Function of miR‑25 in the invasion and metastasis of esophageal squamous carcinoma cells and bioinformatical analysis of the miR-106b-25 cluster

Abstract

Abstract. MicroRNAs (miRNAs/miRs) are a class of small, non-coding RNA molecules that serve a key function in carcinogenesis and tumor progression. Recent evidence indicates that miRNAs may act as powerful regulators of migration and invasion. The present study aimed to investigate the effect of miR-25 on the invasion and metastasis of KYSE-150 and EC109 esophageal squamous cell carcinoma (ESCC) cells, and predict the mechanism of this effect by bioinformatically analyzing the miR-106b-25 cluster. In order to alter the expression of miR-25 in the two cell lines, a miR-25 inhibitor or mimic were transfected into the cells, which were then studied via Transwell migration and invasion assays. Subsequently, the target genes of the miR-106b-25 cluster were predicted using miRanda, PicTar, TargetScan and miRTarbase, and the functions of the target genes were predicted via Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Then, a protein-protein interaction (PPI) network was produced using the Search Tool for the Retrieval of Interacting Genes. The results revealed that overexpressing miR-25 led to significantly increased cell migration and invasion in KYSE150 and EC109 cells. Suppressing miR-25 resulted in significantly decreased cell migration and invasion in KYSE150 cells, while the result was not significant in EC109 cells. Target genes of the miR-106b-25 cluster were significantly enriched in the biological process regulation of cellular metabolic process and several cancer-associated pathways, such as those for glioma and melanoma. The PPI network revealed that PTEN, TP53, MDM2, E2F1, PRMT5, MCM2, RB1, CDKN1A, SHAD7 and EZH2 may serve core roles within the network and associate with one another during the pathogenesis of ESCC. These results indicate that a high expression of miR-25 promotes the invasion and metastasis of ESCC cells, while the influence of low expression of miR-25 differs with cells with different degrees of differentiation. Invasion and metastasis are not effected in cells with poor differentiation, while they were decreased in well differentiated cells. Furthermore, PTEN, TP53, MDM2, E2F1, PRMT5, MCM2, RB1, CDKN1A, SHAD7 and EZH2 may be targeted by the miR-106b-25 cluster, and act together to regulate the development of ESCC. IntroductionEsophageal cancer is an important public health problem worldwide, as the eighth most common cancer and sixth most common cause of cancer-associated mortality (1). Esophageal squamous cell carcinoma (ESCC) accounts for 90% of all histological types of esophageal carcinoma in the highest risk area, North-central China, which ranks first in ESCC morbidity and mortality rates (2). Genetic heterogeneity and complex regulatory networks make it difficult to treat ESCC (3). Thus, identifying the regulatory pathways for the stratification of ESCC is of great clinical significance.MicroRNAs (miRNAs/miRs) are single-stranded RNAs of 18-24 nucleotides in length that post-transcriptionally regulate gene expression by directly bindin...

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