title: EVI1 oncogene promotes KRAS pathway through suppression of microRNA-96 in pancreatic carcinogenesis.
abstract: Despite frequent KRAS mutation, the early molecular mechanisms of pancreatic ductal adenocarcinoma (PDAC) development have not been fully elucidated. By tracking a potential regulator of another feature of PDAC precursors, acquisition of foregut or gastric epithelial gene signature, we herein report that aberrant overexpression of ecotropic viral integration site 1 (EVI1) oncoprotein, which is usually absent in normal pancreatic duct, is a widespread marker across the full spectrum of human PDAC precursors and PDAC. In pancreatic cancer cells, EVI1 depletion caused remarkable inhibition of cell growth and migration, indicating its oncogenic roles. Importantly, we found that EVI1 upregulated KRAS expression through suppression of a potent KRAS suppressor, miR-96, in pancreatic cancer cells. Collectively, the present findings suggest that EVI1 overexpression and KRAS mutation converge on activation of the KRAS pathway in early phases of pancreatic carcinogenesis and propose EVI1 and/or miR-96 as early markers and therapeutic targets in this dismal disease.
authors.affiliation: Department of Pathology, University of Tokyo, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Molecular Pathology, University of Tokyo, Tokyo, Japan.
authors.forename: H I
authors.initials: HI
authors.lastname: Suzuki
authors.affiliation: Department of Pathology, University of Tokyo, Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Shibahara
authors.affiliation: Department of Pathology, University of Tokyo, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kunita
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Isagawa
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Yoshimi
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kurokawa
authors.affiliation: Department of Molecular Pathology, University of Tokyo, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Miyazono
authors.affiliation: Genome Science Division, RCAST, University of Tokyo, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: Department of Pathology, University of Tokyo, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ishikawa
authors.affiliation: Department of Pathology, University of Tokyo, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Fukayama
mesh_terms: D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D000074008:MDS1 and EVI1 Complex Locus Protein; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D011519:Proto-Oncogenes / Q000235:genetics*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C117307:KRAS protein, human; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; C541492:MIRN96 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins