title: Dicer is required for maintenance of adult pancreatic acinar cell identity and plays a role in Kras-driven pancreatic neoplasia.
abstract: The role of miRNA processing in the maintenance of adult pancreatic acinar cell identity and during the initiation and progression of pancreatic neoplasia has not been studied in detail. In this work, we deleted Dicer specifically in adult pancreatic acinar cells, with or without simultaneous activation of oncogenic Kras. We found that Dicer is essential for the maintenance of acinar cell identity. Acinar cells lacking Dicer showed increased plasticity, as evidenced by loss of polarity, initiation of epithelial-to-mesenchymal transition (EMT) and acinar-to-ductal metaplasia (ADM). In the context of oncogenic Kras activation, the initiation of ADM and pancreatic intraepithelial neoplasia (PanIN) were both highly sensitive to Dicer gene dosage. Homozygous Dicer deletion accelerated the formation of ADM but not PanIN. In contrast, heterozygous Dicer deletion accelerated PanIN initiation, revealing complex roles for Dicer in the regulation of both normal and neoplastic pancreatic epithelial identity.
authors.affiliation: The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Yue J
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: The Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Florencia
authors.initials: F
authors.lastname: McAllister
authors.affiliation: The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; The Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Bailey
authors.affiliation: The Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Sherri-Gae
authors.initials: SG
authors.lastname: Scott
authors.affiliation: The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Audrey M
authors.initials: AM
authors.lastname: Hendley
authors.affiliation: The McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; The Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Leach
authors.affiliation: The Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Bidyut
authors.initials: B
authors.lastname: Ghosh
mesh_terms: D061354:Acinar Cells / Q000378:metabolism*; D000818:Animals; D016764:Cell Polarity / Q000502:physiology; D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D051379:Mice; D010179:Pancreas / Q000166:cytology*; D010190:Pancreatic Neoplasms / Q000201:enzymology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D043244:Ribonuclease III / Q000172:deficiency / Q000378:metabolism*
chemical_list: C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)