Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Int J Oncol. 2012 Jun;40(6):1821-30. doi: 10.3892/ijo.2012.1391. Epub 2012 Feb 29.
Our expression signatures of human cancer including bladder cancer (BC) revealed that the expression of microRNA-1 (miR-1) and microRNA-133a (miR-133a) is significantly reduced in cancer cells. In the human genome, miR-1 and miR-133a are located on the same chromosomal region (miR-1-2 and miR-133a-1 on 18q11.2, and miR-1-1 and miR-133a-2 on 20q13.33) called cluster. In this study, we identified the novel molecular targets commonly regulated by miR-1 and miR-133a in BC. Genome-wide molecular target search and luciferase reporter assays showed that prothymosin-α (PTMA) and purine nucleoside phosphorylase (PNP) are directly regulated by miR-1 and miR-133a. Silencing of these two genes significantly inhibited cell proliferation and invasion, and increased apoptosis in BC cells. Immunohistochemistry showed that PTMA expression levels were significantly higher in BC compared to normal bladder epitheliums. PTMA and PNP were identified as new target genes regulated by the miR-1 and miR-133a cluster in BC. These genes may function as oncogenes contributing to cell proliferation and invasion in BC. Tumor suppressive miR-1 and miR-133a-mediated novel molecular targets may provide new insights into the potential mechanisms of BC oncogenesis.
我们对人类癌症的表达谱分析，包括膀胱癌（BC），揭示了 miRNA-1（miR-1）和 miRNA-133a（miR-133a）在癌细胞中的表达显著降低。在人类基因组中，miR-1 和 miR-133a 位于同一染色体区域（miR-1-2 和 miR-133a-1 在 18q11.2 上，miR-1-1 和 miR-133a-2 在 20q13.33 上），称为簇。在这项研究中，我们鉴定了 BC 中由 miR-1 和 miR-133a 共同调控的新型分子靶标。全基因组分子靶标搜索和荧光素酶报告基因检测显示，胸腺素-α前体（PTMA）和嘌呤核苷磷酸化酶（PNP）是 miR-1 和 miR-133a 的直接靶标。这两个基因的沉默显著抑制了 BC 细胞的增殖和侵袭，并增加了细胞凋亡。免疫组织化学显示，与正常膀胱上皮相比，BC 中 PTMA 的表达水平显著升高。PTMA 和 PNP 被确定为 BC 中 miR-1 和 miR-133a 簇调控的新靶基因。这些基因可能作为癌基因，促进 BC 细胞的增殖和侵袭。肿瘤抑制 miR-1 和 miR-133a 介导的新型分子靶标可能为 BC 致癌机制的潜在机制提供新的见解。
