title: Activation of GATA binding protein 6 (GATA6) sustains oncogenic lineage-survival in esophageal adenocarcinoma.
abstract: Gene amplification is a tumor-specific event during malignant transformation. Recent studies have proposed a lineage-dependency (addiction) model of human cancer whereby amplification of certain lineage transcription factors predisposes a survival mechanism in tumor cells. These tumor cells are derived from tissues where the lineage factors play essential developmental and maintenance roles. Here, we show that recurrent amplification at 18q11.2 occurs in 21% of esophageal adenocarcinomas (EAC). Utilization of an integrative genomic strategy reveals a single gene, the embryonic endoderm transcription factor GATA6, as the selected target of the amplification. Overexpression of GATA6 is found in EACs that contain gene amplification. We find that EAC patients whose tumors carry GATA6 amplification have a poorer survival. We show that ectopic expression of GATA6, together with FGFR2 isoform IIIb, increases anchorage-independent growth in immortalized Barrett's esophageal cells. Conversely, siRNA-mediated silencing of GATA6 significantly reduces both cell proliferation and anchorage-independent growth in EAC cells. We further demonstrate that induction of apoptotic/anoikis pathways is triggered upon silencing of GATA6 in EAC cells but not in esophageal squamous cells. We show that activation of p38α signaling and up-regulation of TNF-related apoptosis-inducing ligand are detected in apoptotic EAC cells upon GATA6 deprivation. We conclude that selective gene amplification of GATA6 during EAC development sustains oncogenic lineage-survival of esophageal adenocarcinoma.
authors.affiliation: Department of Surgery, Department of Pathology, and Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA. linlin@umich.edu
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bass
authors.forename: William W
authors.initials: WW
authors.lastname: Lockwood
authors.forename: Zhuwen
authors.initials: Z
authors.lastname: Wang
authors.forename: Amy L
authors.initials: AL
authors.lastname: Silvers
authors.forename: Dafydd G
authors.initials: DG
authors.lastname: Thomas
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Chang
authors.forename: Jules
authors.initials: J
authors.lastname: Lin
authors.forename: Mark B
authors.initials: MB
authors.lastname: Orringer
authors.forename: Weiquan
authors.initials: W
authors.lastname: Li
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Glover
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Giordano
authors.forename: Wan L
authors.initials: WL
authors.lastname: Lam
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: David G
authors.initials: DG
authors.lastname: Beer
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D017209:Apoptosis / Q000235:genetics; D001471:Barrett Esophagus / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics*; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D053938:DNA Fragmentation; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology*; D050993:GATA6 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D005784:Gene Amplification / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D034741:RNA, Small Interfering / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; D051497:Receptor, Fibroblast Growth Factor, Type 2; D048051:p38 Mitogen-Activated Protein Kinases