Bhise Neha S, Chauhan Lata, Shin Miyoung, Cao Xueyuan, Pounds Stanley, Lamba Vishal, Lamba Jatinder K
Department of Pharmacotherapy and Translational Research, University of FloridaGainesville, FL, USA; Department of Experimental and Clinical Pharmacology, University of MinnesotaMinneapolis, MN, USA.
Department of Pharmacotherapy and Translational Research, University of Florida Gainesville, FL, USA.
Front Pharmacol. 2016 Jan 28;6:324. doi: 10.3389/fphar.2015.00324. eCollection 2015.
Cytarabine is the primary chemotherapeutic agent used for treatment of acute myeloid leukemia (AML). Disease relapse after initial remission remains one of the most pressing therapeutic challenges in the treatment of AML. Relapsed disease is often resistant to cytarabine and subsequent salvage therapy is ineffective. Recent studies have shown that some microRNAs (miRNAs) are associated with prognosis, but have not yet explored the role of miRNAs in cellular response to cytarabine. We identified 20 miRNAs that associate with the in vitro cytarabine chemo-sensitivity or apoptotic response of eight AML cell lines. Out of the 20 miRNAs, data on 18 miRNAs was available in AML patients from The Cancer Genome Atlas database. Our stepwise-integrated analyses (step 1 - miRNA-target mRNA that were significantly correlated in AML patients; step 2 - mRNAs from step 1 with significant association with overall survival (OS)) identified 23 unique miRNA-mRNA pairs predictive of OS in AML patients. As expected HOX genes (HOXA9, HOXB7, and HOXA10) were identified to be regulated by miRs as well as predictive of worse OS. Additionally, miR107-Myb, miR-378-granzyme B involved in granzyme signaling and miR10a-MAP4K4 were identified to be predictive of outcome through integrated analysis. Although additional functional validations to establish clinical/pharmacologic importance of miRNA-mRNA pairs are needed, our results from RNA electrophoretic mobility shift assay confirmed binding of miR-10a, miR-378, and miR-107 with their target genes GALNT1, GZMB, and MYB, respectively. Integration of pathogenic and pharmacologically significant miRNAs and miRNA-mRNA relationships identified in our study opens up opportunities for development of targeted/miRNA-directed therapies.
阿糖胞苷是用于治疗急性髓系白血病（AML）的主要化疗药物。初始缓解后疾病复发仍然是AML治疗中最紧迫的治疗挑战之一。复发性疾病通常对阿糖胞苷耐药，随后的挽救治疗无效。最近的研究表明，一些微小RNA（miRNA）与预后相关，但尚未探讨miRNA在细胞对阿糖胞苷反应中的作用。我们鉴定出20种与8种AML细胞系的体外阿糖胞苷化疗敏感性或凋亡反应相关的miRNA。在这20种miRNA中，来自癌症基因组图谱数据库的AML患者中有18种miRNA的数据可用。我们的逐步综合分析（步骤1 - AML患者中显著相关的miRNA-靶标mRNA；步骤2 - 步骤1中与总生存期（OS）显著相关的mRNA）确定了23对独特的miRNA-mRNA对，可预测AML患者的OS。正如预期的那样，HOX基因（HOXA9、HOXB7和HOXA10）被确定受miR调控，并且可预测较差的OS。此外，通过综合分析确定miR107-Myb、参与颗粒酶信号传导的miR-378-颗粒酶B和miR10a-MAP4K4可预测预后。尽管需要额外的功能验证来确定miRNA-mRNA对的临床/药理学重要性，但我们的RNA电泳迁移率变动分析结果证实了miR-10a、miR-378和miR-107分别与其靶基因GALNT1、GZMB和MYB结合。我们研究中鉴定出的致病性和药理学上重要的miRNA以及miRNA-mRNA关系的整合为开发靶向/miRNA导向疗法提供了机会。
