Targeting of K-Ras and Akt by microRNA against mutant K-ras colorectal cancer cells

초록

K-Ras mutations are a major cause of drug resistance to molecular-targeted therapies. To address the functional relevance of miRNAs in mutant K-Ras cancers, we transfected exogenous K-Ras(G12V) into human embryonic kidney 293 and MRC5 cells with wild-type K-Ras and B-Raf genes, and we comprehensively profiled the dysregulated miRNAs. The result showed that mature miRNA oligonucleotide (miR)-4689, one of the significantly down-regulated miRNAs in K-Ras(G12V) overexpressed cells, was found to exhibit a potent growth-inhibitory and proapoptotic effect both in vitro and in vivo. miR-4689 expression was significantly down-regulated in cancer tissues compared to normal mucosa, and it was particularly decreased in mutant KRAS CRC tissues. Overall, this study provided additional evidence that mutant K-Ras functions as a broad regulator of the EGFR signaling cascade by inhibiting miR-4689, which negatively regulates both Ras/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt pathways. These activities indicated that miR-4689 may be a promising therapeutic agent in mutant K-Ras CRC.