Widespread activation of the DNA damage response in human pancreatic intraepithelial neoplasia.
Widespread activation of the DNA damage response in human pancreatic intraepithelial neoplasia.
复制标题
DOI：
10.1038/modpathol.2009.114
复制
发表时间：
2009-11
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
胰腺上皮内瘤变（PanIN）病变是胰腺癌最常见的非侵袭性前体病变。我们推测PanIN上皮内积累的DNA损伤激活了检查点机制。组织微阵列由81例手术切除的原发性胰腺腺癌和一组独立的58个PanIN病变（31个PanIN-1、14个PanIN-2和13个PanIN-3）构建。使用抗γ H2 AXSer 139、抗磷酸ATMSer 1981、抗磷酸Chk 2 Thr 68和抗p53进行免疫组织化学标记。结合核室标记的面积和强度确定每个病变的“组织学评分”。与胰腺导管上皮（评分2.36）相比，在非侵袭性前驱病变（PanIN-1、-2和-3评分分别为4.34、6.21和7.50）中观察到γ H2 AXSer 139标记的进行性增加，与DNA损伤的逐步升级一致（ANOVA，P<0.0001）。同时，在所有组织学分级的PanIN病变中均观察到ATM-Chk 2检查点通路的激活。具体而言，PanIN-1、PanIN-2和PanIN-3的pATMSer 1981组织学评分分别为4.83、5.14和7.17，而导管上皮为2.33方差分析，P<0.0001; pChk 2 Thr 68的相应评分在PanINs-1、-2和-3中分别为5.43、7.64和5.44，而在导管上皮中为2.75（方差分析，P<0.0001）。相比之下，在导管上皮和PanIN-1和2（组织学评分为0-1.86）中观察到核p53缺失至最小，仅在PanIN-3和浸润性瘤形成（组织学评分为4.00和4.22）阶段观察到显著上调（对应于突变失活）。癌细胞核p53的积累与ATM-Chk 2检查点的减弱和“基线”水平的恢复有关。总之，ATM-Chk 2检查点通路的激活通常在PanIN中观察到，可能是对致癌基因突变和端粒功能障碍等事件造成的累积DNA损伤的响应。p53功能的丧失似乎是绕过该检查点并随后进展为浸润性腺癌的关键决定因素。
Pancreatic intraepithelial neoplasia (PanIN) lesions are the most common non-invasive precursors of pancreatic adenocarcinoma. We postulated that accumulating DNA damage within the PanIN epithelium activates checkpoint mechanisms. Tissue microarrays were constructed from 81 surgically resected primary pancreatic adenocarcinomas, and an independent set of 58 PanIN lesions (31 PanIN-1, 14 PanIN-2, and 13 PanIN-3). Immunohistochemical labeling was performed using anti- γH2AXSer139, anti-phosphoATMSer1981, anti-phosphoChk2Thr68, and anti-p53. A “histologic score” combining area and intensity of labeling in the nuclear compartment was determined for each lesion. A progressive increase in γH2AXSer139 labeling, consistent with escalating DNA damage, was observed in the non-invasive precursor lesions (scores of 4.34, 6.21, and 7.50, respectively for PanIN-1, -2, and -3), compared to pancreatic ductal epithelium (score 2.36) (ANOVA, P<0.0001). In conjunction, activation of the ATM-Chk2 checkpoint pathway was observed in all histological grades of PanIN lesions. Specifically, pATMSer1981 histologic scores for PanIN-1, PanIN-2, and PanIN-3 were 4.83, 5.14, and 7.17, respectively, versus 2.33 for ductal epithelium (ANOVA, P<0.0001); the corresponding scores for pChk2Thr68 were 5.43, 7.64, and 5.44 in PanINs-1, -2, and -3, respectively, versus 2.75 in ductal epithelium (ANOVA, P<0.0001). In contrast, absent to minimal nuclear p53 was observed in ductal epithelium, and in PanINs-1 and 2 (histologic score of 0-1.86), with a significant upregulation (corresponding to mutational inactivation) seen only at the stage of PanIN-3 and invasive neoplasia (histologic score of 4.00 and 4.22). Nuclear p53 accumulation in cancers was associated with attenuation of the ATM-Chk2 checkpoint and a restitution of “baseline” levels. To conclude, activation of the ATM-Chk2 checkpoint pathway is commonly observed in PanINs, likely in response to the accumulating DNA damage from events such as oncogene mutations and telomere dysfunction. Loss of p53 function appears to be a critical determinant for bypassing this checkpoint and the subsequent progression to invasive adenocarcinoma.
登录
查看更多内容
影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
影响因子：
50.3
作者：
Hingorani, SR;Wang, LF;Tuveson, DA
通讯作者：
Tuveson, DA
影响因子：
50.3
作者：
Hingorani, SR;Petricoin, EF;Tuveson, DA
通讯作者：
Tuveson, DA