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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 p38? 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.

SUBMITTER: Lin L

PROVIDER: S-EPMC3306720 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Activation of GATA binding protein 6 (GATA6) sustains oncogenic lineage-survival in esophageal adenocarcinoma.

Lin Lin L Bass Adam J AJ Lockwood William W WW Wang Zhuwen Z Silvers Amy L AL Thomas Dafydd G DG Chang Andrew C AC Lin Jules J Orringer Mark B MB Li Weiquan W Glover Thomas W TW Giordano Thomas J TJ Lam Wan L WL Meyerson Matthew M Beer David G DG

Proceedings of the National Academy of Sciences of the United States of America 20120228 11

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). ...[more]

PMID: 22375031

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Dataset Information

Activation of GATA binding protein 6 (GATA6) sustains oncogenic lineage-survival in esophageal adenocarcinoma.

Publications

Activation of GATA binding protein 6 (GATA6) sustains oncogenic lineage-survival in esophageal adenocarcinoma.

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