Bile Acid Reflux Contributes to Development of Esophageal Adenocarcinoma via Activation of Phosphatidylinositol-Specific Phospholipase Cγ2 and NADPH Oxidase NOX5-S
Copyright policy )Bile Acid Reflux Contributes to Development of Esophageal Adenocarcinoma via Activation of Phosphatidylinositol-Specific Phospholipase Cγ2 and NADPH Oxidase NOX5-S
Abstract Gastroesophageal reflux disease complicated by Barrett's esophagus (BE) is a major risk factor for esophageal adenocarcinoma (EA). However, the mechanisms of the progression from BE to EA are not fully understood. Besides acid reflux, bile acid reflux may also play an important role in the progression from BE to EA. In this study, we examined the role of phosphatidylinositol-specific phospholipase C (PI-PLC) and a novel NADPH oxidase NOX5-S in bile acid–induced increase in cell proliferation. We found that taurodeoxycholic acid (TDCA) significantly increased NOX5-S expression, hydrogen peroxide (H2O2) production, and cell proliferation in EA cells. The TDCA-induced increase in cell proliferation was significantly reduced by U73122, an inhibitor of PI-PLC. PI-PLCβ1, PI-PLCβ3, PI-PLCβ4, PI-PLCγ1, and PI-PLCγ2, but not PI-PLCβ2 and PI-PLCδ1, were detectable in FLO cells by Western blot analysis. Knockdown of PI-PLCγ2 or extracellular signal-regulated kinase (ERK) 2 mitogen-activated protein (MAP) kinase with small interfering RNAs (siRNA) significantly decreased TDCA-induced NOX5-S expression, H2O2 production, and cell proliferation. In contrast, knockdown of PI-PLCβ1, PI-PLCβ3, PI-PLCβ4, PI-PLCγ1, or ERK1 MAP kinase had no significant effect. TDCA significantly increased ERK2 phosphorylation, an increase that was reduced by U73122 or PI-PLCγ2 siRNA. We conclude that TDCA-induced increase in NOX5-S expression and cell proliferation may depend on sequential activation of PI-PLCγ2 and ERK2 MAP kinase in EA cells. It is possible that bile acid reflux present in patients with BE may increase reactive oxygen species production and cell proliferation via activation of PI-PLCγ2, ERK2 MAP kinase, and NADPH oxidase NOX5-S, thereby contributing to the development of EA. Cancer Res; 70(3); 1247–55
- Brown University United States
- Emory University United States
- Rhode Island Hospital United States
Mitogen-Activated Protein Kinase 1, Cholagogues and Choleretics, Esophageal Neoplasms, Phosphodiesterase Inhibitors, Bile Reflux, Blotting, Western, Membrane Proteins, NADPH Oxidases, Hydrogen Peroxide, Adenocarcinoma, Gene Expression Regulation, Enzymologic, Bile Acids and Salts, Enzyme Activation, Gene Expression Regulation, Neoplastic, Isoenzymes, NADPH Oxidase 5, Cell Line, Tumor, Humans, Estrenes, Cell Proliferation
Mitogen-Activated Protein Kinase 1, Cholagogues and Choleretics, Esophageal Neoplasms, Phosphodiesterase Inhibitors, Bile Reflux, Blotting, Western, Membrane Proteins, NADPH Oxidases, Hydrogen Peroxide, Adenocarcinoma, Gene Expression Regulation, Enzymologic, Bile Acids and Salts, Enzyme Activation, Gene Expression Regulation, Neoplastic, Isoenzymes, NADPH Oxidase 5, Cell Line, Tumor, Humans, Estrenes, Cell Proliferation
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