KRAS is one of the most frequently mutated proto-oncogenes in pancreatic ductal adenocarcinoma (PDAC) and aberrantly activated in triple-negative breast cancer (TNBC). A profound role of microRNAs (miRNAs) in the pathogenesis of human cancer is being uncovered, including in cancer therapy. Using in silico prediction algorithms, we identified miR-873 as a potential regulator of KRAS, and we investigated its role in PDAC and TNBC. We found that reduced miR-873 expression is associated with shorter patient survival in both cancers. miR-873 expression is significantly repressed in PDAC and TNBC cell lines and inversely correlated with KRAS levels. We demonstrate that miR-873 directly bound to the 3′ UTR of KRAS mRNA and suppressed its expression. Notably, restoring miR-873 expression induced apoptosis; recapitulated the effects of KRAS inhibition on cell proliferation, colony formation, and invasion; and suppressed the activity of ERK and PI3K/AKT, while overexpression of KRAS rescued the effects mediated by miR-873. Moreover, in vivo delivery of miR-873 nanoparticles inhibited KRAS expression and tumor growth in PDAC and TNBC tumor models. In conclusion, we provide the first evidence that miR-873 acts as a tumor suppressor by targeting KRAS and that miR-873-based gene therapy may be a therapeutic strategy in PDAC and TNBC.

KRAS是胰腺导管腺癌（PDAC）中最常见的突变原癌基因之一，在三阴性乳腺癌（TNBC）中被异常激活。microRNA（miRNA）在人类癌症发病机理中的重要作用已被发现，包括在癌症治疗中。在计算机上使用预测算法，我们确定了miR-873是KRAS的潜在调控因子，我们研究了其在PDAC和TNBC中的作用。我们发现在两种癌症中，miR-873表达降低与患者生存期缩短有关。在PDAC和TNBC细胞系中，miR-873的表达受到显着抑制，并且与KRAS水平成反比。我们证明了miR-873直接与KRAS mRNA的3'UTR结合并抑制了其表达。值得注意的是，恢复miR-873的表达可诱导细胞凋亡。概述了KRAS抑制对细胞增殖，集落形成和侵袭的影响；并抑制ERK和PI3K / AKT的活性，而KRAS的过表达挽救了miR-873介导的作用。而且，体内miR-873纳米颗粒的递送抑制了PDAC和TNBC肿瘤模型中的KRAS表达和肿瘤生长。总之，我们提供了第一个证据，证明miR-873通过靶向KRAS发挥抑癌作用，并且基于miR-873的基因治疗可能是PDAC和TNBC中的治疗策略。