Abstract 1910: Tumor-suppressive microRNAs (miR-26a/b, miR-29a/b/c and miR-218) concertedly regulate metastasis-promoting LOXL2 in prostate cancer

Abstract

Abstract BACKGROUNDS: Most patients with prostate cancer (PCa) initially respond to androgen-deprivation therapy, but eventually becomes hormone-insensitive and progress to castration-resistant prostate cancer (CRPC). CRPC is difficult to treat, and most clinical trials for advanced PCa have shown limited benefits, with disease progression and metastasis to the skeleton or other sites. Therefore, understanding the molecular mechanisms of CRPC and the metastatic pathways underlying PCa using genomic approaches would help to prevent and improve therapies for the disease. Our previous studies showed that three tumor-suppressive microRNAs (miRNAs), miR-26a/b, miR-29a/b/c and miR-218, significantly inhibited cancer cell migration and invasion. Therefore, we hypothesized that these miRNAs-regulated target genes deeply contributed to cancer metastasis. METHODS: Genome-wide gene expression analysis and in silico analysis were applied to investigate molecular targets regulated by miR-26a/b, miR-29a/b/c and miR-218 in PCa cells. A luciferase reporter assay was carried out to determine whether 3’ UTR of target genes have actual biding sites for these miRNAs. To investigate the functional role of target genes in PCa cells, loss-of-function studies by using siRNAs of targets genes were performed. RESULTS: Our in silico analysis and luciferase reporter assays showed that lysyl oxidase-like 2 (LOXL2) was directly regulated by tumor-suppressive miR-26a/b, miR-29a/b/c and miR-218 in PCa cells. Overexpression of LOXL2 was observed in PCa clinical specimens by immunohistochemical staining. Moreover, downregulating the LOXL2 gene significantly inhibited cell migration and invasion in PCa cells. The function of the LOXL2 is covalent crosslinking of collagen and/or elastin in the ECM. Aberrant expression of LOXL2 has been reported in several diseases, including cancers. CONCLUSIONS: Our present data showed that the gene promoting metastasis, LOXL2, was epigenetically regulated by tumor-suppressive microRNAs, miR-26a/b, miR-29a/b/c and miR-218 providing important insights into the molecular mechanisms of PCa metastasis. Elucidation of tumor-suppressive miRNAs regulated molecular pathways and targets could provide new information on potential therapeutic strategies in PCa. Citation Format: Mayuko Kato, Akira Kurozumi, Yusuke Goto, Ryosuke Matsushita, Ichiro Fukumoto, Atsushi Okato, Rika Nishikawa, Shinichi Sakamoto, Tomohiko Ichikawa, Naohiko Seki. Tumor-suppressive microRNAs (miR-26a/b, miR-29a/b/c and miR-218) concertedly regulate metastasis-promoting LOXL2 in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1910.