Interaction between endogeneous mutator AID and exogenous oncogenic factors in carcinogenesis

激活诱导型胞苷脱氨酶(AID)是一种独特的能在基因组中诱导突变的酶，是免疫球蛋白基因的体细胞超突变和类切换重组的重要因子。本研究表明，AID不仅在活化的B淋巴细胞中表达，而且在慢性肝炎的肝脏和肝细胞癌组织中也有表达。丙型肝炎病毒感染可上调肝细胞中的辅助性蛋白表达。在胃中，幽门螺杆菌感染可诱导胃上皮细胞AID表达。在胃癌细胞系中表达的AID可以诱导肿瘤抑制基因P53的点突变。这些发现共同提示AID参与了慢性炎症和感染背景下发生的上皮性癌的发病机制。为了阐明AID在癌症中的作用，我们在小鼠身上进行了化学致癌实验。最初，我们使用了带有普遍存在的结构性启动子的AID转基因小鼠，但由于致死性淋巴瘤的频繁和早期死亡，这些启动子被证明不适合进行定量研究。第二项试验使用缺乏淋巴细胞的小鼠，由于频繁肺炎导致生长迟缓而失败。因此，我们开始了第三个试验，利用皮肤特异性角蛋白14启动子产生了一种新的AID转基因小鼠系。将获得的小鼠回交到易发生皮肤肿瘤的FVB/N品系。由化学物质诱导的皮肤肿瘤才刚刚开始。

Activation-induced cytidine deaminase(AID) is a unique enzyme that can induce mutations in the genome and is an essential factor for somatic hypermutation and class-switch recombination of the immunoglobulin genes. This study revealed that AID was expressed not only in activated B lymphocytes but also in the liver under chronic hepatitis and tissues of hepatocellular carcinoma. AID expression in hepatocytes was upregulated by infection with hepatitis C virus. In the stomach, AID expression was induced in the epithelium by infection with Helicobacter pylori. AID expressed in a gastric cancer cell line could induce point mutations in a tumor suppressor p53 gene. These findings collectively suggested involvement of AID in the pathogenesis of epithelial cancer arising in the background of chronic inflammation and infection. To clarify role of AID in cancer, experiments of chemical-induced carcinogenesis were performed in mice. Initially, we used AID transgenic mice with ubiquitous and constitutive promoter, which were turned out to be unsuitable for the quantitative study because of frequent and early death from lethal lymphoma. The second trial using mice that lack lymphocytes failed due to growth retardation by frequent pneumonia. Therefore, we started the third trial generating a novel line of AID transgenic mice using skin-specific keratin 14 promoter. Obtained mice were backcrossed to FVB/N strain, which is prone to develop skin tumor. The skin tumor induction by chemicals has just begun.