論文 - 詳細
| RRC ID | 43287 |
|---|---|
| 著者 | Komori J, Marusawa H, Machimoto T, Endo Y, Kinoshita K, Kou T, Haga H, Ikai I, Uemoto S, Chiba T. |
| タイトル | Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma. |
| ジャーナル | Hepatology |
| Abstract |
UNLABELLED: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. CONCLUSION:The proinflammatory cytokine-induced aberrant production of AID might link bile duct inflammation to an enhanced genetic susceptibility to mutagenesis, leading to cholangiocarcinogenesis. |
| 巻・号 | 47(3) |
| ページ | 888-96 |
| 公開日 | 2008-3-1 |
| DOI | 10.1002/hep.22125 |
| PMID | 18306229 |
| MeSH | Aged Bile Duct Neoplasms / enzymology Bile Duct Neoplasms / etiology* Bile Duct Neoplasms / pathology Bile Ducts, Intrahepatic* / drug effects Bile Ducts, Intrahepatic* / enzymology Bile Ducts, Intrahepatic* / pathology Cells, Cultured Cholangiocarcinoma / enzymology Cholangiocarcinoma / etiology* Cholangiocarcinoma / pathology Cholangitis / complications* Cholangitis / enzymology Cholangitis / pathology Cyclin-Dependent Kinase Inhibitor p16 / genetics Cytidine Deaminase / analysis Cytidine Deaminase / genetics Cytidine Deaminase / metabolism* Cytokines / pharmacology Female Genetic Predisposition to Disease Humans Male Middle Aged Mutagenesis Mutation Proto-Oncogene Proteins c-myc / genetics Tumor Suppressor Protein p53 / genetics |
| IF | 14.679 |
| 引用数 | 80 |
| WOS 分野 | GASTROENTEROLOGY & HEPATOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | SSP-25(RCB1293) RBE(RCB1292) |