Pharmacological regulation of bladder cancer by miR-130 family seed-targeting LNA

Bladder cancer causes an estimated 150,000 deaths per year worldwide. However, no major improvements in clinical outcomes have been achieved in the past several decades; therefore, a promising therapeutic agent is required. Recent studies revealed the existence of multiple subtypes of bladder cancer with distinct molecular signatures. To create novel therapeutics for such heterogeneous cancers, a target molecule should regulate various cancer-related signaling pathways. Here, we focused on the oncogenic miR-130 family (miR-130b, miR-301a, and miR-301b) as a novel therapeutic target for bladder cancer. The pharmacological inhibition of miR-130 family molecules by seed-targeting with an 8-mer tiny locked nucleic acid (LNA) inhibited 5637 bladder cancer cell growth, migration, and invasion by repressing stress fiber formation. Moreover, the miR-130-targeted LNA suppressed the phosphorylation of both FAK and Akt, resulting in the upregulation of two protein phosphatases, phosphatase and tensin homolog and protein tyrosine phosphatase, non-receptor type 11. In addition, administration of miR-130 family-targeted LNA significantly suppressed tumor growth in an in vivo bladder cancer xenograft model. Taken together, the miR-130 family-targeted LNA is expected to be a promising therapeutic agent for bladder cancer. Abbreviations: miR: micro RNA; LNA: locked nucleic acid; FAK: focal adhesion kinase; PTEN: phosphatase and tensin homolog deleted from chromosome 10; PTPN11: Tyrosine-protein phosphatase nonreceptor type 11; UTR: untranslated region