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Jab1/Cops5 contributes to chemoresistance in breast cancer by regulating Rad51.
Cellular Signalling ( IF 4.4 ) Pub Date : 2018-09-20 , DOI: 10.1016/j.cellsig.2018.09.010
Guohong Liu 1 , Mingxia Yu 2 , Balu Wu 3 , Shuang Guo 2 , Xin Huang 2 , Fuling Zhou 3 , Francois X Claret 4 , Yunbao Pan 5
Affiliation  

Jab1 overexpression correlates with poor prognosis in breast cancer patients, suggestting that targeting the aberrant Jab1 signaling in breast cancer could be a promising strategy. In the current study, we investigate the hypothesis that Jab1 positively regulates the DNA repair protein Rad51 and, in turn, the cellular response of breast cancer to chemotherapy with adriamycin and cisplatin. High-throughput mRNA sequencing (RNA-Seq) data from 113 normal and 1109 tumor tissues (obtained from TCGA) were integrated to our analysis to give further support to our findings. We found that Jab1 was overexpressed in adriamycin-resistant breast cancer cell MCF-7R compared with parental MCF-7 cells, and that knockdown of Jab1 expression conferred cellular sensitivity to adriamycin and cisplatin both in vivo and in vitro. By contrast, exogenous Jab1 expression enhanced the resistance of breast cancer cells to adriamycin and cisplatin. Moreover, we discovered that Jab1 positively regulated Rad51 in p53-dependent manner and that overexpression of Rad51 conferred cellular resistance to adriamycin and cisplatin in Jab1-deficient cells. Data from TCGA further validated an correlation between Jab1 and Rad51 in breast cancer, and elevated Jab1 and Rad51 associated with poor survival in breast cancer patients. Our findings indicate that Jab1 association with Rad51 plays an important role in cellular response to chemotherapy in breast cancer.

中文翻译:

Jab1 / Cops5通过调节Rad51促进乳腺癌的化学耐药性。

Jab1过表达与乳腺癌患者的预后不良相关,表明针对乳腺癌中异常的Jab1信号转导可能是一种有前途的策略。在当前的研究中,我们调查了Jab1阳性调节DNA修复蛋白Rad51的假说,进而调节了乳腺癌对阿霉素和顺铂化疗的细胞反应。来自113个正常和1109个肿瘤组织(从TCGA获得)的高通量mRNA测序(RNA-Seq)数据已整合到我们的分析中,为我们的发现提供了进一步的支持。我们发现,与亲本MCF-7细胞相比,Jab1在耐阿霉素的乳腺癌细胞MCF-7R中过表达,并且敲除Jab1的表达在体内和体外均赋予了细胞对阿霉素和顺铂的敏感性。相比之下,外源性Jab1表达增强了乳腺癌细胞对阿霉素和顺铂的耐药性。此外,我们发现Jab1以p53依赖性方式正调控Rad51,而Rad51的过表达赋予Jab1缺陷细胞对阿霉素和顺铂的细胞抗性。TCGA的数据进一步验证了乳腺癌中Jab1和Rad51之间的相关性,以及与乳腺癌患者存活率低相关的Jab1和Rad51升高。我们的发现表明Jab1与Rad51的关联在乳腺癌细胞对化学疗法的反应中起着重要作用。我们发现Jab1以p53依赖性方式正调控Rad51,而Rad51的过表达赋予Jab1缺陷细胞对阿霉素和顺铂的细胞抗性。TCGA的数据进一步验证了乳腺癌中Jab1和Rad51之间的相关性,以及与乳腺癌患者存活率低相关的Jab1和Rad51升高。我们的发现表明Jab1与Rad51的关联在乳腺癌细胞对化学疗法的反应中起着重要作用。我们发现Jab1以p53依赖性方式正调控Rad51,而Rad51的过表达赋予Jab1缺陷细胞对阿霉素和顺铂的细胞抗性。TCGA的数据进一步验证了乳腺癌中Jab1和Rad51之间的相关性,以及与乳腺癌患者存活率低相关的Jab1和Rad51升高。我们的发现表明Jab1与Rad51的关联在乳腺癌细胞对化学疗法的反应中起着重要作用。
更新日期:2018-09-20
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