Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers worldwide, and its morbidity is exacerbated by the lack of early symptoms. Bioinformatics analyses enable discovery of differentially expressed genes and non-protein-coding RNAs of potential prognostic and/or therapeutic relevance in ESCC and other cancers. Using bioinformatics tools, we searched for dysregulated miRNAs in two ESCC microarray datasets from the Gene Expression Omnibus (GEO) database. After identification of three upregulated and five downregulated miRNAs shared between databases, protein-protein interaction (PPI) network analysis was used to identify the top 10 hub-gene targets. Thereafter, a miRNA-gene interaction network predicted that most hub genes are regulated by miR-196a-5p and miR-1-3p, which are respectively upregulated and downregulated in ESCC. Functional enrichment analyses in the GO and KEGG databases indicated the potential involvement of these miRNAs in tumorigenesis-related processes and pathways, while both differential expression and correlation with T stage were demonstrated for each miRNA in a cohort of ESCC patients. Overexpression showed that miR-196a-5p increased, whereas miR-1-3p attenuated, proliferation and invasion in human ESCC cell lines grown in vitro. These findings suggest miR-196a-5p and miR-1-3p jointly contribute to ESCC tumorigenesis and are potential targets for diagnosis and treatment.
Highlights
Esophageal carcinoma ranked as the ninth most common cancer worldwide in 2018, with both new cases and deaths exceeding 500,000 and a 5-year survival of ~20% [1]
Esophageal squamous cell carcinoma (ESCC) is the predominant esophageal carcinoma histological subtype in China, and lack of early disease signs contributes to its high prevalence and morbidity [2]
Two miRNAs downregulated in ESCC function as tumor suppressors; miR-302b represses the expression of erbb2 receptor tyrosine kinase 4 (ErbB4) whereas miR-134 downregulates PLXNA1 and blocks the mitogenwww.aging-us.com activated protein kinase (MAPK) signaling pathway [7, 8]
Summary
Esophageal carcinoma ranked as the ninth most common cancer worldwide in 2018, with both new cases and deaths exceeding 500,000 and a 5-year survival of ~20% [1]. Attending to the pressing need for more accurate biomarkers for early diagnosis and treatment of ESCC and other cancers, much attention is being devoted to the study of microRNAs (miRNAs), which have shown to influence tumor development by dynamic post-transcriptional regulation of gene expression [3, 4]. Research has shown that several miRNAs are differentially expressed in ESCC and may contribute to its development. Upregulated expression of miR-502 and miR-26b regulates ESCC cell proliferation and tumor progression by promoting the phosphorylation of AKT and controlling cell cycle transitions, respectively [5, 6]. Two miRNAs downregulated in ESCC function as tumor suppressors; miR-302b represses the expression of erbb receptor tyrosine kinase 4 (ErbB4) whereas miR-134 downregulates PLXNA1 and blocks the mitogenwww.aging-us.com activated protein kinase (MAPK) signaling pathway [7, 8]. Given the heterogeneous nature of ESCC, other relevant transcripts among the many differentially expressed miRNAs are likely to affect ESCC pathogenesis
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