Transcriptomic and microRNA Expression Profiles Identify Biomarkers for Predicting Neo-Chemoradiotherapy Response in Esophageal Squamous Cell Carcinomas (ESCC)

Abstract

Neo-chemoradiotherapy (nCRT) before surgery is a standard treatment for locally advanced esophageal cancers. However, the treatment outcome of nCRT varied with different patients. This study aimed to identify potential biomarkers for prediction of nCRT-response in patients with esophageal squamous cell carcinoma (ESCC). Microarray datasets of nCRT responder and non-responder samples (access number GSE45670 and GSE59974) of patients with ESCC were downloaded from Gene Expression Omnibus (GEO) database. The mRNA expression profiles of cancer biopsies from four ESCC patients were analyzed before and after nCRT. Differentially expressed genes (DEGs) and miRNAs were screened between nCRT responder and non-responder ESCC samples. Functional enrichment analysis was conducted for these DEGs followed by construction of protein-protein interaction (PPI) network and miRNA-mRNA regulatory network. Finally, univariate survival analysis was performed to identify candidate biomarkers with prognostic values in ESCC. We identified numerous DEGs and differentially expressed miRNAs from nCRT responder group. GO and KEGG analysis showed that the dysregulated genes were mainly involved in biological processes and pathways, including “response to stimulus”, “cellular response to organic substance”, “regulation of signal transduction”, “AGE-RAGE signaling pathway in diabetic complications”, and “steroid hormone biosynthesis”. After integration of PPI network and miRNA-mRNA network analysis, we found eight genes, TNF, AKR1C1, AKR1C2, ICAM1, GPR68, GNB4, SERPINE1 and MMP12, could be candidate genes associated with disease progression. Univariate cox regression analysis showed that there was no significant correlation between dysregulated miRNAs (such as hsa-miR-34b-3p, hsa-miR-127-5p, hsa-miR-144-3p, and hsa-miR-486-5p, et al.) and overall survival of ESCC patients. Moreover, abnormal expression of MMP12 was significantly correlated with pathological degree, TNM stage, lymph nodes metastasis, and overall survival of ESCC patients (p < 0.05). Taken together, our study identified that MMP12 might be a useful tumor biomarker and therapeutic target for ESCC.