Identification of microRNA-21 as a biomarker for chemoresistance and clinical outcome following adjuvant therapy in resectable pancreatic cancer.
Identification of microRNA-21 as a biomarker for chemoresistance and clinical outcome following adjuvant therapy in resectable pancreatic cancer.
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DOI：
10.1371/journal.pone.0010630
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发表时间：
2010-05-14
期刊：
影响因子：
3.7
通讯作者：
Giaccone G
中科院分区：
文献类型：
--
作者：
Hwang JH;Voortman J;Giovannetti E;Steinberg SM;Leon LG;Kim YT;Funel N;Park JK;Kim MA;Kang GH;Kim SW;Del Chiaro M;Peters GJ;Giaccone G
胰腺导管腺癌(PDAC)预后很差。手术切除后复发的高风险为辅助治疗提供了理论基础。然而，只有一小部分患者受益于辅助治疗。因此，鉴定分子标志物以预测治疗结果是必要的。本研究的目的是评估包括microRNAs在内的新的候选生物标记物的表达是否可以预测接受辅助治疗的PDAC患者的临床结果。采用免疫组织化学方法和实时定量聚合酶链式反应(Real-time PCR)技术，对82例经福尔马林固定的石蜡包埋标本进行蛋白表达和microRNA表达的分析。COX比例风险模型分析显示，在接受辅助治疗(N = 52)的患者亚组中，miR-21表达低于中位数与死亡(HR = 0.316；95%CI = 0.166~0.600；P = 0.0004)和复发(HR = 0.521；95%CI = 0.280~0.967；P = 0.04)显著降低相关。在评估的27个生物学因素和9个临床病理因素中，MIR-21表达状态是唯一最能预测治疗结果的生物标志物。在没有接受辅助治疗的患者中，没有发现明显的相关性。在一项来自意大利病例的45个冰冻PDAC组织的独立验证队列中，所有接受辅助治疗的患者的miR-21表达低于中位数，证实与更长的总体和无病生存期相关。此外，反义miR-21基因可提高PDAC细胞对化疗药物的敏感性。在两个独立的PDAC病例队列中，miR-21的低表达与辅助治疗的益处有关，而抗miR-21在体外增加了抗癌药物的活性。这些数据提供了证据，表明miR-21可能允许分层辅助治疗，并代表了PDAC治疗的新的潜在靶点。
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. The high risk of recurrence following surgical resection provides the rationale for adjuvant therapy. However, only a subset of patients benefit from adjuvant therapy. Identification of molecular markers to predict treatment outcome is therefore warranted. The aim of the present study was to evaluate whether expression of novel candidate biomarkers, including microRNAs, can predict clinical outcome in PDAC patients treated with adjuvant therapy. Formalin-fixed paraffin embedded specimens from a cohort of 82 resected Korean PDAC cases were analyzed for protein expression by immunohistochemistry and for microRNA expression using quantitative Real-Time PCR. Cox proportional hazards model analysis in the subgroup of patients treated with adjuvant therapy (N = 52) showed that lower than median miR-21 expression was associated with a significantly lower hazard ratio (HR) for death (HR = 0.316; 95%CI = 0.166–0.600; P = 0.0004) and recurrence (HR = 0.521; 95%CI = 0.280–0.967; P = 0.04). MiR-21 expression status emerged as the single most predictive biomarker for treatment outcome among all 27 biological and 9 clinicopathological factors evaluated. No significant association was detected in patients not treated with adjuvant therapy. In an independent validation cohort of 45 frozen PDAC tissues from Italian cases, all treated with adjuvant therapy, lower than median miR-21 expression was confirmed to be correlated with longer overall as well as disease-free survival. Furthermore, transfection with anti-miR-21 enhanced the chemosensitivity of PDAC cells. Low miR-21 expression was associated with benefit from adjuvant treatment in two independent cohorts of PDAC cases, and anti-miR-21 increased anticancer drug activity in vitro. These data provide evidence that miR-21 may allow stratification for adjuvant therapy, and represents a new potential target for therapy in PDAC.