BACKGROUND: Prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer death among men in developed countries. Disease progression and the development of hormone refractory disease remain major cause of cancer-related death.Understanding the molecular mechanisms of PCa progression and metastatic pathways using currently available genomic approaches would help to improve therapies for and prevention of the disease. Our recent study of microRNA (miRNA) expression signature of PCa has revealed that microRNA-218 (miR-218) was significantly downregulated in cancer tissues, suggesting that miR-218 may be a putative tumor-suppressive miRNA in PCa. The aim of this study was to investigate the functional significance of miR-218 in PCa and to identify novel miR-218-regulated cancer pathways and target genes involved in PCa oncogenesis and metastasis.METHODS: The expression levels of miR-218 were validated using real-time RT-PCR using PCa clinical specimens and cell lines (PC3 and DU145). Cell proliferation, migration and invasion assays were performed to investigate the functional significance of miR-218 and its target gene, LIM and SH3 protein 1 (LASP1) in PCa cell lines.Cells were transfected with mature miR-218 or si-LASP1 by reverse transfection methods. Genome-wide gene expression data and in silico analysis were used to identify the molecular pathways and putative targets regulated by miR-218.The luciferase reporter assay was applied to identify the actual binding site of miR-218 in target gene. The expression of LASP1 was investigated by immunohistochemistry.RESULTS: The expression levels of miR-218 were significantly downregulated in PCa tissues and PCa cell lines. Restoration of miR-218 in PCa cell lines revealed that miR-218 significantly inhibited cancer cell migration and invasion.Gene expression studies and luciferase reporter assays showed that LASP1 was directly regulated by miR-218. Silencing LASP1 resulted in significant inhibition of cell migration and invasion in PCa cells.The expression of LASP1 was upregulated in cancer tissues as demonstrated byimmunohistochemical staining.CONCLUSIONS: The miR-218 was frequently reduced in PCa clinical specimens and appeared to function as a tumor suppressor through regulation of oncogenic LASP1. The identification of novel molecularpathways and targets regulated by the tumor suppressive miRNAs may lead to a better understanding of PCa progression and metastasis, and the development of new therapeutic strategies to treat this disease.
Citation Format: Rika Nishikawa, Yusuke Goto, Takashi Kinoshita, Shinichi Sakamoto, Takeshi Chiyomaru, Hideki Enokida, Satoko Kojima, Masayuki Nakagawa, Yukio Naya, Tomohiko Ichikawa, Naohiko Seki. Tumor suppressive microRNA-218 inhibits cancer cell migration and invasion via targeting LASP1 in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4371. doi:10.1158/1538-7445.AM2014-4371