Kirsten rat sarcoma virus (KRAS) mutations are frequently detected in many cancers and are major driver genes. Therefore, KRAS inhibitors have been the subject of extensive research. We developed chemically modified MIR143-3p (MIR143#12), which exhibits higher anticancer activity and nuclease resistance than other commercial inhibitors. MIR143#12 potently suppressed cell growth in colorectal and pancreatic cancer cell lines via apoptosis induced by repression of the entire rat sarcoma virus (RAS) network, which was achieved by silencing KRAS, Son of sevenless homolog 1 (SOS1), AKT, and extracellular signal-regulated kinase (ERK). We investigated the mechanistic advantages of MIR143#12 in various KRAS mutant colorectal cancer cell lines. Its effects were stronger than those of knockdown of KRAS alone in colon cancer cells because silencing of KRAS by small interfering RNA (siRNA) did not decrease the protein expression levels of AKT or ERKs. The KRAS mRNA recruitment system, called the “positive circuit” under effector signaling pathways, may contribute to insensitivity of KRAS mutant cancers to MIR143#12 and siRNAs. In an in vivo study, we newly demonstrated that MIR143#12 induced neoangiogenesis in the tumor microenvironment with growth suppression. Based on the present results, it is crucial to down-regulate not only KRAS but also the entire KRAS signaling network, which may be accomplished by MIR143#12.

克尔斯滕大鼠肉瘤病毒( KRAS ) 突变经常在许多癌症中检测到，并且是主要的驱动基因。因此，KRAS抑制剂一直是广泛研究的主题。我们开发了化学修饰的 MIR143-3p (MIR143#12)，它比其他商业抑制剂具有更高的抗癌活性和核酸酶抗性。MIR143#12 通过抑制整个大鼠肉瘤病毒 (RAS) 网络诱导的细胞凋亡有效抑制结直肠癌细胞系和胰腺癌细胞系的细胞生长，这是通过沉默KRAS、Son of Sevenless Homolog 1 ( SOS1 )、AKT和细胞外实现的信号调节激酶（ERK）。我们研究了 MIR143#12 在各种 KRAS 突变结直肠癌细胞系中的机制优势。它的作用比单独敲低KRAS在结肠癌细胞中的作用更强，因为通过小干扰 RNA (siRNA) 沉默KRAS不会降低 AKT 或 ERK 的蛋白质表达水平。KRAS mRNA 募集系统，称为效应信号通路下的“正向回路”，可能导致 KRAS 突变癌症对 MIR143#12 和 siRNA 不敏感。在体内研究中，我们新证明了 MIR143#12 在肿瘤微环境中诱导新血管生成并抑制生长。根据目前的结果，不仅要下调 KRAS，还要下调整个 KRAS 信号网络，这可以通过 MIR143#12 来完成。