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.

Regulatory crosstalk between lineage-survival oncogenesKLF5, GATA4andGATA6cooperatively promotes gastric cancer development

“…For example, GATA6 has been implicated in oesophageal and pancreatic cancers14 15 while KLF5 may be involved in pancreas,16 and intestinal tumours,16 17 (see Discussion). However, additional research is required to clarify the exact functions of these factors in cancer development.…”

TGM2: A Cell Surface Marker in Esophageal Adenocarcinomas

“…32 Briefly, 73 EAC DNAs were genotyped using the Genome-Wide Human Sty I 250K SNP Array (Affymetrix). Copy number analyses with SNP arrays were performed as a log 2 copy number ratio exceeding 0.848 for amplifications and −0.737 for deletions.…”

Turning Skyscrapers into Town Houses: Insights into Barrett's Esophagus

“…For example, BE tissue samples show higher FOXA2 expression than normal esophageal squamous epithelia and, indeed, FOXA2 overexpression in esophageal squamous NES-B3T cells results in MUC2 expression [56] . Similarly, GATA6 expression is also increased in BE lesions compared to normal esophageal epithelium [57] and the overexpression of GATA6, together with FGFR2IIb, has been found to increase the anchorage-independent growth of the BE cell line CP-A [58] . Conflicting results show that upregulated miR-145 in BE lesions downregulates GATA6 and inhibits proliferation in nonneoplastic esophageal Het-1A cells [59] .…”

“…In vitro, acidic and/or bile acid treatment of non-neoplastic Het-1A cells results in increased CDX-2 expres- CDX-2 upregulated in BE tissues [38,44,45], complex formation with SMAD4 [17] and induction of intestinal markers [39] GATA6 increased expression in BE [57], and overexpression, together with FGFR2IIb, increased the anchorage-independent growth [58] HOXB genes higher levels in BE samples and overexpression increased columnar markers [61] TLR4 overexpressed in BE, and activation led to NF-κB signaling [62] Insights into Barrett's Esophagus sion via promoter demethylation [39] . Moreover, acidic treatment of Het-1A cells has been found to activate Hedgehog signaling with subsequent bone morphogenetic protein 4 (BMP4) expression and intestinalization [66] .…”