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Aberrant AID expression and human cancer development

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Abstract

Cancer develops via a multistep process that occurs through the accumulation of somatic mutations of tumor-related genes that govern cell proliferation, regeneration, and apoptosis. The question how normal cells acquire the genetic changes that lead to malignant transformation is, however, unknown at present. Activation-induced cytidine deaminase (AID) produces immune-diversity by inducing somatic hypermutations and class-switch recombinations in human immunoglobulin genes. Unfortunately, this function of AID as a genome mutator could aim at the generation of somatic mutations in various host genes of non-lymphoid tissues and contribute to tumorgenesis. Notably, aberrant AID expression can be triggered by several pathogenic factors, including Helicobacter pylori infection and proinflammatory cytokine stimulation, in human epithelial cells, whereas AID expression is absent in those cells under physiologic conditions. Thus, aberrant AID activity in epithelial tissues may provide the critical link between inflammation, somatic mutations, and cancer development.

Introduction

In contrast to normal human cells that replicate their DNA with exceptional accuracy, most cancer cells arise from a stepwise accumulation of genetic changes. The genomes of incipient cancer cells acquire alterations in the nucleotide sequences of proto-oncogenes, tumor-suppressor genes, and other genes that control cell proliferation, regeneration, and apoptosis (Hahn & Weinberg, 2002). Because normal mutation rates cannot account for the accumulation of multiple mutations in tumor cells (Loeb, Loeb, & Anderson, 2003), certain molecular mechanisms must be present to account for the nucleotide alterations observed in most human cancer cells. One mechanism that may account for the enhanced susceptibility to mutagenesis is a genetic defect in the DNA repair pathways. For example, impairments of the mismatch repair system result in a familial colorectal cancer syndrome, defects in nucleotide excision repair are associated with skin cancer, and defects in homologous recombination and double-strand break repair are associated with breast cancer and lymphoma (Hoeijmakers, 2001). The frequency of such defects in the DNA repair system, however, is generally low among human cancers. Thus, how a large number of genetic mutations arise during the course of cancer development remains a fundamental question. We provide an overview of the novel molecular mechanism by which normal epithelial cells acquire DNA mutations under pathologic conditions, including chronic inflammation, and pathogenic viral or bacterial infections.

Section snippets

Nucleotide-editing enzymes that can induce mutations in DNA and/or RNA

To maintain homeostasis and conserve genetic information, cells have several systems to prevent mutations, and repair any changes in nucleotide sequences, thus avoiding harmful sporadic nucleotide alterations, so-called “somatic mutations”. In contrast to normal cells, however, cancer cells usually acquire a variety of somatic mutations during the transformation process. Recently, a novel enzyme family was highlighted in association with the mechanism of mutagenesis. Cytidine deaminases are

AID is capable of inducing mutations in DNA sequences

Among the APOBEC family, AID has a unique ability with favorable function. Antigen stimulation of activated B lymphocytes triggers somatic hypermutations, which diversifies the variable region of the immunoglobulin genes, and AID expression is essential for this process. The finding that AID induces the production of somatic hypermutations in the immunoglobulin gene indicates that AID can induce nucleotide alterations in human DNA sequences. The activity of AID as a genome mutator leads to the

Aberrant AID expression in gastric epithelial cells in association with Helicobacter pylori infection

The majority of human gastric cancers arise in the stomach with clinical features of chronic gastritis (Aoi, Marusawa, Sato, Chiba, & Maruyama, 2006). The most important causative pathogen for chronic gastric inflammation and a class one carcinogen for human gastric cancer is H. pylori infection (Chiba, Seno, Marusawa, Wakatsuki, & Okazaki, 2006). The mechanisms that link H. pylori-induced chronic gastric inflammation and cancer development remain unclear, but it is thought to involve a

Conclusion and future aspects

Proinflammatory cytokine induction of AID expression via the NF-κB activation pathway is not limited to gastric epithelial cells. Indeed, AID expression is also mediated by TNF-α or interleukin-1β in human hepatocytes (Endo et al., 2007). More importantly, hepatitis C virus (HCV) strongly triggers AID expression in hepatocytes in collaboration with proinflammatory cytokines (Endo et al., 2007), and ectopic AID expression is observed in human liver specimens with chronic hepatic inflammation

Acknowledgement

I am grateful to Dr. Yoko Endo for help of manuscript preparation.

References (19)

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