Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma

Abstract

Chronic inflammation plays a critical role in oncogenesis in various human organs. Epidemiological studies have demonstrated that patients with primary sclerosing cholangitis have a predisposition to develop cholangiocarcinoma (CC). However, the molecular mechanisms that account for the development of bile duct carcinomas are not well defined. We recently provided evidence that activation-induced cytidine deaminase (AID), a member of the DNA/ RNA editing enzyme family, is implicated in human tumorigenesis via its mutagenic activity. We found here that ectopic AID production is induced in response to tumor necrosis factor-␣ ( C holangiocarcinoma (CC) is an epithelial neoplasm that originates from the bile duct and can occur at any level of the biliary tree. 1,2 The incidence CC is increasing worldwide; it is the second most common primary hepatobiliary malignancy. 2 Although most CC arise in the absence of apparent risk factors, chronic inflammation of the biliary epithelium plays a critical role for their development. 2 In fact, primary sclerosing cholangitis (PSC) is the commonest predisposing condition for cholangiocarcinogenesis, and the prevalence of CC in patients with PSC ranges from 9% to 23%, with a cumulative annual risk of 1.5% per year of the disease. 1 Other risk factors for cholangiocarcinogenesis are also associated with chronic biliary tract inflammation, including chronic choledocholithiasis, liver fluke infestation, hepatolithiasis, Caroli's disease, and hepatitis C viral infection. 1 It has been hypothesized that the increased risk of CC in these conditions occurs because of chronic epithelial inflammation leading to cell proliferation, along with enhanced production of endogenous mutagens in the bile. 1 However, the precise molecular mechanism that accounts for the development of CC on the basis of chronic biliary tract inflammation remains unsolved.

Viral hepatitis-associated intrahepatic cholangiocarcinoma shares common disease processes with hepatocellular carcinoma

“…It is known that chronic infection, for example, because of hepatitis B or C virus infection, plays a primary role not only in trans-activating cellular proto-oncogenes and/or disrupting tumour suppressor genes, but also in causing chronic inflammation. Sustained cell proliferation in a micro-environment rich in inflammatory cells, cytokines/chemokines, growth factors and DNA-damaging agents (such as reactive oxygen and nitrogen species because of long-term inflammation) will lead to permanent genetic alterations and subsequent neoplastic transformation of the proliferating cells (Komori et al, 2008). For example, interleukin-6, an inflammatory cytokine, promotes human cholangiocarcinoma cells grown in vivo by inhibiting apoptosis through the activation of miRNAs including miR let-7a and miR370, thereby modulating the activation of STAT-3 pathways (Meng et al, 2007(Meng et al, , 2008Smirnova et al, 2007).…”

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

“…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.…”

Targeting activation-induced cytidine deaminase prevents colon cancer development despite persistent colonic inflammation

“…Recently, we demonstrated that one of the human nucleotide-editing enzymes, activation-induced cytidine deaminase (AID), induces somatic mutations in several tumor-related genes, including TP53, in gastrointestinal epithelial cells ; Kou et al, 2007;Matsumoto et al, 2007;Komori et al, 2008). AID was originally identified as an inducer of somatic mutations and class switch recombination of immunoglobulin genes, which diversifies the antibody production in B lymphocytes (Muramatsu et al, 2000).…”

“…Although AID expression is restricted to activated B cells under physiologic conditions, the inflammatory response can trigger aberrant AID expression in various epithelial organs. Stimulation of proinflammatory cytokines such as tumor necrosis factor (TNF)-a induces AID expression in hepatocytes, cholangiocytes and gastric epithelial cells Matsumoto et al, 2007;Komori et al, 2008). More importantly, aberrant AID expression in these epithelial cells results in the generation of nucleotide alterations in tumor-related genes and possible malignant transformation of the AID-expressing cells.…”