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 KRAS-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 KRAS-mutant
colorectal cancer 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 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 CXCR2 and PIK3R1
mRNA and suppressed the NF-κB signaling pathway in KRAS-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 KRAS-mutant
colorectal cancer and KRAS wild-type
colorectal cancer. Mol
Cancer Ther; 17(5); 977-87. ©2018 AACR.