Activation of GATA binding protein 6 (GATA6) sustains oncogenic lineage-survival in esophageal adenocarcinoma
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 deri...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences
2012
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| Online Access: | http://hdl.handle.net/1721.1/74591 |
| _version_ | 1826214798642118656 |
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| author | Lin, Lin Meyerson, Matthew L. Lockwood, William W. Wang, Zhuwen Silvers, Amy L. Bass, Adam J. Thomas, Dafydd G. Chang, Andrew C. Lin, Jules Orringer, Mark B. Li, Weiquan Glover, Thomas W. Giordano, Thomas J. Lam, Wan L. Beer, David G. |
| author2 | Broad Institute of MIT and Harvard |
| author_facet | Broad Institute of MIT and Harvard Lin, Lin Meyerson, Matthew L. Lockwood, William W. Wang, Zhuwen Silvers, Amy L. Bass, Adam J. Thomas, Dafydd G. Chang, Andrew C. Lin, Jules Orringer, Mark B. Li, Weiquan Glover, Thomas W. Giordano, Thomas J. Lam, Wan L. Beer, David G. |
| author_sort | Lin, Lin |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T16:11:19Z |
| format | Article |
| id | mit-1721.1/74591 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:11:19Z |
| publishDate | 2012 |
| publisher | National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/745912024-07-19T19:58:46Z Activation of GATA binding protein 6 (GATA6) sustains oncogenic lineage-survival in esophageal adenocarcinoma Lin, Lin Meyerson, Matthew L. Lockwood, William W. Wang, Zhuwen Silvers, Amy L. Bass, Adam J. Thomas, Dafydd G. Chang, Andrew C. Lin, Jules Orringer, Mark B. Li, Weiquan Glover, Thomas W. Giordano, Thomas J. Lam, Wan L. Beer, David G. Broad Institute of MIT and Harvard Meyerson, Matthew 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. National Cancer Institute (U.S.) (Grant P50CA90578) 2012-11-07T20:38:21Z 2012-11-07T20:38:21Z 2012-03 2010-08 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/74591 Lin, L. et al. “Activation of GATA Binding Protein 6 (GATA6) Sustains Oncogenic Lineage-survival in Esophageal Adenocarcinoma.” Proceedings of the National Academy of Sciences (2012). ©2012 by the National Academy of Sciences en_US http://dx.doi.org/10.1073/pnas.1011989109 Proceedings of the National Academy of Sciences application/pdf National Academy of Sciences PNAS |
| spellingShingle | Lin, Lin Meyerson, Matthew L. Lockwood, William W. Wang, Zhuwen Silvers, Amy L. Bass, Adam J. Thomas, Dafydd G. Chang, Andrew C. Lin, Jules Orringer, Mark B. Li, Weiquan Glover, Thomas W. Giordano, Thomas J. Lam, Wan L. Beer, David G. Activation of GATA binding protein 6 (GATA6) sustains oncogenic lineage-survival in esophageal adenocarcinoma |
| title | Activation of GATA binding protein 6 (GATA6) sustains oncogenic lineage-survival in esophageal adenocarcinoma |
| title_full | Activation of GATA binding protein 6 (GATA6) sustains oncogenic lineage-survival in esophageal adenocarcinoma |
| title_fullStr | Activation of GATA binding protein 6 (GATA6) sustains oncogenic lineage-survival in esophageal adenocarcinoma |
| title_full_unstemmed | Activation of GATA binding protein 6 (GATA6) sustains oncogenic lineage-survival in esophageal adenocarcinoma |
| title_short | Activation of GATA binding protein 6 (GATA6) sustains oncogenic lineage-survival in esophageal adenocarcinoma |
| title_sort | activation of gata binding protein 6 gata6 sustains oncogenic lineage survival in esophageal adenocarcinoma |
| url | http://hdl.handle.net/1721.1/74591 |
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