H. pylori Infection Is Associated with DNA Damage of Lgr5-Positive Epithelial Stem Cells in the Stomach of Patients with Gastric Cancer
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H. pylori (Hp) infection is a major risk factor in gastric carcinogenesis leading to epithelial mutagenesis, and may affect gastric epithelial stem cells.
To characterize the expression of Lgr5, a marker of epithelial stem cells in human gastric mucosa, to determine whether Hp infection affects Lgr5-positive epithelial cells (LPECs) and whether LPECs are susceptible to DNA damage associated with Hp infection.
Lgr5 expression was characterized in non-neoplastic gastric mucosa from 52 patients (34 with and 18 without gastric cancer (GC); 21 Hp-positive (Hp+) and 31 Hp-negative (Hp−)) by immunohistochemical and immunofluorescence staining. To determine the extent of DNA damage in LPECs, nuclear 8-hydroxydeoxyguanosine (8OHdG), a marker of DNA damage associated with oxidative stress, was measured by quantitative spectral image analysis.
LPECs were primarily present in gastric antrum. Higher numbers of LPECs were seen in Hp+ than in Hp− non-neoplastic mucosa of GC patients, P = .006, but not in patients without GC. 8OHdG levels in LPECs were significantly higher than in Lgr5-negative epithelial cells in Hp+ GC patients (P = .012) but not in Hp− cases (P = .414), whereas no difference was seen between Hp+ and Hp− mucosa of patients without GC.
The Lgr5-positive epithelial stem cell pool is expanded in Hp-associated gastritis in the antrum of patients with GC. In GC patients with active Hp infection, LPECs may be more susceptible to DNA damage than Lgr5-negative epithelial cells, suggesting that Hp infection may contribute to GC risk by affecting epithelial stem cells in the human stomach.
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- Warren JR, Marshall B. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet. 1983;1:1273–1275.
- Marshall BJ. Helicobacter pylori: the etiologic agent for peptic ulcer. JAMA. 1995;274:1064–1066. CrossRef
- Kimura K. Gastritis and gastric cancer. Asia. Gastroenterol Clin North Am. 2000;29:609–621. CrossRef
- Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading of gastritis. The updated Sydney system. International workshop on the histopathology of gastritis, Houston 1994. Am J Surg Pathol. 1996;20:1161–1181. CrossRef
- Herrera V, Parsonnet J. Helicobacter pylori and gastric adenocarcinoma. Clin Microbiol Infect. 2009;15:971–976. CrossRef
- Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–2917. CrossRef
- Kim JJ, Tao H, Carloni E, Leung WK, Graham DY, Sepulveda AR. Helicobacter pylori impairs DNA mismatch repair in gastric epithelial cells. Gastroenterology. 2002;123:542–553. CrossRef
- Yao Y, Tao H, Park DI, Sepulveda JL, Sepulveda AR. Demonstration and characterization of mutations induced by Helicobacter pylori organisms in gastric epithelial cells. Helicobacter. 2006;11:272–286. CrossRef
- Sepulveda AR, Yao Y, Yan W, et al. CpG methylation and reduced expression of O6-methylguanine DNA methyltransferase is associated with Helicobacter pylori infection. Gastroenterology. 2010;138:1836–1844. CrossRef
- Qiao XT, Gumucio DL. Current molecular markers for gastric progenitor cells and gastric cancer stem cells. J Gastroenterol. 2011;46:855–865. CrossRef
- Barker N, Huch M, Kujala P, et al. Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell. 2010;6:25–36. CrossRef
- Simon E, Petke D, Boger C, et al. The spatial distribution of LGR5+ cells correlates with gastric cancer progression. PLoS ONE. 2012;7:e35486. CrossRef
- Barker N, van Es JH, Kuipers J, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007;449:1003–1007. CrossRef
- Becker L, Huang Q, Mashimo H. Immunostaining of Lgr5, an intestinal stem cell marker, in normal and premalignant human gastrointestinal tissue. Sci World J. 2008;8:1168–1176. CrossRef
- Farinati F, Cardin R, Degan P, et al. Oxidative DNA damage accumulation in gastric carcinogenesis. Gut. 1998;42:351–356. CrossRef
- Hahm KB, Lee KJ, Choi SY, et al. Possibility of chemoprevention by the eradication of Helicobacter pylori: oxidative DNA damage and apoptosis in H. pylori infection. Am J Gastroenterol. 1997;92:1853–1857.
- Kuchino Y, Mori F, Kasai H, et al. Misreading of DNA templates containing 8-hydroxydeoxyguanosine at the modified base and at adjacent residues. Nature. 1987;327:77–79. CrossRef
- Barker N, Clevers H. Leucine-rich repeat-containing G-protein-coupled receptors as markers of adult stem cells. Gastroenterology. 2010;138:1681–1696. CrossRef
- Yao Y, Tao H, Kim JJ, et al. Alterations of DNA mismatch repair proteins and microsatellite instability levels in gastric cancer cell lines. Lab Invest. 2004;84:915–922. CrossRef
- Yoshizawa K, Jelezcova E, Brown AR, et al. Gastrointestinal hyperplasia with altered expression of DNA polymerase beta. PLoS ONE. 2009;4:e6493. CrossRef
- Houghton J, Stoicov C, Nomura S, et al. Gastric cancer originating from bone marrow-derived cells. Science. 2004;306:1568–1571. CrossRef
- Correa P, Houghton J. Carcinogenesis of Helicobacter pylori. Gastroenterology. 2007;133:659–672. CrossRef
- Mills JC, Shivdasani RA. Gastric epithelial stem cells. Gastroenterology. 2011;140:412–424. CrossRef
- Correa P. Human gastric carcinogenesis: a multistep and multifactorial process—First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 1992;52:6735–6740.
- Gologan A, Graham DY, Sepulveda AR. Molecular markers in Helicobacter pylori-associated gastric carcinogenesis. Clin Lab Med. 2005;25:197–222. CrossRef
- Farinati F, Cardin R, Russo VM, Busatto G, Franco M, Rugge M. Helicobacter pylori CagA status, mucosal oxidative damage and gastritis phenotype: a potential pathway to cancer? Helicobacter. 2003;8:227–234. CrossRef
- Sepulveda AR, Goyal A. Helicobacter pylori and Gastric Neoplasms In: Tan, D. & Lauwers, GY, eds. Advances in Surgical Pathology: Gastric Cancer. Philadelphia, PA: Lippincott Williams and Wilkins; 2011:22–37.
- Takeda K, Kinoshita I, Shimizu Y, Matsuno Y, Shichinohe T, Dosaka-Akita H. Expression of LGR5, an intestinal stem cell marker, during each stage of colorectal tumorigenesis. Anticancer Res. 2011;31:263–270.
- H. pylori Infection Is Associated with DNA Damage of Lgr5-Positive Epithelial Stem Cells in the Stomach of Patients with Gastric Cancer
Digestive Diseases and Sciences
Volume 58, Issue 1 , pp 140-149
- Cover Date
- Print ISSN
- Online ISSN
- Springer US
- Additional Links
- Helicobacter pylori
- DNA damage
- Stem cells
- Industry Sectors
- Author Affiliations
- 1. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3400 Spruce Street, Founders 6, Philadelphia, PA, 19104, USA
- 2. Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
- 3. Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
- 4. Department of Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA