Comprehensive analysis of ceRNA network of ERCC4 in colorectal cancer.
Comprehensive analysis of ceRNA network of ERCC4 in colorectal cancer.
复制标题
结直肠癌ERCC4 ceRNA网络综合分析
作者：
Hu H;Liu S;Chu A;Chen J;Xing C;Jing J
目的ERCC4是核苷酸切除修复（NER）中最重要的分子之一，因其在结直肠癌（CRC）中的高表达而受到研究。本研究旨在了解ERCC4在结直肠癌中的竞争性内源性RNA （ceRNA）网络。方法与材料采用TCGA数据库检测泛癌组织ERCC4 mRNA的表达。基于人蛋白图谱（Human protein Atlas， HPA）评估ERCC4蛋白表达。我们在结直肠癌中筛选了两组ERCC4high和ERCC4low表达的delncrna和demirna。然后利用Starbase数据库构建基于delncrna和demirna的lncRNA-miRNA-ERCC4调控网络，并利用Cytoscape软件进行可视化。采用Kaplan-Meier分析评价ceRNA网络的预后价值。进一步，RT-PCR验证了ceRNA网络中代表性分子在结直肠癌和正常组织中的表达。并利用RNAactDrug数据库评价了这些分子与药物敏感性的关系。结果ERCC4 mRNA水平在多种肿瘤中过表达，包括结直肠癌。ERCC4蛋白水平在结直肠癌中也有高表达。从ercc4高表达组和ercc4低表达组的结直肠癌样本中共鉴定出1885个delncrna和68个demirna。通过Starbase数据库的预测，我们从demirna和delncrna中得到了ERCC4的相互作用mirna和lncrna，并构建了lncRNA-miRNA-ERCC4调控网络。Kaplan-Meier生存曲线结果显示，miR-200c-3p（风险比[HR] = 0.62, P = 0.032）、MALAT1（风险比[HR] = 1.54, P = 0.016）、AC005520.2（风险比[HR] = 1.75, P = 0.002）与结直肠癌的预后显著相关。经RT-PCR验证，我们发现ERCC4和MALAT1在结直肠癌中较正常组织上调，miR-200c-3p下调。MALAT1与miR-200c-3p呈显著负相关。药敏分析显示，ERCC4、miR-200c、MALAT1均与顺铂相关。结论我们构建了CRC中ERCC4的ceRNA网络，其中MALAT1-miR-200c-3p-ERCC4轴可能参与了CRC的发生、预后和化疗敏感性。这些发现可能为研究ERCC4和NER通路在结直肠癌中的分子机制提供新的线索和见解。
Objective ERCC4 is one of the most significant molecules of Nucleotide Excision Repair (NER), which has been researched due to its high expression in colorectal cancer (CRC). This study aimed to find out the ceRNA (competitive endogenous RNA) network of ERCC4 in CRC. Methods and Materials Pan cancer mRNA expression of ERCC4 was evaluated using TCGA database. The protein expression of ERCC4 was evaluated based on the Human Protein Atlas (HPA). We screened DElncRNAs and DEmiRNAs in two groups of ERCC4high and ERCC4low expression in CRC. Then a lncRNA-miRNA-ERCC4 regulatory network was constructed based on DElncRNAs and DEmiRNAs using Starbase database and visualized by Cytoscape software. Kaplan-Meier analysis was performed to evaluate the prognostic value of the ceRNA network. Further, RT-PCR was performed to validate the expression of the representative molecules in the ceRNA network in CRC and normal tissues. The relationship between drug sensitivity and these molecules were also evaluated using RNAactDrug database. Results ERCC4 was overexpressed in a variety of tumors at mRNA levels, including CRC. High expression of ERCC4 was also observed on protein level in CRC. A total of 1,885 DElncRNAs and 68 DEmiRNAs were identified from CRC samples in ERCC4high and ERCC4low expression groups. Predicted by the Starbase database, we got interacting miRNAs and lncRNAs of ERCC4 from the DEmiRNAs and DElncRNAs, and a lncRNA-miRNA-ERCC4 regulatory network was constructed. Kaplan-Meier survival curves results showed that miR-200c-3p (hazard ratio [HR] = 0.62, P = 0.032), MALAT1 (HR = 1.54, P = 0.016), and AC005520.2 (hazard ratio [HR] = 1.75, P = 0.002) were significantly associated with the prognosis of CRC. After validation by RT-PCR, we found that ERCC4 and MALAT1 were up-regulated in CRC compared with normal tissues, while miR-200c-3p was down-regulated. A strong negative correlation was observed between MALAT1 and miR-200c-3p. Drug sensitivity analysis showed that ERCC4, miR-200c and MALAT1 were all associated with Cisplatin. Conclusion We constructed a ceRNA network of ERCC4 in CRC, of which the MALAT1-miR-200c-3p-ERCC4 axis may be involved in the development, prognosis and chemotherapy sensitivity of CRC. These findings might provide novel clues and insights on the molecular mechanisms of ERCC4 and NER pathway in CRC.
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DOI：
10.1038/nrc.2017.99
发表时间：
2018-01
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Anastasiadou E;Jacob LS;Slack FJ
通讯作者：
Slack FJ
影响因子：
8
作者：
Lin, R.;Maeda, S.;Edgington, T. S.
通讯作者：
Edgington, T. S.
影响因子：
2.8
作者：
Jiang, Yimei;Ji, Xiaopin;Zhao, Ren
通讯作者：
Zhao, Ren
影响因子：
4.2
作者：
Ning, Jie;Jiao, Yang;Gu, Kangsheng
通讯作者：
Gu, Kangsheng
影响因子：
4.8
作者：
Mu, D;Hsu, DS;Sancar, A
通讯作者：
Sancar, A