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.

中文翻译：

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miR-29b 副产物序列通过抑制 KRAS 突变结肠癌细胞中的 NF-κB 信号传导而表现出有效的肿瘤抑制活性

我们之前已经证明 miR-29b-3p 是一种有希望的基于 miRNA 的治疗结直肠癌的方法。在这项研究中，我们旨在阐明 miR-29b-1-5p 作为下一代治疗方法的价值，尤其是对于 KRAS 突变的结直肠癌。RT-PCR检测显示miR-29b-3p的表达水平较高，其伴侣链miR-29b-1-5p在临床结直肠癌样本中的表达水平可忽略不计。Mimic-miR-29b-1-5p 显着抑制 KRAS 突变的结直肠癌细胞系 DLD1 和 SW480 以及 KRAS 野生型 HT29 细胞的增殖。通过 miR-29b-1-5p 链或其相反的互补序列进一步检查增殖活性，因为 miR-29b-1-5p 是一种过客 miRNA 并且可能没有生理功能。我们发现与 miR-29b-1-5p 完全相反的互补链，但不是 miR-29b-1-5p，具有强大的抗肿瘤作用，并将这种副产物 miRNA 序列命名为“MIRTX”。MIRTX 直接靶向 CXCR2 和 PIK3R1 mRNA 的 3'-UTR 并抑制 KRAS 突变的结直肠癌细胞中的 NF-κB 信号通路。MIRTX 通过下调抗凋亡 BCL2、BCL-xL 和 MCL1 以及上调裂解的 caspase-3 和裂解的 PARP，在 DLD1 中诱导细胞凋亡。在小鼠异种移植模型中，使用超碳酸磷灰石作为递送载体全身施用 MIRTX 显着抑制了 DLD1 和 HT29 细胞的肿瘤生长，而没有任何特定的毒性。总之，这些发现表明，通过这种基于 miRNA 的新疗法抑制 NF-κB 信号传导可能是一种有前途的治疗难治性 KRAS 突变型结直肠癌和 KRAS 野生型结直肠癌的方法。摩尔癌症治疗; 17(5); 977-87。©2018 AACR。