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  • br To illustrate the impact of miRNAs involved in the

    2019-10-30


    To illustrate the impact of miRNAs involved in the pathogenesis of CRC, we conducted pathway enrichment analysis based on predicted or validated targets. We first analyzed the differential Chloramphenicol levels of miR-144-3p, miR-425-5p, and miR-1260b based on the miRNA data, including 270 tumor samples and 8 normal samples downloaded from TCGA database (Table S6). The significant P values of the three miRNAs were calculated using the t-test and adjusted using the Benjamini–Hochberg method. miR-1260b was significantly upregu-lated, whereas miR-144-3p and miR-425-5p were significantly down-regulated in tumor samples compared with the normal samples (Table 3). Subsequently, we predicted a list of putative miRNA inter-acting targets by downloading the mRNA data containing 287 tumor samples and 41 normal samples (Table S7). The mRNA data showed 3310 significantly upregulated genes and 1793 significantly down-regulated genes. miR-1260b had 53 target genes significantly down-regulated in tumors, whereas miR-425-5p and miR-144-3p had re-spectively 159, 162 target genes significantly upregulated in tumors (Table S8). In combination with the CTD database, nine MARKER-re-lated genes were observed in CRC, including ABCA1, ABCA8, EFEMP1, MAOB, RET, STARD8, ABCA10, LRRC3B, and SFRP1. The differentially expressed target genes and the miRNA-mRNA networks are shown in Fig. 4.
    The predicted target genes were used for pathway enrichment analysis by using KEGG pathway map and Reactome pathway database. The results from pathway enrichment analysis based on predicted or validated targets from the dysregulated miRNAs revealed a number of cancer-associated pathways. The miRNA pathways were significantly enriched in the KEGG pathway, as shown in Fig. 5A. miR-144-3p was enriched in the axon guidance pathway (P = 0.002), whereas miR-425-5p was enriched in the calcium signaling pathway (P = 0.000); how-ever, miR-1260b was not enriched in any pathway (Table 4). Numerous Reactome signal enrichment pathways in miRNAs (Table S9) were observed, but only the most significant pathways are shown in Fig. 5B. miR-144-3p was mainly enriched in the phosphoinositide 3-kinase (PI3K) and platelet-derived growth factor (PDGF) pathways (P < 0.01), whereas miR-425-5p was mainly enriched in the guanylate cyclase and cyclic guanosine monophosphate (cGMP) pathways (P < 0.01); how-ever, miR-1260b was still not significantly enriched. These key reg-ulators and signal transduction pathways may form feedback loops with miRNAs to modulate apoptosis, cell cycle, cell migration, and invasion in CRC development.
    4. Discussion
    CRC is one of the most commonly diagnosed cancers. This cancer can be prevented because most CRC cells originate from their precursor adenomatous polyps [25]. Screening mainly aims to detect the sporadic CRC cases in people aged ≥ 50 years [26]. Recently, a multitarget stool
    DNA test has been made commercially available in the United States. Although this test is the most sensitive noninvasive CRC screening test, further research is needed in several areas, such as cost-effectiveness of DNA stool testing in real-life populations [27]. Previous studies showed 
    that compared with mRNA levels, miRNA analysis may be more effi-cient to understand the biological behavior of diseases [28,29]. Mitchell et al.confirmed the existence of abundant and stable miRNAs in plasma. miRNAs offer numerous advantages, such as excellent sensitivity and
    Table 2
    Diagnostic performance of biochemical indicators commonly used in CRC compared with the panel of miR-144-3p, miR-425-5p, miR-1260b.
    SEN: sensitivity; SPE: specificity.
    Table 3
    miRNA Log2(FC) P adj. P
    FC: fold change. adj.P: adjusted P value.