title: Concurrent Targeting of KRAS and AKT by MiR-4689 Is a Novel Treatment Against Mutant KRAS Colorectal Cancer.
abstract: KRAS mutations are a major cause of drug resistance to molecular-targeted therapies. Aberrant epidermal growth factor receptor (EGFR) signaling may cause dysregulation of microRNA (miRNA) and gene regulatory networks, which leads to cancer initiation and progression. To address the functional relevance of miRNAs in mutant KRAS cancers, we transfected exogenous KRAS(G12V) into human embryonic kidney 293 and MRC5 cells with wild-type KRAS and BRAF 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 KRAS(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. miR-4689 directly targets v-ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS) and v-akt murine thymoma viral oncogene homolog 1(AKT1), key components of two major branches in EGFR pathway, suggesting KRAS overdrives this signaling pathway through inhibition of miR-4689. Overall, this study provided additional evidence that mutant KRAS 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 KRAS CRC.
authors.affiliation: Department of Surgery, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hiraki
authors.affiliation: Department of Surgery, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Nishimura
authors.affiliation: Department of Surgery, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Surgery, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Xin
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Surgery, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Surgery, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Miyo
authors.affiliation: Department of Surgery, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Nishida
authors.affiliation: Department of Surgery, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Uemura
authors.affiliation: Department of Surgery, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Taishi
authors.initials: T
authors.lastname: Hata
authors.affiliation: Department of Surgery, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takemasa
authors.affiliation: Department of Surgery, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Tsunekazu
authors.initials: T
authors.lastname: Mizushima
authors.affiliation: Department of Chemistry, Biomedical Research Centre for Signal Transduction Networks, Inha University, Incheon, Korea.
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Soh
authors.affiliation: Department of Surgery, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.affiliation: Department of Surgery, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Surgery, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamamoto