Abstract
BackgroundNeoadjuvant chemoradiotherapy (nCRT) followed by surgery benefits survival for patients with esophageal squamous cell carcinomas (ESCC) compared with surgery alone, but the clinical outcomes of nCRT are heterogeneous. This study aimed to elucidate transcriptional factor (TF) regulation network and competitive endogenous RNA (ceRNA) network determining response of ESCC to nCRT.Materials and MethodsRNA microarray data of GSE59974 and GSE45670 were analyzed to investigate the significant changes of lincRNAs, miRNAs, mRNAs in responders and non-responders of nCRT in ESCC. Functional and enrichment analyses were conducted by clusterProfiler. The target lincRNAs and mRNAs of miRNAs were predicted by miRWalk. The ceRNA and TF regulatory networks were constructed using Cytoscape.ResultsDifferentially expressed genes between responders and non-responders mainly enriched in biological process including Wnt signaling pathway and regulation of cell development and morphogenesis involved in differentiation. Besides, these genes showed enrichment in molecular function of glycosaminoglycan binding, metalloendopeptidase inhibitor and growth factor activity. KEGG analysis enriched these genes in pathways of neurotrophin signaling pathway, cell adhesion molecules and Wnt signaling pathway. We also constructed ceRNA network and TF network regulating response of ESCC to nCRT. Core regulatory miRNAs were miR-520a, miR-548am, miR-3184, miR-548d, miR-4725, miR-148a, miR-4659a and key regulatory TFs included MBNL1, SLC26A3, BMP4, ZIC1 and ANKRD7.ConclusionWe identified significantly altered lincRNAs, miRNAs and mRNAs involved in the nCRT response of ESCC. In addition, the ceRNA regulatory network of lincRNA-miRNA-mRNA and TF regulatory network were constructed, which would elucidate novel molecular mechanisms determining nCRT response of ESCC, thus providing promising clues for clinical therapy.
Highlights
As a common malignant tumour of upper digestive tract, esophageal squamous cell carcinoma (ESCC) represents a significant health burden worldwide due to its aggressive growth (Kang et al, 2015)
It has been proved that neoadjuvant chemoradiotherapy followed by surgery benefits survival for patients with esophageal squamous cell carcinomas (ESCC) compared with surgery alone, which is recommended in the guidelines for ESCC therapy (Allum et al, 2011)
The results showed that the differentially expressed gene mainly enriched in biological process (BP) including positive regulation of cell morphogenesis involved in differentiation, negative regulation of Wnt signaling pathway and positive regulation of cell development
Summary
As a common malignant tumour of upper digestive tract, esophageal squamous cell carcinoma (ESCC) represents a significant health burden worldwide due to its aggressive growth (Kang et al, 2015). Neoadjuvant chemoradiotherapy (nCRT) followed by surgery benefits survival for patients with esophageal squamous cell carcinomas (ESCC) compared with surgery alone, but the clinical outcomes of nCRT are heterogeneous. Expressed genes between responders and non-responders mainly enriched in biological process including Wnt signaling pathway and regulation of cell development and morphogenesis involved in differentiation. These genes showed enrichment in molecular function of glycosaminoglycan binding, metalloendopeptidase inhibitor and growth factor activity. The ceRNA regulatory network of lincRNA-miRNA-mRNA and TF regulatory network were constructed, which would elucidate novel molecular mechanisms determining nCRT response of ESCC, providing promising clues for clinical therapy
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