Sequence Variation in Mature MicroRNA-499 Confers Unfavorable Prognosis of Lung Cancer Patients Treated with Platinum-Based Chemotherapy
Sequence Variation in Mature MicroRNA-499 Confers Unfavorable Prognosis of Lung Cancer Patients Treated with Platinum-Based Chemotherapy
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成熟 MicroRNA-499 的序列变异导致接受铂类化疗的肺癌患者预后不良。
DOI：
10.1158/1078-0432.ccr-14-1174
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发表时间：
2015-04-01
影响因子：
11.5
通讯作者：
Lu, Jiachun
中科院分区：
文献类型：
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作者：
Qiu, Fuman;Yang, Lei;Lu, Jiachun
目的：本研究旨在探讨成熟微小RNA（miRNA）序列中的单核苷酸多态性（SNP）与肺癌预后之间的关联，并验证这些SNP的功能。
实验设计：在中国南方人群的576例肺癌患者中分析了8个SNP（hsa - mir - 499中的rs3746444T>C、hsa - mir - 608中的rs4919510C>G、hsa - mir - 3152中的rs13299349G>A、hsa - mir - 4293中的rs12220909G>C、hsa - mir - 4513中的rs2168518G>A、hsa - mir - 4520a中的rs8078913T>C、hsa - mir - 5579中的rs11237828T>C以及hsa - mir - 5689中的rs9295535T>C），并分别在另外两个包含346例和368例患者的队列中对显著结果进行验证。进行了一系列实验以评估这些潜在有功能的SNP的相关性。
结果：我们发现微小RNA - 499的rs3746444T>C多态性在发现组[风险比（HR），1.24；95%置信区间（CI），1.02 - 1.49；P = 0.028]、验证组I（HR，1.31；95% CI，1.01 - 1.71；P = 0.048）以及验证组II（HR，1.45；95% CI，1.12 - 1.86；P = 0.004）中均显示肺癌患者预后不良。CT/CC变异体的不良影响在接受铂类化疗的患者中更为显著。进一步的功能检测表明，rs3746444C变异等位基因影响多个癌症相关基因的表达，并通过顺铂耐药性在体内外影响肺癌细胞的增殖和肿瘤生长。
结论：我们的研究结果表明，成熟miR - 499序列中的rs3746444T>C多态性可通过调节癌症相关基因的表达导致预后不良，从而参与肿瘤发生和抗化疗，这可能是预测肺癌患者预后的一个有用的生物标志物。（C）2015美国癌症研究协会
Purpose: This study was implemented to investigate the associations between SNP in mature microRNA (miRNA) sequence and lung cancer prognosis and to verify the function of those SNP. Experimental Design: Eight SNPs (rs3746444T>C in hsa-mir-499, rs4919510C>G in hsa-mir-608, rs13299349G>A in hsa-mir-3152, rs12220909G>C in hsa-mir-4293, rs2168518G>A in hsa-mir-4513, rs8078913T>C in hsa-mir-4520a, rs11237828T>C in hsa-mir-5579, and rs9295535T>C in hsa-mir-5689) were analyzed in a southern Chinese population with 576 patients with lung cancer, and the significant results were validated in two additional cohorts of 346 and 368 patients, respectively. A series of experiments were performed to evaluate the relevancies of those potentially functional SNPs. Results: We found that the microRNA-499 rs3746444T>C polymorphism exhibited a consistently poor prognosis for patients with lung cancer in the discovery set [HR, 1.24; 95% confidence interval (CI), 1.02–1.49; P = 0.028], in the validation set I (HR, 1.31; 95% CI, 1.01–1.71; P = 0.048) and in the validation set II (HR, 1.45; 95% CI, 1.12–1.86; P = 0.004). The adverse effect of CT/CC variants was more remarkable in patients receiving platinum-based chemotherapy. Further functional assays demonstrated that the rs3746444C variant allele influences the expression of several cancer-related genes and affects lung cancer cells' proliferation and tumor growth in vivo and in vitro via the cisplatinum resistance. Conclusion: Our findings suggested that the rs3746444T>C polymorphism in mature miR-499 sequence could contribute to poor prognosis by modulating cancer-related genes' expression and thus involve tumorigenesis and anti-chemotherapy, which may be a useful biomarker to predict lung cancer patients' prognosis. Clin Cancer Res; 21(7); 1602–13. ©2015 AACR.