Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
ReviewHelicobacter pylori infection generates genetic instability in gastric cells
Section snippets
Helicobacter pylori and gastric cancer
Helicobacter pylori is a Gram-negative, microaerophilic bacteria that colonizes the stomach of at least half of the world's population [1]. It is acquired during childhood and can persist for the rest of the host's life, if left untreated. The chronic inflammation that accompanies the infection is a risk factor for the development of gastric carcinoma [2]. H. pylori has been considered by the World Health Organization as a class I carcinogen [3].
There are two major variants of gastric
Genetic instability in gastric carcinoma
In gastric carcinoma a number of epi/genetic alterations have been described such as hypermethylation of CpG islands in promoter regions [84]. In several tumor suppressor genes, CpG island promoter methylation is associated with transcriptional silencing [85]. For instance, methylation of the promoter of E-cadherin is detected in 51% of gastric carcinomas, independently of the subtype [86], [87]. E-cadherin is a cell adhesion molecule and silencing by promoter methylation results in loss of
DNA repair
Genetic instability is a hallmark of cancer. Therefore, one would expect that if H. pylori infection causes damage to DNA or decreases the activity of DNA repair pathways it will allow accumulation of mutations that can cause activation of oncogenes or inactivation of tumor suppressor genes, that with time will increase the risk for development of gastric cancer. In this context, one of the most studied DNA repair mechanisms has been the MMR pathway.
Human MMR is initiated by the binding of a
Translation of basic knowledge to clinical research
Clinical data show that the results obtained in vitro are also true in patients. Gastric mucosa from patients infected with H. pylori show an increase in ROS and RNS (reactive nitrogen species), and consequently oxidative damage, compared to the gastric mucosa of non-infected patients [52], [127], [154], [155], [156], [157], [158]. The damage is in some cases reduced after eradication therapy [127]. There is also a correlation between the levels of DNA damage observed in H. pylori-infected
Model
Based on the available literature it is possible to identify 3 mechanisms by which H. pylori infection leads to loss of genomic integrity and promote carcinogenesis (Fig. 1):
- 1.
Increase in DNA damage and decrease in repair activity
- 2.
Mutations in mtDNA
- 3.
Induction of a transient mutator phenotype resulting in mutations in the DNA upon infection with H. pylori.
Due to H. pylori infection and to inflammatory response, increased amounts of ROS are generated in the gastric epithelial cells that induce
Acknowledgements
The authors thank Sascha Emilie Liberti for critical reading of the manuscript.
Grant support: Portuguese Science and Technology Foundation PIC/IC/82923/2007, NORDEA Foundation, Portuguese Science and Technology Foundation fellowship (A.M.D. Machado).
Ana Manuel Dantas Machado is a PhD student at the University of Roskilde, Denmark and Institute of Molecular Pathology and Immunology of the University of Porto, Portugal. Her main scientific interests are focused on H. pylori infection and its effect on DNA damage and repair of gastric cells.
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Cited by (0)
Ana Manuel Dantas Machado is a PhD student at the University of Roskilde, Denmark and Institute of Molecular Pathology and Immunology of the University of Porto, Portugal. Her main scientific interests are focused on H. pylori infection and its effect on DNA damage and repair of gastric cells.
Céu Figueiredo, PhD, is a Professor at the Faculty of Medicine, University of Porto, Portugal and a principal investigator at the Cancer Genetics group at the Institute of Molecular Pathology and Immunology of the University of Porto, Portugal. Her main scientific interests are focused on H. pylori infection and its association to gastric cancer.
Raquel Seruca, MD, PhD, is the leader of the Cancer Genetics group at the Institute of Molecular Pathology and Immunology of the University of Porto, Portugal. Her main scientific interests are focused on oncobiology and cancer genetics, namely signaling pathways involved in colorectal and gastric cancer.
Lene Juel Ramussen, PhD, is a Professor at the Faculty of Health Sciences, University of Copenhagen, Denmark and Managing Director of Center for Healthy Aging, University of Copenhagen, Denmark. Her main scientific interests are focused on DNA repair pathways involved in colorectal and gastric cancer as well as mitochondrial-mediated genetic instability in human disease.