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Original Article EV71 Infection Causes Differential Expression of Micrornas in Colon Carcinoma Cells

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Original Article EV71 Infection Causes Differential Expression of Micrornas in Colon Carcinoma Cells Int J Clin Exp Pathol 2016;9(10):10363-10372 www.ijcep.com /ISSN:1936-2625/IJCEP0035672 Original Article EV71 infection causes differential expression of microRNAs in colon carcinoma cells Zhihong Nie1*, Fanfan Cao2*, Bojing Li1, Lili Yuan3 1Department of Gastroenterology, Shanghai Gongli Hospital, The Second Military Medical University, Pudong New Area, Shanghai 200135, P.R. China; 2Sino-French Cooperative Central Lab, Shanghai Gongli Hospital, The Second Military Medical University, Pudong New Area, Shanghai 200135, P.R. China; 3Department of Gestroenterology, Shanxi Dayi Hospital, Taiyuan, Shanxi, P.R. China. *Co-first authors. Received July 13, 2016; Accepted July 21, 2016; Epub October 1, 2016; Published October 15, 2016 Abstract: Purpose: We aimed to clarify the mechanism of EV71 infection impacting microRNA (miRNA) expression by identifying the differentially expressed miRNAs and key target genes in human colon carcinoma cells with EV71 infection. Methods: The miRNA expression profile GSE57372 was downloaded from gene expression omnibus data- base. The differentially expressed miRNAs were identified and target genes were screened using miRWalk, followed by gene ontology (GO) function analysis for the target genes using DAVID. Besides, the co-regulation network was constructed using cytoscape and GO analysis was performed for the co-regulated target genes. Results: A total of 23 differentially expressed miRNAs were identified, including 16 up-regulated miRNAs and 7 down-regulated miR- NAs. Total 2501 target genes were screened, which were regulated by 7 miRNAs, including 4 up-regulated miRNAs (hsa-miR-548a-3p, hsa-miR-570, hsa-miR-601 and hsa-miR-638) and 3 down-regulated miRNAs (hsa-miR-29b, hsa- miR-326 and hsa-miR-484). These genes were mainly enriched in the biological processes of neuron differentiation, cell morphogenesis involved in neuron differentiation and cellular component morphogenesis. Total 47 target genes were co-regulated, in which NDST1, DLGAP2, PKNOX2 and MYT1 were identified as key target genes and enriched in processes of neuron project, intracellular signaling cascade and intracellular non-membrane-bounded organelle. The hsa-miR-29b, hsa-miR-484 and hsa-miR-638 were identified as key miRNAs, which regulated all 4 key target genes. Conclusion: EV71 infection altered the expression of hsa-miR-29b, hsa-miR-484 and hsa-miR-638 which may play key roles in the progression of nervous lesions by co-regulating the expression of 4 key target genes, includ- ing NDST1, DLGAP2, PKNOX2 and MYT1. Keywords: EV71, colon cancer HT29, significant microRNA, target genes, gene ontology terms Introduction microRNAs (miRNAs) are endogenous RNA with a length of about 22-nucleotide [5] and serve Enterovirus 71 (EV71) is a virus of the genus as major-regulators of gene expression by pair- Enterovirus in the Picornaviride family, which is ing to the mRNAs of protein-coding genes to first isolated in California, USA [1]. EV71 is con- direct their posttranscriptional repression [6]. sidered to be a major cause of hand, foot, and In recent years, miRNAs have been considered mouth disease (HFMD) which is characterized as key regulators in many biological processes by multiple lesions on skins and mucosa of [7], and the alteration of miRNA expression is oral, hand and foot [2]. In addition, some sev- ere neurologic complications, such as enceph- highly associated with development of some alitis and polio-like paralysis, also develop in diseases, such as various human cancers [8]. patients infected by EV71 [3]. This virus is In case of EV71 infection, Cui et al. [9] identified mainly transmitted by hand contact and young cellular miRNAs and biological processes children are the highest risk group [4]. Recently, involved in the host response to EV71 infection, analysis on mechanism of EV71 infection has supporting that certain miRNAs might be essen- been performed, which may provide a new tial in the host-pathogen interactions. Thus, fur- insight for both academic research and clinical ther analysis on the miRNAs in EV71 infection is treatment. implicated for the research of treatment. MiRNAs in EV71 infected colon cancer cells In the present study, we downloaded the miRNA Prediction and functional analysis of target microarray profile of GSE57372 from Gene genes Expression Omnibus (GEO) database. This dataset was obtained from colon carcinoma The target genes of significant differentially cell line HT29 which is isolated from a expressed miRNAs were identified by using Caucasian female with colon tumor [10], and is miRWalk [16], in which 10 algorithms were ref- widely used in various researches of intestinal erenced, including DIANAmT, miRanda, miRDB, cell function and diseases [11] including EV71 miRWalk, RNAhybrid, PICTAR4, PICTAR5, PITA, infection [12]. There are EV71 infected samples RNA22 and Targetscan. The genes that were and not infected samples in this dataset. The detected by more than 5 algorithms were differentially expressed miRNAs between the screened for the construction of co-regulation two groups were screened. Then the target network. Cytocape [17] was used for visualiza- genes of miRNAs were performed functional tion of the network. Besides, the target genes analysis. Besides, co-regulated network was of all miRNAs were performed Gene Ontology constructed and key target genes were identi- (GO) biological process (BP) analysis using fied. We aimed to clarify the mechanism of DAVID [18]. EV71 infection impacting miRNA expression by Co-regulation network construction and key identifying key miRNAs and key target genes in target genes analysis colon carcinoma cells. The TRANSFAC database on eukaryotic tran- Materials and methods scriptional regulation is a database comprises Microarray data and data preprocessing data of transcription factors, target genes and regulatory binding cites [19]. The Univer- The miRNA microarray profile of GSE57372 was sity of California Santa Cruz (UCSC) Genome downloaded from Gene Expression Omnibus Browser is a web-based set of tool providing (GEO) database in National Center for Biote- access to a database of genome sequence and chnology Information (NCBI) (http://www.ncbi. annotation [20]. Transcription factors among nlm.nih.gov/geo/) based on the platform of the target genes were screened based on the GPL14613 [miRNA-2_0] Affymetrix Multispe- TRANSFAC database [21] and the information cies miRNA-2_0 Array. The microarray profile on transcription regulation was analyzed with contains 6 human colon carcinoma cells (HT29) UCSC database. In addition, analysis of all samples, including 3 EV71 infected samples three GO terms, including biological process and 3 not infected samples as control. (BP), cellular component (CC) and molecular function (MF), was performed for the target The probe-level data were converted into gene genes coregulated by miRNAs by using DAVID expression measures. If multiple probes corre- [18] with p-value<0.05. sponded to the same gene expression value, Results their mean value was calculated as the gene expression value. For probes with missing val- Screening of differentially expressed miRNA ues, we used KNN method of impute package in R language to supplement the missing val- As shown in Figure 1A, the obscuring variations ues [13]. Quantile normalization was performed in raw expression data were normalized after by using preprocessCore package in R lan- being preprocessed. A total of 23 significant guage [14] and box plots were generated. differentially expressed miRNAs were identi- fied, including 16 up-regulated miRNAs and 7 Screening of differentially expressed miRNA down-regulated miRNAs. The volcano plot was shown in Figure 1B. After the microarray data were preprocessed, the differentially expressed miRNAs between Prediction and functional analysis of target EV71 infection group and control group were genes identified by using limma package in R [15] with p-value<0.05 and |log2 FC (fold change)|> According to the 10 algorithms in miRWalk, a 0.585. network of 3091 interactions were constructed 10364 Int J Clin Exp Pathol 2016;9(10):10363-10372 MiRNAs in EV71 infected colon cancer cells Figure 1. Box plots and volcano plots of data normalization. A: Box plots of data normalization. The x-coordinate represents samples; y-coordinate rep- resents microRNAs expression values. The green box plots are controls and red ones are experimental samples. The whiskers in the box plots represent sample median. B: Volcano plot of dif- ferentially expressed microRNAs. (Figure 2), in which 7 differentially expressed The top five significant GO terms for target miRNAs, including 4 up-regulated miRNAs (hsa- genes were listed in Table 1. The target genes miR-548a-3p, hsa-miR-570, hsa-miR-601 and of up-regulated miRNAs were mainly enriched hsa-miR-638) and 3 down-regulated miRNAs in cell morphogenesis, cellular component mor- (hsa-miR-29b, hsa-miR-326 and hsa-miR-484), phogenesis, dendrite development and regula- and 2501 target genes were involved. In the tion of transcription from RNA polymerase II 2501 target genes, collagen, type XI, alpha 1 promoter. The target genes of down-regulated (COL11A1), collagen, type III, alpha 1 (COL3A1) miRNAs were significantly enriched in the pro- and hemicentin 1 (HMCN1) were detected by all cesses of neuron differentiation, cell morpho- 10 algorithms. genesis involved in neuron differentiation, 10365 Int J Clin Exp Pathol 2016;9(10):10363-10372 MiRNAs in EV71 infected colon cancer cells Figure 2. microRNA regulation network. Red nodes:
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