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临床病理及功能评估显示NBS1是上皮性卵巢癌铂耐药的一个预测指标。

Clinicopathological and Functional Evaluation Reveal NBS1 as a Predictor of Platinum Resistance in Epithelial Ovarian Cancers.

作者信息

Alblihy Adel, Alabdullah Muslim L, Ali Reem, Algethami Mashael, Toss Michael S, Mongan Nigel P, Rakha Emad A, Madhusudan Srinivasan

机构信息

Translational Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham NG5 1PB, UK.

Medical Center, King Fahad Security College (KFSC), Riyadh 11461, Saudi Arabia.

出版信息

Biomedicines. 2021 Jan 8;9(1):56. doi: 10.3390/biomedicines9010056.

DOI:10.3390/biomedicines9010056
PMID:33435622
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7826685/
Abstract

Platinum resistance seriously impacts on the survival outcomes of patients with ovarian cancers. Platinum-induced DNA damage is processed through DNA repair. NBS1 is a key DNA repair protein. Here, we evaluated the role of NBS1 in ovarian cancers. NBS1 expression was investigated in clinical cohorts (protein level ( = 331) and at the transcriptomic level ( = 1259)). Pre-clinically, sub-cellular localization of NBS1 at baseline and following cisplatin therapy was tested in platinum resistant (A2780cis, PEO4) and sensitive (A2780, PEO1) ovarian cancer cells. NBS1 was depleted and cisplatin sensitivity was investigated in A2780cis and PEO4 cells. Nuclear NBS1 overexpression was associated with platinum resistance ( = 0.0001). In univariate and multivariate analysis, nuclear NBS1 overexpression was associated with progression free survival (PFS) (-values = 0.003 and 0.017, respectively) and overall survival (OS) (-values = 0.035 and 0.009, respectively). NBS1 mRNA overexpression was linked with poor PFS ( = 0.011). Pre-clinically, following cisplatin treatment, we observed nuclear localization of NBS1 in A2780cis and PEO4 compared to A2780 and PEO1 cells. NBS1 depletion increased cisplatin cytotoxicity, which was associated with accumulation of double strand breaks (DSBs), S-phase cell cycle arrest, and increased apoptosis. NBS1 is a predictor of platinum sensitivity and could aid stratification of ovarian cancer therapy.

摘要

铂耐药严重影响卵巢癌患者的生存结局。铂诱导的DNA损伤通过DNA修复进行处理。NBS1是一种关键的DNA修复蛋白。在此，我们评估了NBS1在卵巢癌中的作用。在临床队列中研究了NBS1的表达（蛋白质水平（n = 331）和转录组水平（n = 1259））。在临床前，在铂耐药（A2780cis、PEO4）和敏感（A2780、PEO1）卵巢癌细胞中测试了NBS1在基线和顺铂治疗后的亚细胞定位。在A2780cis和PEO4细胞中敲低NBS1并研究顺铂敏感性。核NBS1过表达与铂耐药相关（P = 0.0001）。在单变量和多变量分析中，核NBS1过表达与无进展生存期（PFS）相关（P值分别为0.003和0.017）和总生存期（OS）相关（P值分别为0.035和0.009）。NBS1 mRNA过表达与不良的PFS相关（P = 0.011）。在临床前，顺铂治疗后，我们观察到与A2780和PEO1细胞相比，A2780cis和PEO4细胞中NBS1的核定位。NBS1敲低增加了顺铂的细胞毒性，这与双链断裂（DSB）的积累、S期细胞周期停滞和凋亡增加有关。NBS1是铂敏感性的预测指标，可有助于卵巢癌治疗的分层。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f529/7826685/dbd31a59fdc4/biomedicines-09-00056-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f529/7826685/fd3af924dd60/biomedicines-09-00056-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f529/7826685/e87b1ac3f94a/biomedicines-09-00056-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f529/7826685/f1e21cab51da/biomedicines-09-00056-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f529/7826685/dbd31a59fdc4/biomedicines-09-00056-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f529/7826685/fd3af924dd60/biomedicines-09-00056-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f529/7826685/e87b1ac3f94a/biomedicines-09-00056-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f529/7826685/f1e21cab51da/biomedicines-09-00056-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f529/7826685/dbd31a59fdc4/biomedicines-09-00056-g004.jpg

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