Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma
Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma
复制标题
DOI：
10.1002/hep.22125
复制
发表时间：
2008-03-01
期刊：
影响因子：
13.5
通讯作者：
Chiba, Tsutomu
中科院分区：
文献类型：
--
作者：
Komori, Junji;Marusawa, Hiroyuki;Chiba, Tsutomu
慢性炎症在人体各器官的肿瘤发生中起着关键作用。流行病学研究表明，原发性硬化性胆管炎患者易患胆管癌。然而，导致胆道癌发生的分子机制还不是很清楚。我们最近提供的证据表明，激活诱导型胞苷脱氨酶(AID)是DNA/RNA编辑酶家族的成员，通过其诱变活性参与人类肿瘤的发生。我们在这里发现，在人胆管癌细胞中，异位AID的产生是通过IkappaB激酶依赖的核因子-kappaB(NF-kappa B)激活途径来响应肿瘤坏死因子-α(TNF-α)的刺激而诱导的。AID在胆管细胞中的异常表达导致肿瘤相关基因的体细胞突变，包括p53、c-myc和Ink4a/p16序列的启动子区域。在人类组织标本中，实时逆转录聚合酶链式反应(RT-PCR)分析显示，30例癌组织中有28例(93%)A-ID显著增加，而在正常肝脏中仅检测到微量的AID。免疫组织化学结果显示，所有受检的癌组织标本均显示癌细胞内源性AID蛋白过表达。此外，在20例胆汁上皮中，有16例在原发性硬化性胆管炎组织中检测到AID免疫染色。结论：促炎细胞因子诱导的AID的异常产生可能与胆管炎症与突变的遗传易感性有关，从而导致胆管癌变。
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-kappa B (NF-kappa B) 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 A-ID 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.