Identification of Transcriptional Markers and microRNA-mRNA Regulatory Networks in Colon Cancer by Integrative Analysis of mRNA and microRNA Expression Profiles in Colon Tumor Stroma.

Md Nazim Uddin,Xiaosheng Wang,Mengyuan Li

doi:10.3390/cells8091054

Md Nazim Uddin, Xiaosheng Wang + Show 1 more

Open Access

https://doi.org/10.3390/cells8091054

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Journal: Cells	Publication Date: Sep 8, 2019
Citations: 29	License type: CC BY 4.0

Affiliation: China Pharmaceutical University

Abstract

The aberrant expression of microRNAs (miRNAs) and genes in tumor microenvironment (TME) has been associated with the pathogenesis of colon cancer. An integrative exploration of transcriptional markers (gene signatures) and miRNA–mRNA regulatory networks in colon tumor stroma (CTS) remains lacking. Using two datasets of mRNA and miRNA expression profiling in CTS, we identified differentially expressed miRNAs (DEmiRs) and differentially expressed genes (DEGs) between CTS and normal stroma. Furthermore, we identified the transcriptional markers which were both gene targets of DEmiRs and hub genes in the protein–protein interaction (PPI) network of DEGs. Moreover, we investigated the associations between the transcriptional markers and tumor immunity in colon cancer. We identified 17 upregulated and seven downregulated DEmiRs in CTS relative to normal stroma based on a miRNA expression profiling dataset. Pathway analysis revealed that the downregulated DEmiRs were significantly involved in 25 KEGG pathways (such as TGF-β, Wnt, cell adhesion molecules, and cytokine–cytokine receptor interaction), and the upregulated DEmiRs were involved in 10 pathways (such as extracellular matrix (ECM)-receptor interaction and proteoglycans in cancer). Moreover, we identified 460 DEGs in CTS versus normal stroma by a meta-analysis of two gene expression profiling datasets. Among them, eight upregulated DEGs were both hub genes in the PPI network of DEGs and target genes of the downregulated DEmiRs. We found that three of the eight DEGs were negative prognostic factors consistently in two colon cancer cohorts, including COL5A2, EDNRA, and OLR1. The identification of transcriptional markers and miRNA–mRNA regulatory networks in CTS may provide insights into the mechanism of tumor immune microenvironment regulation in colon cancer.

Highlights

The tumor microenvironment (TME) is complex “ecosystems” which comprises many different cell types including stromal cells [1]
A literature review showed that all seven miRNAs downregulated in colon tumor stroma (CTS) have been associated with colon cancer and other cancer types
Our results showed that hsa-miR-21-5p, hsa-mir-21-3p, and hsa-mir-409-3p were downregulated in CTS, while their expression levels were increased in Colorectal cancer (CRC)

Summary

Introduction

The tumor microenvironment (TME) is complex “ecosystems” which comprises many different cell types including stromal cells [1]. Cells 2019, 8, 1054 poor prognosis in CRC [4,5,6]. MicroRNAs (miRNAs) play a critical role in modulating the TME in CRC [7]. Bullock et al showed that stromal and epithelial miRNAs play key roles during CRC progression [8]. Hiyoshi et al revealed that the elevated expression of miRNAs-34b and -34c in stromal tissues is associated with poor prognosis in colon cancer [9]. These prior studies demonstrated the significant contribution of aberrantly expressed miRNAs in colorectal tumor stroma to CRC growth, invasion, and metastasis

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