title: Trisomy of the Dscr1 gene suppresses early progression of pancreatic intraepithelial neoplasia driven by oncogenic Kras.
abstract: Individuals with Down syndrome exhibit remarkably reduced incidence of most solid tumors including pancreatic cancer. Multiple mechanisms arising from the genetic complexity underlying Down syndrome has been suggested to contribute to such a broad cancer protection. In this study, utilizing a genetically engineered mouse model of pancreatic cancer, we demonstrate that trisomy of the Down syndrome critical region-1 (Dscr1), an endogenous calcineurin inhibitor localized on chromosome 21, suppresses the progression of pancreatic intraepithelial neoplasia-1A (PanIN-1A) to PanIN-1B lesions without affecting the initiation of PanIN lesions mediated by oncogenic Kras(G12D). In addition, we show that Dscr1 trisomy attenuates nuclear localization of nuclear factor of activated T-cells (NFAT) accompanied by upregulation of the p15(Ink4b) tumor suppressor and reduction of cell proliferation in early PanIN lesions. Our data suggest that attenuation of calcineurin-NFAT signaling in neoplastic pancreatic ductal epithelium by a single extra copy of Dscr1 is sufficient to inhibit the progression of early PanIN lesions driven by oncogenic Kras, and thus may be a potential mechanism underlying reduced incidence of pancreatic cancer in Down syndrome individuals.
authors.affiliation: Department of Molecular and Cellular Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi 440-746, Republic of Korea.
authors.forename: Jang Choon
authors.initials: JC
authors.lastname: Lee
authors.forename: Jimin
authors.initials: J
authors.lastname: Shin
authors.forename: Kwan-Hyuck
authors.initials: KH
authors.lastname: Baek
mesh_terms: D000818:Animals; D017209:Apoptosis; D002135:Calcium-Binding Proteins; D002278:Carcinoma in Situ / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D004314:Down Syndrome / Q000150:complications / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015398:Signal Transduction; D014314:Trisomy; D015854:Up-Regulation
chemical_list: D002135:Calcium-Binding Proteins; C493968:Cdkn2b protein, mouse; D050762:Cyclin-Dependent Kinase Inhibitor p15; C511512:DSCR1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: CDK; CK-19; Down syndrome; Down syndrome critical region-1; Dscr1; Dyrk1a; NFAT; Oncogenic Kras(G12D); PDA; PanIN; Pancreatic cancer; TUNEL; cyclin-dependent kinase; cytokeratin-19; dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A; nuclear factor of activated T-cells; p15(Ink4b); pancreatic ductal adenocarcinoma; pancreatic intraepithelial neoplasia; terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling