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RAD51 高表达促进 KRAS 突变型肺癌细胞的 DNA 损伤修复和存活。

High expression of RAD51 promotes DNA damage repair and survival in KRAS-mutant lung cancer cells.

机构信息

Department of pharmacy, First Affiliated Hospital of Nanchang University, Nanchang 330039, China.

Department of Oncology, Beijing Daxing District People's Hospital, Capital Medical University, Beijing 102600, China.

出版信息

BMB Rep. 2019 Feb;52(2):151-156. doi: 10.5483/BMBRep.2019.52.2.213.

DOI:10.5483/BMBRep.2019.52.2.213
PMID:30638176
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6443323/
Abstract

RAD51 recombinase plays a critical role in homologous recombination and DNA damage repair. Here we showed that expression of RAD51 is frequently upregulated in lung cancer tumors compared with normal tissues and is associated with poor survival (hazard ratio (HR) = 2, P = 0.0009). Systematic investigation of lung cancer cell lines revealed higher expression of RAD51 in KRAS mutant (MT) cells compared to wildtype (WT) cells. We further showed that MT KRAS, but not WT KRAS, played a critical role in RAD51 overexpression via MYC. Moreover, our results revealed that KRAS MT cells are highly dependent on RAD51 for survival and depletion of RAD51 resulted in enhanced DNA double strand breaks, defective colony formation and cell death. Together, our results suggest that mutant KRAS promotes RAD51 expression to enhance DNA damage repair and lung cancer cell survival, suggesting that RAD51 may be an effective therapeutic target to overcome chemo/radioresistance in KRAS mutant cancers. [BMB Reports 2019; 52(2): 151-156].

摘要

RAD51 重组酶在同源重组和 DNA 损伤修复中起着关键作用。在这里，我们发现与正常组织相比，RAD51 在肺癌肿瘤中的表达经常上调，并且与不良预后相关（风险比（HR）=2，P=0.0009）。对肺癌细胞系的系统研究表明，KRAS 突变（MT）细胞中 RAD51 的表达高于野生型（WT）细胞。我们进一步表明，MT KRAS 而非 WT KRAS 通过 MYC 对 RAD51 过表达起着关键作用。此外，我们的结果表明，KRAS MT 细胞对 RAD51 的依赖性很高，RAD51 的缺失会导致 DNA 双链断裂增加、集落形成缺陷和细胞死亡。总之，我们的结果表明，突变型 KRAS 促进 RAD51 的表达，以增强 DNA 损伤修复和肺癌细胞的存活，这表明 RAD51 可能是克服 KRAS 突变型癌症化疗/放疗耐药的有效治疗靶点。[BMB 报告 2019；52(2): 151-156]。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3efa/6443323/1eaaa6f8e7f2/bmb-52-151f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3efa/6443323/6cc10c6cb77a/bmb-52-151f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3efa/6443323/8016600fe3dd/bmb-52-151f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3efa/6443323/b5a81d7a9f78/bmb-52-151f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3efa/6443323/1eaaa6f8e7f2/bmb-52-151f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3efa/6443323/6cc10c6cb77a/bmb-52-151f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3efa/6443323/8016600fe3dd/bmb-52-151f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3efa/6443323/b5a81d7a9f78/bmb-52-151f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3efa/6443323/1eaaa6f8e7f2/bmb-52-151f4.jpg

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