Data from A miR-29b Byproduct Sequence Exhibits Potent Tumor-Suppressive Activities via Inhibition of NF-κB Signaling in <i>KRAS</i>-Mutant Colon Cancer Cells

Abstract

<div>Abstract<p>We previously demonstrated that miR-29b-3p is a hopeful miRNA-based therapy against colorectal cancer. In this study, we aimed to clarify a value of miR-29b-1-5p as a next-generation treatment, especially for <i>KRAS</i>-mutant colorectal cancer. RT-PCR assay showed that the expression of miR-29b-3p was high, and its partner strand, miR-29b-1-5p, level was only negligible in clinical colorectal cancer samples. Mimic-miR-29b-1-5p significantly inhibited proliferation of <i>KRAS</i>-mutant colorectal cancer cell lines DLD1 and SW480 and <i>KRAS</i> 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 physiologic function. We found that completely opposite complementary strand to miR-29b-1-5p, but not miR-29b-1-5p, possessed a potent antitumor effect and named this byproduct miRNA sequence “MIRTX.” MIRTX directly targeted the 3′-UTR of <i>CXCR2</i> and <i>PIK3R1</i> mRNA and suppressed the NF-κB signaling pathway in <i>KRAS</i>-mutated colorectal cancer cells. MIRTX induced apoptosis in DLD1 with downregulation of antiapoptotic BCL2, BCL-xL, and MCL1 and upregulation 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-κB signaling by this novel miRNA-based therapeutic could be a promising treatment against refractory <i>KRAS</i>-mutant colorectal cancer and <i>KRAS</i> wild-type colorectal cancer. <i>Mol Cancer Ther; 17(5); 977–87. ©2018 AACR</i>.</p></div>