title: Transcriptome analysis of pancreatic cancer reveals a tumor suppressor function for HNF1A.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is driven by the accumulation of somatic mutations, epigenetic modifications and changes in the micro-environment. New approaches to investigating disruptions of gene expression networks promise to uncover key regulators and pathways in carcinogenesis. We performed messenger RNA-sequencing in pancreatic normal (n = 10) and tumor (n = 8) derived tissue samples, as well as in pancreatic cancer cell lines (n = 9), to determine differential gene expression (DE) patterns. Sub-network enrichment analyses identified HNF1A as the regulator of the most significantly and consistently dysregulated expression sub-network in pancreatic tumor tissues and cells (median P = 7.56×10(-7), median rank = 1, range = 1-25). To explore the effects of HNF1A expression in pancreatic tumor-derived cells, we generated stable HNF1A-inducible clones in two pancreatic cancer cell lines (PANC-1 and MIA PaCa-2) and observed growth inhibition (5.3-fold, P = 4.5×10(-5) for MIA PaCa-2 clones; 7.2-fold, P = 2.2×10(-5) for PANC-1 clones), and a G0/G1 cell cycle arrest and apoptosis upon induction. These effects correlated with HNF1A-induced down-regulation of 51 of 84 cell cycle genes (e.g. E2F1, CDK2, CDK4, MCM2/3/4/5, SKP2 and CCND1), decreased expression of anti-apoptotic genes (e.g. BIRC2/5/6 and AKT) and increased expression of pro-apoptotic genes (e.g. CASP4/9/10 and APAF1). In light of the established role of HNF1A in the regulation of pancreatic development and homeostasis, our data suggest that it also functions as an important tumor suppressor in the pancreas.
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA, Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, E-28029 Madrid, Spain, Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute and Bioinformatics and Molecular Analysis Section, Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892, USA, Department of Laboratory Medicine and Pathology and Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA and Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Hoskins
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA, Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, E-28029 Madrid, Spain, Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute and Bioinformatics and Molecular Analysis Section, Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892, USA, Department of Laboratory Medicine and Pathology and Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA and Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Jinping
authors.initials: J
authors.lastname: Jia
authors.affiliation: Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, E-28029 Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Flandez
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA, Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, E-28029 Madrid, Spain, Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute and Bioinformatics and Molecular Analysis Section, Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892, USA, Department of Laboratory Medicine and Pathology and Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA and Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Hemang
authors.initials: H
authors.lastname: Parikh
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute and.
authors.forename: Wenming
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA, Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, E-28029 Madrid, Spain, Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute and Bioinformatics and Molecular Analysis Section, Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892, USA, Department of Laboratory Medicine and Pathology and Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA and Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Collins
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA, Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, E-28029 Madrid, Spain, Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute and Bioinformatics and Molecular Analysis Section, Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892, USA, Department of Laboratory Medicine and Pathology and Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA and Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Mickey A
authors.initials: MA
authors.lastname: Emmanuel
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA, Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, E-28029 Madrid, Spain, Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute and Bioinformatics and Molecular Analysis Section, Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892, USA, Department of Laboratory Medicine and Pathology and Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA and Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Abdisamad
authors.initials: A
authors.lastname: Ibrahim
authors.affiliation: Bioinformatics and Molecular Analysis Section, Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: John
authors.initials: J
authors.lastname: Powell
authors.affiliation: Department of Laboratory Medicine and Pathology and.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, E-28029 Madrid, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Malats
authors.affiliation: Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA and.
authors.forename: William R
authors.initials: WR
authors.lastname: Bamlet
authors.affiliation: Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA and.
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
authors.affiliation: Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, E-28029 Madrid, Spain, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
authors.affiliation: Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA, Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, E-28029 Madrid, Spain, Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute and Bioinformatics and Molecular Analysis Section, Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892, USA, Department of Laboratory Medicine and Pathology and Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA and Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain amundadottirl@mail.nih.gov.
authors.forename: Laufey T
authors.initials: LT
authors.lastname: Amundadottir
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D016147:Genes, Tumor Suppressor; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D012333:RNA, Messenger