MicroRNA在晚期大肠癌一线化疗疗效中的预测作用

摘要

背景与目的：大肠癌是一种高发病率的恶性肿瘤，化疗可以减少肿瘤的生长和复发。当前较为重要的是探究标志物能够预测化疗耐药标志物，从而帮助确定治疗方案。方法：选取2007年11月-2010年5月复旦大学附属肿瘤医院大肠外科Ⅳ期大肠癌患者手术标本，术后患者都使用大肠癌术后规范化一线化疗(希罗达+奥沙利铂)。选取化疗耐药与有效癌组织标本各3例共6例使用microRNA芯片检测。筛选出有统计学意义的miRNA：miR-4299、miR-196b、miR-324-5p、miR-455-3p和miR-939，将候选miRNA在100例Ⅳ期大肠癌患者手术癌组织标本中进行real-time PCR验证。结果：通过芯片筛选，共5个miRNA可能与大肠癌一线化疗耐药有关。miR-4299和miR-196b对化疗耐药有显著诊断意义。miR-4299的AUC为0.784，而miR-196b的AUC为0.647。两个联合诊断AUC为0.848，敏感度和特异度分别为67.9%和90.9%。结论：miR-4299和miR-196b有可能作为诊断对大肠癌一线化疗耐药的标志物。%Background and purpose: Colorectal cancer (CRC) is the most frequently occurring primary malignant tumor. Chemotherapy can reduce the risk of local and distant relapse. Therefore, it is very important to ifnd new biomarkers that can predict chemoresistant and help in treatment decisions. Methods:In this study, we examined the expression levels of 1 200 human miRNAs in 6 CRC tissues, using miRNA proifling assay arrays. A validation study was done to corroborate a subset of the results, including expression levels of miR-4299, miR-196b, miR-324-5p, miR-455-3p and miR-939, by analyzing 100 specimens of stageⅣcolorectal adenocarcinoma (not respond and respond to the chemotherapy) to quantitative real-time PCR. We modeled the relationship between the expression levels of these miRNAs and the survival rate of 100 CRC patients by Kaplan-Meier method. Results:Expression proifles in CRCs suggested that 5 miRNAs were candidate markers associated with the chemoresistance of colorectal cancer. We found that miR-4299 and-196b had signiifcant diagnostic value for chemoresistance CRC. miR-4299 yielded an AUC (the areas under the ROC curve) of 0.784 and miR-196b yielded an AUC of 0.647 in discriminating CRC from controls. Combined ROC analysis using these 2 miRNAs revealed an elevated AUC of 0.848 with 67.9%sensitivity and 90.9%speciifcity in discriminating chemoresistance CRC. The low level of miR-4299 expression and the high level of-196b expression are signiifcantly correlated with the good survival of CRC patients. Conclusion:These data suggest that miR-4299 and-196b have strong potential as novel biomarkers for chemoresistant detection of colorectal cancer.