文章：

缺氧，DNA修复和基因不稳定

Hypoxia, DNA repair and genetic instability

原文发布日期：2008-03-01

DOI: 10.1038/nrc2344

类型: Review Article

开放获取: 否

要点：

1. The presence of intratumoural hypoxia is a negative prognostic indicator for many patients as it has been associated with increased local failure following radiotherapy and increased distant metastatic spread.
2. Hypoxia can drive the metastatic phenotype secondary to genetic instability, increased angiogenesis, decreased apoptosis and upregulation of a number of genes involved in the metastatic cascade (such as osteopontin, lysyl oxidase and vascular endothelial growth factor).
3. Both acute and chronic hypoxia exist in human tumours and these may have different biological consequences as a function of changes in hypoxia-inducible factor 1α-mediated transcription, altered protein translation and differential activation of hypoxia-associated cell cycle checkpoints.
4. Hypoxic cells can acquire a mutator phenotype that consists of decreased DNA repair, an increased mutation rate and increased chromosomal instability.
5. Defects in homologous recombination and mismatch repair have been documented in tumour cells that are exposed to chronic hypoxia.
6. Defective DNA repair in hypoxic cells could alter the sensitivity to radiotherapy and chemotherapy and render cells susceptible to molecular-targeted agents that are selectively toxic to checkpoint-deficient or repair-deficient tumour cells.

要点翻译：

1. 肿瘤内缺氧的存在对许多患者而言是一个不良预后指标，因为它与放疗后局部复发率升高及远处转移扩散加剧相关。
2. 缺氧可通过遗传不稳定性、血管生成增加、细胞凋亡减少以及转移级联反应相关基因（如骨桥蛋白、赖氨酰氧化酶和血管内皮生长因子）的上调，驱动转移表型的形成。
3. 人类肿瘤中同时存在急性和慢性缺氧，二者可能因缺氧诱导因子1α介导的转录变化、蛋白质翻译改变以及缺氧相关细胞周期检查点的差异激活而产生不同的生物学效应。
4. 缺氧细胞可能获得突变表型，表现为DNA修复能力下降、突变率增加和染色体不稳定性增强。
5. 已有研究证实，暴露于慢性缺氧的肿瘤细胞存在同源重组和错配修复缺陷。
6. 缺氧细胞中的DNA修复缺陷可能改变其对放疗和化疗的敏感性，并使细胞易受分子靶向药物的影响——这类药物对检查点缺陷或修复缺陷的肿瘤细胞具有选择性毒性。

英文摘要：

Areas of hypoxic tumour tissue are known to be resistant to treatment and are associated with a poor clinical prognosis. There are several reasons why this might be, including the capacity of hypoxia to drive genomic instability and alter DNA damage repair pathways. Significantly, current models fail to distinguish between the complexities of the hypoxic microenvironment and the biological effects of acute hypoxia exposures versus longer-term, chronic hypoxia exposures on the transcription and translation of proteins involved in genetic stability and cell survival. Acute and chronic hypoxia might lead to different biology within the tumour and this might have a direct effect on the design of new therapies for the treatment of hypoxic tumours.

摘要翻译： 

已知肿瘤组织的缺氧区域对治疗具有抗性，并与不良的临床预后相关。这可能有多方面的原因，包括缺氧诱导基因组不稳定并改变DNA损伤修复通路的能力。重要的是，目前的模型无法区分缺氧微环境的复杂性，以及急性缺氧暴露与长期慢性缺氧暴露对参与遗传稳定性和细胞存活的蛋白质转录和翻译的不同生物学效应。急性和慢性缺氧可能在肿瘤内导致不同的生物学变化，这可能直接影响针对缺氧肿瘤新疗法的设计。

原文链接：

Hypoxia, DNA repair and genetic instability