Abstract 1103: Molecular targets regulated by tumor suppressive <i>microRNA-1</i> and <i>microRNA-133a</i> in bladder cancer
Authors: Hirofumi Yoshino, Hideki Enokida, Takeshi Yamasaki, Hideo Hidaka, Takeshi Chiyomaru, Nijiro Nohata, Naohiko Seki, Masayuki Nakagawa
Journal: Cancer Research (2012)

Abstract (Background) Bladder cancer (BC) is the fourth most common tumor diagnosed and the second most common cancer of the genitourinary tract in Japan. Though there have been significant advances in treatment, including surgical technique and adjuvant chemotherapy, approximately 70% of first diagnosed BC recurs after treatment, and 10% to 15% of recurrent tumors proceed to muscle invasion and metastasis. Therefore, it is crucial to find a new strategy for BC diagnosis and treatment based on recent genome analysis in BC oncogenesis. Our expression signatures of human cancer including bladder cancer (BC) revealed that the expression of microRNA-1 (miR-1) and microRNA-133a (miR-133a) were significantly reduced in cancer cells. In human genome, miR-1 and miR-133a located same chromosomal regions (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 investigated the functional significance of miR-1 and miR-133a and identify the novel molecular targets regulated by miR-1 and miR-133a commonly in BC. (Methods) Cell proliferation, invasion, migration and apoptosis assay was performed by restoration of mature miR-1 and/or miR-133a in BC cell lines. Genome-wide gene expression analysis was performed to identify the molecular networks of miR-1 and miR-133a by microarray technique. A luciferase reporter assay was used to identify the actual binding site between miR-1 and miR-133a and its candidate target genes. Cell proliferation, invasion, migration and apoptosis assays were performed to investigate the targets genes in BC cell lines. To investigate of expression of target genes, immunohistochemistry was performed by using BC tissue microarray. (Results) Restoration of miR-1 and/or miR-133a significantly inhibited cell proliferation migration and invasion in cancer cells. Apoptosis assay showed that significant apoptotic cells were induced by miR-1 and/or miR-133a transfection. Genome-wide molecular targets search and luciferase reporter assay showed that Transgelin2 (TAGLN2), prothymosin-alpha (PTMA) and purine nucleoside phosphorylase (PNP) were directly regulated by miR-1 and miR-133a commonly. Silencing of the target genes studies demonstrated significant inhibition of cell proliferation and invasion, and increase of apoptosis in BC cells. Immunohistochemistry showed that TAGLN2 and PTMA expression level was significantly higher in BC than normal bladder epitheliums. (Conclusions) miR-1 and miR-133a function as tumor suppressor in BC. TAGLN2, PTMA and PNP were directly regulated by tumor suppressive miR-1 and miR-133a commonly. These genes may function as oncogenes contributed to cell proliferation and invasion in BC. Tumor suppressive miR-1 and miR-133a mediates novel molecular targets provide new insights into the potential mechanisms of BC oncogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1103. doi:1538-7445.AM2012-1103