Comprehensive analysis of ceRNA network of ERCC4 in colorectal cancer

Abstract

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.