A miR-29b Byproduct Sequence Exhibits Potent Tumor Suppressive Activities via Inhibition of NF-{kappa}B Signaling in KRAS Mutant Colon Cancer Cells

We previously demonstrated that miR-29b-3p is a hopeful microRNA (miRNA)-based therapies against colorectal cancer (CRC). In this study, we aimed to clarify a value of miR-29b-1-5p as a next generation treatment, especially for KRAS mutant CRC. RT-PCR assay showed that expression of miR-29b-3p was high and its partner strand, miR-29b-1-5p level was only negligible in clinical CRC samples. Mimic-miR-29b-1-5p significantly inhibited proliferation of KRAS mutant CRC cell lines DLD1 and SW480 and KRAS wild type HT29 cells. Proliferative activity was further examined by either miR-29b-1-5p strand or its opposite complementary sequence because miR-29b-1-5p is a passenger miRNA and may have no physiological function. We found that completely opposite complementary strand to miR-29b-1-5p, but not miR-29b-1-5p possessed a potent anti-tumor effect and named this byproduct miRNA sequence "MIRTX." MIRTX directly targeted the 3'-UTR of CXCR2 and PIK3R1 mRNA and suppressed the NF-B signaling pathway in KRAS mutated CRC cells. in KRAS mutant CRC cells. MIRTX induced apoptosis in DLD1 with down-regulation of anti-apoptotic BCL2, BCL-xL, and MCL1 and up-regulation of cleaved caspase 3 and cleaved PARP. In mouse xenograft models, systemic administration of MIRTX using a super carbonate apatite as a delivery vehicle significantly inhibited tumor growth of DLD1 and HT29 cells without any particular toxicities. In conclusion, these findings indicate that inhibition of NF-B signaling by this novel miRNA-based therapeutic could be a promising treatment against refractory KRAS mutant CRC and KRAS wild CRC.

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