Complex engagement of DNA damage response pathways in human cancer and in lung tumor progression
Complex engagement of DNA damage response pathways in human cancer and in lung tumor progression
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DOI：
10.1093/carcin/bgm108
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发表时间：
2007-10-01
期刊：
影响因子：
4.7
通讯作者：
di Fagagna, Fabrizio d'Adda
中科院分区：
文献类型：
--
作者：
Nuciforo, Paolo Giovanni;Luise, Chiara;di Fagagna, Fabrizio d'Adda
肿瘤的发生和发展为DNA损伤的产生和随后的DNA损伤反应（DDR）途径的激活提供了多种场合。DDR信号通路涉及ATM、CHK2、53BP1等关键因子的参与以及组蛋白H2AX （γ -H2AX）的磷酸化。通过高通量组织微阵列对人类肿瘤和正常组织中DDR的系统研究发现，ATM和γ - h2ax参与肿瘤，但其激活程度受所涉及的器官和细胞类型的强烈影响，而53BP1的丢失是所研究肿瘤中最一致的特征。出乎意料的是，我们还在形态学正常的组织中观察到活化的DDR标记，也与炎症有关。对DDR在肺肿瘤发生不同阶段的动态参与的分析表明，53BP1的丢失发生在从正常到发育不良转变的早期，而激活形式的ATM和CHK2，而不是γ - h2ax，最初在侵袭前病变中积累，然后在肿瘤进展过程中丢失。在单个肺肿瘤中，ATM、CHK2的激活和53BP1的存在一致相关，而γ - h2ax与激活的ATM不相关。最后，对关键临床病理参数与活化的DDR因子之间关系的研究表明，局部肿瘤扩展的减少与ATM、CHK2的磷酸化和53BP1的存在之间存在统计学意义的相关性，而与早期肺癌的生存或复发等参数没有发现显著相关性。
Tumor initiation and progression provide a multitude of occasions for the generation of DNA damage and the consequent activation of the DNA damage response (DDR) pathway. DDR signaling involves the engagement of key factors such as ATM, CHK2, 53BP1 and the phosphorylation of histone H2AX (gamma-H2AX). The systematic study of DDR in human tumors and normal tissues by high-throughput tissue microarrays revealed that ATM and gamma-H2AX were engaged in cancer but the extent of their activation was strongly affected by the organ and cell type involved, whereas 53BP1 loss was the most consistent feature among the tumor studied. Unexpectedly, we also observed activated DDR markers in morphologically normal tissues, also in association with inflammation. Analysis of the dynamic engagement of DDR along the different stages of lung tumorigenesis showed that 53BP1 loss occurs early at the transition from normal to dysplastic change whereas the activated forms of ATM and CHK2, but not gamma-H2AX, initially accumulate in pre-invasive lesions and are then lost during tumor progression. In individual lung tumors, the activation of ATM, CHK2 and the presence of 53BP1 were consistently correlated, whereas gamma-H2AX did not correlate with activated ATM. Finally, the study of associations between critical clinicopathological parameters and activated DDR factors highlighted a statistically meaningful correlation between reduced local tumor extension and the phosphorylation of ATM, CHK2 and the presence of 53BP1, whereas no significant correlations with parameters such as survival or relapse of early-stage lung carcinomas were found.