Activation-Induced Cytidine Deaminase Contributes to Pancreatic Tumorigenesis by Inducing Tumor-Related Gene Mutations.
Activation-Induced Cytidine Deaminase Contributes to Pancreatic Tumorigenesis by Inducing Tumor-Related Gene Mutations.
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DOI：
10.1158/0008-5472.can-14-3028
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发表时间：
2015-08
期刊：
影响因子：
11.2
通讯作者：
Y. Sawai;Y. Kodama;Takahiro Shimizu;Yuji Ota;T. Maruno;Y. Eso;A. Kurita;M. Shiokawa;Y. Tsuji-Y.-Tsuj
中科院分区：
文献类型：
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作者：
Y. Sawai;Y. Kodama;Takahiro Shimizu;Yuji Ota;T. Maruno;Y. Eso;A. Kurita;M. Shiokawa;Y. Tsuji-Y.-Tsuj
胰腺导管腺癌（PDAC）是通过各种基因突变的积累而发生的。然而，PDAC发展中突变的潜在机制尚未完全了解。最近对各种癌症的突变模式与特定诱变剂之间的密切关联的了解使我们研究了激活诱导的胞苷脱氨酶（AID）（一种DNA编辑酶）在胰腺肿瘤发生中的可能参与。我们的免疫组化结果显示AID蛋白表达在人类腺泡导管化生，胰腺上皮内瘤变，PDAC。AID蛋白表达的量和强度均随着人PDAC组织中癌前病变到癌性病变的进展而增加。为了进一步评估异位上皮AID表达在胰腺肿瘤发生中的意义，我们分析了AID转基因（AIDTg）小鼠的表型。与我们的假设一致，即AID参与胰腺肿瘤发生的突变机制，我们发现在AID Tg小鼠的胰腺中发生癌前病变。使用深度测序，我们还在我们对AID Tg小鼠的整个胰腺的分析中检测到Kras和c-Myc突变。此外，桑格测序证实了Kras、c-Myc和Smad 4突变的存在，在通过激光捕获显微切割分离的AID Tg小鼠的癌前病变中存在AID的典型突变足迹。总之，我们的研究结果表明，艾滋病有助于胰腺癌前病变的发展，诱导肿瘤相关基因突变。我们的新小鼠模型没有故意操纵特定的肿瘤相关基因，为分析PDAC中涉及的突变提供了一个强大的系统。
Pancreatic ductal adenocarcinoma (PDAC) develops via an accumulation of various gene mutations. The mechanism underlying the mutations in PDAC development, however, is not fully understood. Recent insight into the close association between the mutation pattern of various cancers and specific mutagens led us to investigate the possible involvement of activation-induced cytidine deaminase (AID), a DNA editing enzyme, in pancreatic tumorigenesis. Our immunohistochemical findings revealed AID protein expression in human acinar ductal metaplasia, pancreatic intraepithelial neoplasia, and PDAC. Both the amount and intensity of the AID protein expression increased with the progression from precancerous to cancerous lesions in human PDAC tissues. To further assess the significance of ectopic epithelial AID expression in pancreatic tumorigenesis, we analyzed the phenotype of AID transgenic (AID Tg) mice. Consistent with our hypothesis that AID is involved in the mechanism of the mutations underlying pancreatic tumorigenesis, we found precancerous lesions developing in the pancreas of AID Tg mice. Using deep sequencing, we also detected Kras and c-Myc mutations in our analysis of the whole pancreas of AID Tg mice. In addition, Sanger sequencing confirmed the presence of Kras, c-Myc, and Smad4 mutations, with the typical mutational footprint of AID in precancerous lesions in AID Tg mice separated by laser capture microdissection. Taken together, our findings suggest that AID contributes to the development of pancreatic precancerous lesions by inducing tumor-related gene mutations. Our new mouse model without intentional manipulation of specific tumor-related genes provides a powerful system for analyzing the mutations involved in PDAC.