Expression of activation‐induced cytidine deaminase in human hepatocytes during hepatocarcinogenesis

Abstract

Activation-induced cytidine deaminase (AID) plays a role as a genome mutator in activated B cells, and inappropriate expression of AID has been implicated in the immunopathological phenotype of human B-cell malignancies. Notably, we found that the transgenic mice overexpressing AID developed lung adenocarcinoma and hepatocellular carcinoma (HCC), suggesting that ectopic expression of AID can lead to tumorigenesis in epithelial tissues as well. To examine the involvement of AID in the development of human HCC, we analyzed the AID expression and its correlation with mutation frequencies of the p53 gene in liver tissues from 51 patients who underwent resection of primary HCCs. The specific expression, inducibility by cytokine stimulation and mutagenic activity of AID were investigated in cultured human hepatocytes. Only trace amounts of AID transcripts were detected in the normal liver; however, endogenous AID was significantly upregulated in both HCC and surrounding noncancerous liver tissues with underlying chronic hepatitis or liver cirrhosis (p < 0.05). Most liver tissues with underlying chronic inflammation with endogenous AID upregulation already contained multiple genetic changes in the p53 gene. In both hepatoma cell lines and cultured human primary hepatocytes, the expression of AID was substantially induced by TGF-b stimulation. Aberrant activation of AID in hepatocytes resulted in accumulation of multiple genetic alterations in the p53 gene. Our findings suggest that the aberrant expression of AID is observed in human hepatocytes with several pathological settings, including chronic liver disease and HCC, which might enhance the genetic susceptibility to mutagenesis leading to hepatocarcinogenesis. ' 2006 Wiley-Liss, Inc.

Accumulation of Somatic Mutations in TP53 in Gastric Epithelium With Helicobacter pylori Infection

“…Consistently, several studies have reported that genetic aberrations are frequently detected in non-tumorous inflamed epithelial tissues where the risk of cancer development is remarkably high [38][39][40] . For example, TP53 mutations are detected in the inflamed mucosa of the colonic epithelium of patients with inflammatory bowel disease 41,42 .…”

A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations

“…The presence of mutations in non-cancerous tissue expressing AID is reminiscent of a study on human patients with chronic hepatitis (Kou et al, 2006), together suggesting a causal role of AID in tumorigenesis. It is noteworthy that the mutations corresponding to two mutational hot spots in TP53 gene encoding human p53 (R273 and R175) were included in mutations found in TNAP-AID HCC.…”

“…We consider that the TNAP-AID mouse model is useful for human HCC studies because it has been shown that AID is induced in the human pre-cancerous conditions of chronic hepatitis and cirrhosis (Kou et al, 2006). The relatively long latency before HCC development in this model is reasonable, considering that it is a physiological recapitulation of a human tumour phenotype that takes decades to develop.…”

“…The hypothesis is based on the following observations: (1) AID can induce mutations in non-B cells (Yoshikawa et al, 2002); (2) AID transgenic mice develop various tumours, including T-cell lymphoma and lung microadenoma (Okazaki et al, 2003) and (3) AID can be induced in human hepatic, gastric and biliary epithelial cells when stimulated with pro-inflammatory cytokines, such as transforming growth factor-b and tumor necrosis factor-a, and when challenged with pathogens, such as hepatitis C virus (HCV) and Helicobacter pylori. AID is detected in the liver, stomach and bile duct in humans (Kou et al, 2006;Endo et al, 2007;Matsumoto et al, 2007;Komori et al, 2008). On the basis of this evidence, AID is a potential candidate for a mutagen in human cancers.…”

Expression of activation-induced cytidine deaminase in human hepatocytes via NF-κB signaling

“…We demonstrated that aberrant AID expression can induce SHM in a nonimmunoglobulin gene in nonlymphoid cells Yoshikawa et al, 2002), and mice with constitutive expression of AID develop various tumors, including T-cell lymphomas and lung adenomas, suggesting that AID has direct oncogenic potential via the mutagenesis of inappropriate target genes (Okazaki et al, 2003). Notably, we recently revealed that endogenous AID was significantly upregulated in both HCC and surrounding noncancerous liver tissues with underlying cirrhosis or chronic hepatitis, where only minute AID expression is detectable in normal liver (Kou et al, 2007). Moreover, both tumor and nontumor liver tissues with hepatitis C virus (HCV) infection exhibited significantly higher expression levels of the AID gene compared with liver tissues of normal control.…”