Identification of reciprocal microRNA-mRNA pairs associated with metastatic potential disparities in human prostate cancer cells and signaling pathway analysis
Identification of reciprocal microRNA-mRNA pairs associated with metastatic potential disparities in human prostate cancer cells and signaling pathway analysis
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DOI：
10.1002/jcb.29045
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发表时间：
2019-10-01
影响因子：
4
通讯作者：
Kong, Lu
中科院分区：
文献类型：
--
作者：
Ma, Hui;Wang, Li-Yong;Kong, Lu
前列腺癌（PCa）死亡的主要原因是转移；然而，转移机制仍不清楚。 MicroRNA (miRNA) 在癌症发展过程中通过转录后调控改变必需基因的表达模式。该研究主要旨在确定与 PCa 远处转移相关的特定 miRNA-信使 RNA (mRNA) 相互作用和信号通路。应用新的分析方法，结合 miRNA 和基因表达微阵列，筛选正常前列腺上皮细胞系 RWPE-1、高转移人 PCa 细胞系 PC-3M-1E8（H-1E8 或 1E8）和低转移细胞系 PC-3M-2B4（L-2B4 或 2B4）中差异表达的 miRNA-mRNA 对。通过使用 Gene Expression Omnibus 数据库，在患者中鉴定并验证了八种差异表达的候选 miRNA 及其与 PCa 转移密切相关的靶标。其中，与L-2B4细胞相比，在H-1E8细胞中也验证了hsa-miR-92b-3p和hsa-let-7a-5p的过表达以及其靶标的低表达，例如谷胱甘肽-S-转移酶M3（GSTM3）、杆状病毒IAP重复序列3和细胞周期蛋白依赖性激酶抑制剂1（CDKN1A）。生物信息学表明hsa-miR-92b-3p和hsa-let-7a-5p及其靶标可能通过铂类耐药和JAK-STAT信号通路促进PCa转移。顺铂处理的H-1E8和L-2B4细胞显示hsa-miR-92b-3p和hsa-let-7a-5p水平大幅降低；然而，与2B4细胞相比，1E8细胞并没有负向调节靶标GSTM3和CDKN1A表达水平的增加。这一发现表明 hsa-let-7a-5p/CDKN1A 和 hsa-miR-92b-3p/GSTM3 对之间的失调与转移性癌细胞的铂类化疗耐药相关。
The major cause of mortality for prostate cancer (PCa) is metastasis; however, the metastatic mechanism remains unclear. MicroRNAs (miRNAs) alter the expression patterns of essential genes through posttranscriptional regulation during cancer development. The study was mainly aimed at identifying specific miRNA-messenger RNA (mRNA) interactions and signaling pathways associated with PCa distant metastasis. New analytical approaches were applied, combining miRNA and gene expression microarray, to screen differentially expressed miRNA-mRNA pairs in the normal prostate epithelial cell line RWPE-1, the highly-metastatic human PCa cell line PC-3M-1E8 (H-1E8 or 1E8) and the lowly metastatic cell line PC-3M-2B4 (L-2B4 or 2B4). Eight differentially expressed candidate miRNAs and their targets closely related to PCa metastasis were identified and validated in patients by using the Gene Expression Omnibus database. Among them, overexpression of hsa-miR-92b-3p and hsa-let-7a-5p and underexpression of their targets, such as glutathione-S-transferase M3 (GSTM3), baculoviral IAP repeat-containing 3, and cyclin-dependent kinase inhibitor 1 (CDKN1A), were also validated in H-1E8 cells compared with L-2B4 cells. Bioinformatics suggested that hsa-miR-92b-3p and hsa-let-7a-5p and their targets might promote PCa metastasis through platinum-based drug resistance and the JAK-STAT signaling pathway. H-1E8 and L-2B4 cells treated by cisplatin showed the greatly decreased levels of hsa-miR-92b-3p and hsa-let-7a-5p; however, in contrast to 2B4 cells, 1E8 cells did not negatively regulate the increase in the expression levels of the targets GSTM3 and CDKN1A. This finding suggests that the dysregulation between hsa-let-7a-5p/CDKN1A and hsa-miR-92b-3p/GSTM3 pairs is associated with platinum-based chemoresistance of metastatic cancer cells.