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Cited by 38Esophageal Cancer Research and TreatmentGastroesophageal reflux and treatmentsProtein Kinase Regulation and GTPase Signaling

Bile Acid Reflux Contributes to Development of Esophageal Adenocarcinoma via Activation of Phosphatidylinositol-Specific Phospholipase Cγ2 and NADPH Oxidase NOX5-S

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Hong, Jie, Behar, Jose, Wands, Jack, Resnick, Murray, Wang, Li Juan, DeLellis, Ronald A., Lambeth, David, Cao, Weibiao·2010·Cancer Research
DOI 10.1158/0008-5472.can-09-2774PMC PMC3057572

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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 (H(2)O(2)) 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-PLCbeta1, PI-PLCbeta3, PI-PLCbeta4, PI-PLCgamma1, and PI-PLCgamma2, but not PI-PLCbeta2 and PI-PLCdelta1, were detectable in FLO cells by Western blot analysis. Knockdown of PI-PLCgamma2 or extracellular signal-regulated kinase (ERK) 2 mitogen-activated protein (MAP) kinase with small interfering RNAs (siRNA) significantly decreased TDCA-induced NOX5-S expression, H(2)O(2) production, and cell proliferation. In contrast, knockdown of PI-PLCbeta1, PI-PLCbeta3, PI-PLCbeta4, PI-PLCgamma1, or ERK1 MAP kinase had no significant effect. TDCA significantly increased ERK2 phosphorylation, an increase that was reduced by U73122 or PI-PLCgamma2 siRNA. We conclude that TDCA-induced increase in NOX5-S expression and cell proliferation may depend on sequential activation of PI-PLCgamma2 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-PLCgamma2, ERK2 MAP kinase, and NADPH oxidase NOX5-S, thereby contributing to the development of EA.

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  • PLCγ2's necessary role in contributing to excessive ROS production and cell proliferation, induced by taurodeoxycholic acid, causes activation of PI-PLCγ2, ERK-2, and MAPK and production of NADPH oxidase NOX5-S.

    “This is thought to be through PLCγ2’s necessary role in contributing to excessive ROS production and cell proliferation, induced by taurodeoxycholic acid, causing the activation of PI-PLCγ2, ERK-2, and MAPK and production of NADPH oxidase NOX5-S.”

    From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [146]

  • PLCγ2 was found to potentially contribute to the formation of esophageal adenocarcinoma.

    “PLCγ2 was also found to potentially contribute to other tumorogenic situations such as the formation of esophageal adenocarcinoma (146).”

    From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [146]

  • The resulting mutagenic stress may be a factor in the development of esophageal adenocarcinoma.

    “The resulting mutagenic stress may also be a factor in the development of esophageal adenocarcinoma (146).”

    From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [146]

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Authors
Hong, J., Behar, J., Wands, J., Resnick, M., Wang, L. J., DeLellis, R. A., Lambeth, D., & Cao, W.
Affiliations
  • Emory University (US)
  • Authors' Affiliations: Departments of 1Pathology and 2Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island and 3Department of Pathology, Emory University School of Medicine, Atlanta, Georgia
Corresponding author
Cao, Weibiao
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2010-01-31
Volume
70
Issue
3
Pages
1247-1255
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-09-2774
PMC
PMC3057572
OpenAlex
W2080238524
Cited by
38
References
1
Citations by year
2026: 1 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 2 · 2018: 2 · 2017: 4 · 2016: 1 · 2014: 3 · 2013: 3 · 2012: 7
FWCI
5.07
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5r01dk080703-05)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK-080703)
Topics
  • Health Sciences › Medicine › Surgery › Esophageal Cancer Research and Treatment
  • Health Sciences › Medicine › Gastroenterology › Gastroesophageal reflux and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
bile reflux, esophageal adenocarcinoma, Barrett's esophagus, phosphatidylinositol-specific phospholipase C, PLCγ2, taurodeoxycholic acid, hydrogen peroxide, reactive oxygen species, cell proliferation, U73122
MeSH terms
NADPH Oxidase 5, Adenocarcinoma, Bile Acids and Salts, Bile Reflux, Cholagogues and Choleretics, Enzyme Activation, Esophageal Neoplasms, Estrenes, Humans, Hydrogen Peroxide, Isoenzymes, Membrane Proteins, Phosphodiesterase Inhibitors, Pyrrolidinones, Taurodeoxycholic Acid, Blotting, Western, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, NADPH Oxidases, Mitogen-Activated Protein Kinase 1, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Cell Line, Tumor, Cell Proliferation, Phospholipase C gamma

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