DNA damage response genes and the development of cancer metastasis.
DNA damage response genes and the development of cancer metastasis.
复制标题
DOI：
10.1667/rr13515.1
复制
发表时间：
2014-02
影响因子：
3.4
通讯作者：
Lieberman HB
中科院分区：
文献类型：
--
作者：
Broustas CG;Lieberman HB
DNA损伤反应基因在维持健康基因组中起着至关重要的作用。细胞周期检查点和DNA修复基因的缺陷，特别是突变或异常下调，与广泛的人类疾病有关，包括神经退行性疾病和癌症的易感性。另一方面，DNA损伤反应和修复基因的上调也可导致癌症，以及增加癌细胞对DNA损伤治疗的抗性。近年来，很明显，许多参与DNA损伤修复的基因在肿瘤发生中具有额外的作用，最突出的是作为转录（辅）因子。虽然这些基因的缺陷与肿瘤的发生有因果关系，但它们在肿瘤进展中的作用更具争议，而且似乎取决于肿瘤类型。在一些肿瘤如黑色素瘤中，细胞周期检查点/DNA修复基因上调与肿瘤转移相关，而在许多其他癌症中观察到相反的情况。参与DNA损伤反应的几个基因，如RAD 9、PARP 1、BRCA 1、ATM和TP 53，已经通过许多体外生物化学和细胞测定、通过免疫组织化学检查人肿瘤标本或通过DNA全基因组基因表达谱分析与转移相关。这些基因中的许多作为转录效应物来调节与癌症发病机制有关的其他基因。此外，它们在许多人类肿瘤中异常表达，并且与肿瘤发生有因果关系。然而，这些基因的DNA损伤修复功能是促进转移所必需的还是另一种活性是负责的（例如，转录控制）尚未确定。重要的是，尽管有一些令人信服的体外证据，仍然需要研究来证明细胞周期检查点和DNA修复基因在体内调节转移表型中的作用。
DNA damage response genes play vital roles in the maintenance of a healthy genome. Defects in cell cycle checkpoint and DNA repair genes, especially mutation or aberrant downregulation, are associated with a wide spectrum of human disease, including a predisposition to the development of neurodegenerative conditions and cancer. On the other hand, upregulation of DNA damage response and repair genes can also cause cancer, as well as increase resistance of cancer cells to DNA damaging therapy. In recent years, it has become evident that many of the genes involved in DNA damage repair have additional roles in tumorigenesis, most prominently by acting as transcriptional (co-) factors. Although defects in these genes are causally connected to tumor initiation, their role in tumor progression is more controversial and it seems to depend on tumor type. In some tumors like melanoma, cell cycle checkpoint/DNA repair gene upregulation is associated with tumor metastasis, whereas in a number of other cancers the opposite has been observed. Several genes that participate in the DNA damage response, such as RAD9, PARP1, BRCA1, ATM and TP53 have been associated with metastasis by a number of in vitro biochemical and cellular assays, by examining human tumor specimens by immunohistochemistry or by DNA genomewide gene expression profiling. Many of these genes act as transcriptional effectors to regulate other genes implicated in the pathogenesis of cancer. Furthermore, they are aberrantly expressed in numerous human tumors and are causally related to tumorigenesis. However, whether the DNA damage repair function of these genes is required to promote metastasis or another activity is responsible (e.g., transcription control) has not been determined. Importantly, despite some compelling in vitro evidence, investigations are still needed to demonstrate the role of cell cycle checkpoint and DNA repair genes in regulating metastatic phenotypes in vivo.