The role of the DNA damage checkpoint pathway in intraductal papillary mucinous neoplasms of the pancreas
The role of the DNA damage checkpoint pathway in intraductal papillary mucinous neoplasms of the pancreas
复制标题
DOI：
10.1158/1078-0432.ccr-07-0032
复制
发表时间：
2007-08-01
影响因子：
11.5
通讯作者：
Tsuneyoshi, Masazumi
中科院分区：
文献类型：
--
作者：
Miyasaka, Yoshihiro;Nagai, Eishi;Tsuneyoshi, Masazumi
目的：导管内乳头状粘液瘤（IPMN）通常表现为腺瘤向癌的转变，并伴有一些分子异常。ATM-Chk2-p53 DNA损伤检查点激活参与预防几种肿瘤的进展，我们分析了DNA损伤检查点在ipmn进展中的作用。实验设计：128例IPMN分为四组（导管内乳头状黏液腺瘤、交界性IPMN、非侵袭性导管内乳头状黏液癌和侵袭性导管内乳头状黏液癌），使用Thr(68)-磷酸化Chk2抗体进行免疫组织化学染色。还分析了ATM、Chk2和p21 （WAF1）的表达和p53的积累。结果：Chk2磷酸化在所有腺瘤中均可见，且随异型性进展呈显著降低趋势（Cochran-Armitage趋势检验P < 0.0001）。p21（wAF1）的表达也呈下降趋势（P < 0.0001），反映了DNA损伤检查点失活。p53的积累多见于恶性IPMNs。这表明DNA损伤检查点为p53突变提供了选择性压力。结论：我们的研究结果表明，DNA损伤检查点激活发生在IPMNs的早期，并阻止其发展。提示Chk2失活或p53突变对DNA损伤检查点通路的干扰有助于ipmn的癌变。
Purpose: Intraductal papillary mucinous neoplasms (IPMN) are known to show a transition from adenoma to carcinoma accompanied by several molecular abnormalities. ATM-Chk2-p53 DNA damage checkpoint activation, which is involved in prevention of the progression of several tumors, was analyzed to evaluate the role of the DNA damage checkpoint in the progression of IPMNs.Experimental Design: One hundred and twenty-eight IPMNs were classified into four groups (intraductal papillary mucinous adenoma, borderline IPMN, noninvasive intraductal papillary mucinous carcinoma, and invasive intraductal papillary mucinous carcinoma) and stained immunohistochemically using antibody for Thr(68)- phosphorylated Chk2. Expression of ATM, Chk2, and p21 (WAF1) and accumulation of p53 were also analyzed.Results: Chk2 phosphorylation was shown in all adenomas and showed a significant decreasing trend with the progression of atypia (P < 0.0001 by the Cochran-Armitage test for trend). Expression of p21(wAF1) also exhibited a decreasing tendency (P < 0.0001), reflecting DNA damage checkpoint inactivation. p53 accumulation was mostly detected in malignant IPMNs. It was suggested that the DNA damage checkpoint provides a selective pressure for p53 mutation.Conclusion: Our findings indicate that DNA damage checkpoint activation occurs in the early stage of IPMNs and prevents their progression. It is suggested that disturbance of the DNA damage checkpoint pathway due to Chk2 inactivation or p53 mutation contributes to the carcinogenesis of IPMNs.