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

作者：Inoue Akira; Mizushima Tsunekazu; Wu Xin; Okuzaki Daisuke; Kambara Nanami; Ishikawa Sho; Wang Jiaqi; Qian Yamin; Hirose Haruka; Yokoyama Yuhki; Ikeshima Ryo; Hiraki Masayuki; Miyoshi Norikatsu; Takahashi Hidekazu; Haraguchi Naotsugu; Hata Taishi; Matsuda Chu; Doki Yuichiro; Mori Masaki; Yamamoto Hirofumi^*

来源：Molecular Cancer Therapeutics, 2018, 17(5): 977-987.

DOI：10.1158/1535-7163.MCT-17-0850

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 30-UTR of CXCR2 and PIK3R1 mRNA and suppressed the NF-kappa B 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-kappa B signaling by this novel miRNA-based therapeutic could be a promising treatment against refractory KRAS-mutant colorectal cancer and KRAS wild-type colorectal cancer.

• 出版日期2018-5