Acid exposure activates the mitogen-activated protein kinase pathways in Barrett's esophagus

Gastroenterology. 2002 Feb;122(2):299-307. doi: 10.1053/gast.2002.30993.


Background & aims: To explore mechanisms whereby acid reflux might contribute to carcinogenesis in Barrett's esophagus (BE) we studied: (1) the effects of acid on the mitogen-activated protein kinase (MAPK) pathways, cell proliferation, and apoptosis in a Barrett's adenocarcinoma cell line (SEG-1); and (2) the ability of acid to activate the MAPK pathways in vivo in patients with BE.

Methods: SEG-1 cells were exposed to acidic media for 3 minutes, and the activities of 3 MAPKs (ERK, p38, and JNK) were determined. Proliferation was assessed using flow cytometry; cell growth and apoptosis were assessed using cell counts and an apoptosis ELISA assay. MAPK activation was studied in biopsy specimens taken from patients with BE before and after esophageal perfusion for 3 minutes with 0.1N HCl.

Results: Acid-exposed SEG-1 cells exhibited a significant increase in proliferation and total cell numbers, and a significant decrease in apoptosis. These effects were preceded by a rapid increase in the activities of ERK and p38, and a delayed increase in JNK activity. PD 98059 abolished the acid-induced increase in G0/G1 and decrease in subG0 phases of the cell cycle. Both SB 203580 and DN-JNK 1/2 inhibited the acid-induced progression from G0/G1 to G2/M. The acid-induced decrease in apoptosis was abolished by inhibition of either ERK or p38. In the patients, acid exposure significantly increased the activity of p38 in the metaplastic epithelium.

Conclusions: Acid increases proliferation and survival, and decreases apoptosis in SEG-1 cells by activating the MAPK pathways. Acid also activates the MAPK pathways in BE in vivo. These findings suggest that acid might contribute to carcinogenesis in BE through activation of MAPK pathways.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Apoptosis / drug effects
  • Barrett Esophagus / metabolism*
  • Barrett Esophagus / pathology
  • Biopsy
  • Cell Count
  • Cell Division / drug effects
  • Cell Survival / drug effects
  • Enzyme Activation / drug effects
  • Esophageal Neoplasms / metabolism*
  • Esophageal Neoplasms / pathology
  • Humans
  • Hydrochloric Acid / pharmacology*
  • JNK Mitogen-Activated Protein Kinases*
  • MAP Kinase Kinase 4
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / physiology
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Mucous Membrane / enzymology
  • Mucous Membrane / pathology
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / enzymology
  • p38 Mitogen-Activated Protein Kinases


  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases
  • Hydrochloric Acid