Abstract A20: Innovative drug discovery for bladder cancer by miR-130 family seed-targeting locked nucleic acid

Bladder cancer causes an estimated 150,000 deaths per year worldwide. Although 15% of the recurrent bladder cancer becomes an invasive type, targeted therapy for malignant bladder cancer does not make much progress. To investigate a novel therapeutic target, we focused on miRNA expression signatures obtained from bladder cancer clinical specimens, and found that the miR-130 family (miR-130b, miR-301a and miR-301b) was significantly up-regulated in bladder cancer specimens compared to adjacent normal urothelial specimens. Functional analyses revealed that the miR-130 family promoted bladder cancer cell migration and invasion by regulating both focal adhesion kinase (FAK) and Akt phosphorylation. Moreover, miR-130b directly targeted Phosphatase and Tensin Homolog Deleted from Chromosome 10 (PTEN), which suppresses FAK and Akt activation. Furthermore, Argonaute2-immunoprecipitation and the subsequent gene array analysis identified tyrosine-protein phosphatase non-receptor type 11 (PTPN11) as another target gene of both miR-130b and miR-301b. Thus, the miR-130 family promotes bladder cancer cell motility by regulating these target genes. We next designed miR-130 family-targeted LNA (Locked Nucleic Acid) that can inhibit entire miR-130 family through a common seed sequence. miR-130 family-targeted LNA suppressed bladder cancer cell proliferation, migration and invasion powerfully by targeting both PTEN and PTPN11. Furthermore, miR-130 family-targeted LNA significantly inhibits bladder tumor growth in a murine xenograft model. Taken together, the miR-130 family has a crucial role for malignant progression of bladder cancer and thus miR-130 family-targeted LNA could be a promising molecular-targeted drug for bladder cancer. Citation Format: Hiroshi Egawa, Kentaro Jingushi, Yuko Ueda, Kaori Kitae, Wataru Nakata, Kazutoshi Fujita, Motohide Uemura, Norio Nonomura, Kazutake Tsujikawa. Innovative drug discovery for bladder cancer by miR-130 family seed-targeting locked nucleic acid. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A20.