Medicine in focusAberrant AID expression and human 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.
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2013, Molecular and Cellular ProteomicsTranslocations in Normal B Cells and Cancers. Insights from New Technical Approaches
2013, Advances in ImmunologyCitation Excerpt :In some translocations, such as the t(14;18) found in FL and the t(11;14) in MCL, it is thought that RAG and AID activity might collaborate in the generation of DSBs at the Bcl-2 and Bcl-1 loci (Tsai et al., 2008). In non-B cells, AID expression has been found in gastric (Matsumoto et al., 2007), liver, and colorectal tumors (Marusawa, 2008), and a role has also been suggested in germ cell tumors (Okazaki et al., 2007), breast cancer (Pauklin, Sernández, Bachmann, Ramiro, & Petersen-Mahrt, 2009), and prostate cancer (Lin et al., 2009). Nonprogrammed pathologic DSBs can originate in G1-arrested or cycling cells by a variety of mechanisms resulting from (1) exposure to physical agents, such as ionizing radiations; or (2) the malfunctioning of cellular biochemical processes, such as the production of reactive oxygen species (ROS) or breaks in fragile sites during impaired replication.
AID expression is correlated with Bcr-Abl expression in CML-LBC and can be down-regulated by As2O3 and/or imatinib
2011, Leukemia ResearchCitation Excerpt :However, results from previous investigations suggested that AID was not exclusively expressed in activated B cells. AID was detected in the gastric tissues infected by Helicobacter pylori, in liver tissues of HCV patients, as well as in some kinds of tumors, such as breast cancer, hepatoma and prostatic carcinoma [10]. Klemm also reported significant expression of AID mRNA in CML-LBC blasts, but little or no expression in CML-CP cells.
Role of Activation-Induced Cytidine Deaminase in Inflammation-Associated Cancer Development
2011, Advances in ImmunologyCitation Excerpt :The TGF-β-Smad protein axis acts as an oncogenic cytokine through the induction of angiogenesis and immune suppression (Miyazono et al., 2003). Together, these findings support the hypothesis that inflammatory stimulation of epithelial cells could induce the aberrant AID expression and initiate and/or promote oncogenic pathways by enhancing susceptibility to mutagenesis (Kinoshita and Nonaka, 2006; Marusawa, 2008; Marusawa and Chiba, 2010). The causal link between inflammation, AID expression, and the representative inflammation-associated human cancers is discussed in the following section.
Uracil in DNA-Its biological significance
2010, Mutation Research - Reviews in Mutation ResearchCitation Excerpt :This suggests that AID expression, at least in human gastric epithelial cells, is regulated through activation of the NF-κB pathway [29,30]. Aberrant AID expression directly leads to p53 mutagenesis in gastric cancer [29,30]. However the question: ‘how does AID mutate the p53 gene?’