Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma.
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-alpha (TNF-alpha) stimulation via the IkappaB kinase-dependent nuclear factor-kappaB (NF-kappaB) activation pathway in human cholangiocarcinoma-derived cells. Aberrant expression of AID in biliary cells resulted in the generation of somatic mutations in tumor-related genes, including p53, c-myc, and the promoter region of the INK4A/p16 sequences. In human tissue specimens, real-time reverse transcription polymerase chain reaction (RT-PCR) analyses revealed that AID was increased significantly in 28 of 30 CC tissues (93%), whereas only trace amounts of AID were detected in the normal liver. Immunohistochemistry showed that all of the CC tissue samples examined showed overproduction of endogenous AID protein in cancer cells. Moreover, immunostaining for AID was detectable in 16 of 20 bile epithelia in the tissues underlying primary sclerosing cholangitis.


CONCLUSIONS
The proinflammatory cytokine-induced aberrant production of AID might link bile duct inflammation to an enhanced genetic susceptibility to mutagenesis, leading to cholangiocarcinogenesis.
Komori
Junji
J
Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Marusawa
Hiroyuki
H
Machimoto
Takafumi
T
Endo
Yoko
Y
Kinoshita
Kazuo
K
Kou
Tadayuki
T
Haga
Hironori
H
Ikai
Iwao
I
Uemoto
Shinji
S
Chiba
Tsutomu
T
D000368:Aged; D001650:Bile Duct Neoplasms / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002478:Cells, Cultured; D018281:Cholangiocarcinoma / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D002761:Cholangitis / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D003564:Cytidine Deaminase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D016296:Mutagenesis; D009154:Mutation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D019941:Cyclin-Dependent Kinase Inhibitor p16; D016207:Cytokines; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase