MicroRNA molecular profiling identifies potential signaling pathways conferring resistance to chemoradiation in locally-advanced rectal adenocarcinoma.
MicroRNA molecular profiling identifies potential signaling pathways conferring resistance to chemoradiation in locally-advanced rectal adenocarcinoma.
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DOI：
10.18632/oncotarget.25652
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发表时间：
2018-06-22
期刊：
影响因子：
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通讯作者：
Williams TM
中科院分区：
文献类型：
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作者：
Pettit C;Webb A;Walston S;Chatterjee M;Chen W;Frankel W;Croce C;Williams TM
越来越多的人对使用放化疗(CRT)进行直肠癌的非手术治疗感兴趣，确定哪些患者可能从这种方法中受益最大是至关重要的。这项研究通过评估CRT前后的表达谱，确定了miRNAs(MiRs)与临床结果和治疗耐药相关。40例患者中，病理完全应答(PCR9例)和病理不完全应答(PIR)31例。从40例治疗前肿瘤标本和31例放化疗后病理不完全反应(PIR)的手术标本中提取microRNA。使用广义线性模型来识别与聚合酶链式反应相关的MIR。使用线性混合效应模型来识别治疗前后差异表达的MIR。用COX比例风险模型对MIR表达的平均值进行二分法，并对临床结果进行评估。有9个MIR与聚合酶链式反应相关(p<；0.05)，但在错误发现率校正后没有显著差异。在PIR患者中，68个miR在CRT治疗前和治疗后的表达存在差异(FDR p<；0.05)。独创性通路分析(IPA)证实了与PIR相关的多种信号网络，包括p38MAPK、TP53、AKT、IL-6和RAS。Let-7b的升高与远处转移(DM)、无复发生存期(RFS)和总生存期(OS)的恶化有关(p<；0.05)。NO-MIR与聚合酶链式反应显著相关。我们鉴定了CRT治疗前后肿瘤标本中差异表达的miRs，这些miRs涉及可能导致CRT耐药的多个信号通路。此外，我们还发现let-7b的升高与较差的临床结果(DM、DFS、OS)之间存在关联。
There has been growing interest in using chemoradiation (CRT) for non-operative management of rectal cancer, and identifying patients who might benefit most from this approach is crucial. This study identified miRNAs (miRs) associated with clinical outcomes and treatment resistance by evaluating both pre- and post-CRT expression profiles. Forty patients, 9 with pathologic complete response (pCR) and 31 with pathologic incomplete response (pIR) were included. MicroRNA was extracted from 40 pre-therapy tumor samples and 31 post-chemoradiation surgical samples with pathologic incomplete response (pIR). A generalized linear model was used to identify miRs associated with pCR. A linear mixed effects model was used to identify miRs differentially expressed before and after treatment. miR expression was dichotomized at the mean and clinical outcomes were evaluated using Cox proportional hazard modeling. Nine miRs were associated with pCR (p<0.05), but none were significant after false discovery rate correction. Among patients with pIR, 68 miRs were differentially expressed between the pre and post-CRT groups (FDR p<0.05). Ingenuity pathway analysis (IPA) demonstrated multiple signaling networks associated with pIR, including p38MAPK, TP53, AKT, IL-6, and RAS. Increased let-7b was correlated with increased distant metastasis (DM), worse relapse-free survival (RFS), and worse overall survival (OS) (p<0.05). No miRs were significantly correlated with pCR. We identified miRs that were differentially expressed between pre- and post-CRT tumor samples, and these miRs implicated multiple signaling pathways that may confer resistance to CRT. In addition, we identified an association between increased let-7b and worse clinical outcomes (DM, DFS, OS).