Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 2 (4), 286-93

Bile Acids Initiate Lineage-Addicted Gastroesophageal Tumorigenesis by Suppressing the EGF receptor-AKT Axis

Affiliations

Bile Acids Initiate Lineage-Addicted Gastroesophageal Tumorigenesis by Suppressing the EGF receptor-AKT Axis

Li Gong et al. Clin Transl Sci.

Abstract

While bile acids are a risk factor for tumorigenesis induced by reflux disease, the mechanisms by which they contribute to neoplasia remain undefined. Here, we reveal that in gastroesophageal junction (GEJ) cells bile acids activate a tissue-specific developmental program defining the intestinal epithelial cell phenotype characterizing GEJ metaplasia. Deoxycholic acid (DCA) inhibited phosphorylation of EGF receptors (EGFRs) suppressing the proto-oncogene AKT. Suppression of EGFRs and AKT by DCA actuated an intestine-specific cascade in which NF-kappaB transactivated the tissue-specific transcription factor CDX2. In turn, CDX2 orchestrated a lineage-specific differentiation program encompassing genes characterizing intestinal epithelial cells. Conversely, progression from metaplasia to invasive carcinoma in patients, universally associated with autonomous activation of EGFRs and/or AKT, was coupled with loss of this intestinal program. Thus, bile acids induce intestinal metaplasia at the GEJ by activating the lineage-specific differentiation program involving suppression of EGFR and AKT, activating the NF-kappaB-CDX2 axis. Induction of this axis provides the context for lineage-addicted tumorigenesis, in which autonomous activation of AKT corrupts adaptive intestinal NF-kappaB signaling, amplifying tumorigenic programs.

Figures

Figure 1
Figure 1
Induction of CDX2 and GUCY2C by DCA in GEJ cells, mediated by NF‐κB, recapitulates Barrett's esophagus. (A) DCA increased CDX2 (A1) and GUCY2C (A2) promoter transactivation in OE19 cells. (B) DCA induced CDX2 and GUCY2C protein expression in OE19 cells. (C) GUCY2C is ectopically expressed in GEJ biopsies with Barrett's esophagus, but not in normal GEJ biopsies (magnification, 20×). (D) Dominant negative IkB mutant (IkBM) blocked the effects of DCA on CXD2 (D1) and GUCY2C (D2) promoter transactivation in OE19 cells. *p < 0.05; ***p < 0.001; NS = not significant.
Figure 2
Figure 2
AKT mediates the effects of DCA on CDX2 activity in GEJ cells. DCA inhibited phosphorylation of AKT (A) and decreased the ratio of phosphorylated to total AKT (B) in OE19 cells. (C) Myristolated AKT (myrAkt) blocked the effects of DCA on CDX2 promoter transactivation in OE19 cells. *p < 0.05; **p < 0.01.
Figure 3
Figure 3
DCA inhibited EGFR phosphorylation in GEJ cells. (A) DCA induced dephosphorylation of EGFRs, and decreased the ratio of phosphorylated to total EGFRs, in OE19 cells. (B) AG1478 inhibited EGFR phosphorylation in OE19 cells in a dose‐dependent fashion. (C) Dominant negative EGFR (HER‐CD533) is stably expressed in pMSCV2.2‐transfected OE19 cells (OE19‐HER‐CD533 cells). (D) HER‐CD533 inhibited EGFR phosphorylation, and decreased the ratio of phosphorylated to total EGFRs, in OE19 cells. *p < 0.05; **p < 0.01; ***p < 0.001.
Figure 4
Figure 4
Inhibitors of EGFR phosphorylation mimic the effects of DCA on AKT, CDX2 and GU‐CY2C in GEJ cells. (A) AG1478 inhibited AKT phosphorylation in a dose‐dependent fashion in OE19 cells. (B) HER‐CD533 inhibited AKT phosphorylation in OE19 cells. AG1478 (C1, D1) and HER‐CD533 (C2, D2) increased CDX2 and GUCY2C promoter transactivation (C) and protein expression (D) in OE19 cells. *p < 0.05; **p < 0.01.
Figure 5
Figure 5
Inhibitors of EGFR phosphorylation regulate CDX2 and GUCY2C through NF‐κB in GEJ cells. AG1478 (A1) and HER‐CD533 (A2) increased transactivation of an NF‐κB reporter construct in OE19 cells. Dominant negative IkB mutant blocked the effects of AG1478 (B) and HER‐CD533 (C) on CDX2 (B1, C1) and GUCY2C (B2, C2) promoter transactivation in OE19 cells. *p < 0.05; **p < 0.01; NS = not significant.
Figure 6
Figure 6
DCA induces CXD2 activity through inhibition of EGFRs in GEJ cells. HER‐CD533 blocks DCA‐dependent EGFR dephosphorylation (A) and CDX2 promoter transactivation (B) in OE19 cells. EGF (10 ng/mL) eliminates DCA‐induced EGFR dephosphorylation (C) and CDX2 promoter transactivation (D) in OE19 cells. *p < 0.05; NS = not significant.
Figure 7
Figure 7
Intestinal differentiation programs, reflected by GUCY2C expression, are attenuated across the continuum of transformation at the GEJ. GUCY2C is expressed in GEJ biopsies with Barrett's esophagus and low‐grade dysplasia, but only focally in some patients with high‐grade dysplasia, and not in some adenocarcinomas. Magnification, 40×.

Similar articles

See all similar articles

Cited by 4 articles

Publication types

MeSH terms

Feedback