Aghaee-Bakhtiari Seyed Hamid, Arefian Ehsan, Naderi Mahmood, Noorbakhsh Farshid, Nodouzi Vahideh, Asgari Mojgan, Fard-Esfahani Pezhman, Mahdian Reza, Soleimani Masoud
Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, No. 358, 12th Farwardin Ave, St, Tehran, Iran.
Tumour Biol. 2015 Jun;36(6):4203-12. doi: 10.1007/s13277-015-3057-3. Epub 2015 Jan 22.
The long-lasting inadequacy of existing treatments for prostate cancer has led to increasing efforts for developing novel therapies for this disease. MicroRNAs (miRNAs) are believed to have considerable therapeutic potential due to their role in regulating gene expression and cellular pathways. Identifying miRNAs that efficiently target genes and pathways is a key step in using these molecules for therapeutic purposes. Moreover, computational methods have been devised to help identify candidate miRNAs for each gene/pathway. MAPK and JAK/STAT pathways are known to have essential roles in cell proliferation and neoplastic transformation in different cancers including prostate cancer. Herein, we tried to identify miRNAs that target these pathways in the context of prostate cancer as therapeutic molecules. Genes involved in these pathways were analyzed with various algorithms to identify potentially targeting miRNAs. miR-23a and miR-23b were then selected as the best potential candidates that target a higher number of genes in these pathways with greater predictive scores. We then analyzed the expression of candidate miRNAs in LNCAP and PC3 cell lines as well as prostate cancer clinical samples. miR-23a and miR-23b showed a significant downregulation in cell line and tissue samples, a finding which is consistent with overactivation of these pathways in prostate cancer. In addition, we overexpressed miR-23a and miR-23b in LNCAP and PC3 cell lines, and these two miRNAs decreased IL-6R expression which has a critical role in these pathways. These results suggest the probability of utilizing miR-23a and miR-23b as therapeutic targets for the treatment of prostate cancer.
现有前列腺癌治疗方法的长期不足促使人们加大了开发该疾病新疗法的力度。微小RNA（miRNA）因其在调节基因表达和细胞通路中的作用而被认为具有巨大的治疗潜力。识别能有效靶向基因和通路的miRNA是将这些分子用于治疗目的的关键步骤。此外，人们已经设计出计算方法来帮助识别每个基因/通路的候选miRNA。已知丝裂原活化蛋白激酶（MAPK）和Janus激酶/信号转导和转录激活因子（JAK/STAT）通路在包括前列腺癌在内的不同癌症的细胞增殖和肿瘤转化中起重要作用。在此，我们试图在前列腺癌背景下识别靶向这些通路的miRNA作为治疗分子。使用各种算法分析参与这些通路的基因，以识别潜在的靶向miRNA。然后选择miR-23a和miR-23b作为最佳潜在候选者，它们在这些通路中靶向更多基因且预测得分更高。接着我们分析了候选miRNA在LNCAP和PC3细胞系以及前列腺癌临床样本中的表达。miR-23a和miR-23b在细胞系和组织样本中显著下调，这一发现与前列腺癌中这些通路的过度激活一致。此外，我们在LNCAP和PC3细胞系中过表达miR-23a和miR-23b，这两种miRNA降低了在这些通路中起关键作用的白细胞介素6受体（IL-6R）的表达。这些结果表明将miR-23a和miR-23b用作前列腺癌治疗靶点的可能性。
