有效疗效和中位PFS生存时间。在放化疗前对患者进行基因型检测,在一定程度上可以预测患者对放化疗的敏感性。Objective To investigate relationship between miRNA let-7a,K-ras polymorphisms and efficacy of chemoradiotherapy for esophageal squamous cell carcinoma（ ESCC） patients. Methods Blood specimens of 92 patients and 92 healthy controls were respectively collected. Single nucleotide polymorphisms（ SNPs） of let-7a（rs10877887 and rs13293512） and K-ras rs712 were detected. The genotyping and distribution of SNPs and their relevance with chemoradiotherapy efficacy and median Progression Free Survival（ PFS） time were analyzed. Luciferase reporter gene assay was used to determine whether K-ras is the target gene of let-7a. Results The efficacy of chemoradiotherapy was correlated with ESCC tumor-node-metastasis staging and lymph node metastasis（ LNM）（ P〈0. 05）. As gene polymorphism analysis demonstrating,no significant difference was found in rs10877887,while individuals with rs13293512 CC and non-TT genotypes had increased ESCC risks（ P〈0. 05）,so did those with rs712 TT and non-GG（ P〈0. 05）. Luciferase reporter gene assay showed that K-ras is direct targeting gene of let-7 a. As prognostic analysis showed,individuals with rs10877887 had no effect on efficacy and prognosis,while individuals with rs13293512 CC genotype or rs712 TT and non-GG genotypes had a lower effective treatment rate and shorter median PFS time（ P〈0. 05）. Cox logistic analysis revealed that LNM,Ⅳ stage,rs13293512 CC and rs712 TT genotypes are ESCC risk factors. Conclusion Rs13293512 CC and rs712 TT genotypes increase the risk and the resistance of chemoradiotherapy for locally advanced ESCC,and lower the efficacy of chemoradiotherapy and median PFS time,which implicated sensitivity of patients to chemoradiotherapy can be potentially predicted by genotyping before the chemoradiotherapy.

关 键 词：微小RNA let-7a K-RAS 食管鳞癌 基因多态性 放化疗 预后 靶基因 相关性 

分 类 号：R735.1[医药卫生—肿瘤]