Abstract
BackgroundThe nuclear phosphatase mitogen-activate protein kinase phosphatase-1 (MKP-1) is a key negative regulator of the innate immune response through the regulation of the biosynthesis of proinflammatory cytokines. In colorectal cancer (CRC), which is induced mainly by chronic inflammation, Mkp-1 overexpression was found in addition to disturbances in Mkp-1 functions, which may play a role in cancer development in different types of tumors. However, the potential molecular mechanisms by which Mkp-1 influences CRC development is not clear. Here, we performed global gene expression profiling of Mkp-1 KO mice using RNA sequencing (RNA-seq) to explore the role of Mkp-1 in CRC progression using transcriptome analysis.MethodsAzoxymethane/dextran sodium sulfate (AOM/DSS) mouse models were used to examine the most dramatic molecular and signaling changes that occur during different phases of CRC development in wild-type mice and Mkp-1 KO mice. Comprehensive bioinformatics analyses were used to elucidate the molecular processes regulated by Mkp-1. Differentially expressed genes (DEGs) were identified and functionally analyzed by Gene Ontology (GO), Kyoto Enrichment of Genes and Genomes (KEGG). Then, protein-protein interaction (PPI) network analysis was conducted using the STRING database and Cytoscape software.ResultsPersistent DEGs were different in adenoma and carcinoma stage (238 & 251, respectively) and in WT and MKp-1 KO mice (221& 196, respectively). Mkp-1 KO modulated key molecular processes typically activated in cancer, in particular, cell adhesion, ion transport, extracellular matrix organization, response to drug, response to hypoxia, and response to toxic substance. It was obvious that these pathways are closely associated with cancer development and metastasis. From the PPI network analyses, nine hub genes associated with CRC were identified.ConclusionThese findings suggest that MKp-1 and its hub genes may play a critical role in cancer development, prognosis, and determining treatment outcomes. We provide clues to build a potential link between Mkp-1 and colitis-associated tumorigenesis and identify areas requiring further investigation.Graphical abstract
Highlights
Colorectal cancer (CRC) is the third most common malignancies worldwide [1], with more than 1.2 million new cases diagnosed annually [2]
Mitogen-activated protein kinase phosphatase-1 (Mkp-1) deficiency promotes tumorigenesis in AOM/DSSinduced colitis-associated colorectal cancer (CRC) Treatment of Mkp-1-deficient mice with AOM/dextran sodium sulfate (DSS) (Fig. 1A) triggered the colitis, which was confirmed by a significant decrease in the length of colon in KO mice compared to Wild type (WT) one (Fig. 1D)
Histopathological examination using hematoxylin and eosin (H&E) staining showed that Azoxymethane/dextran sodium sulfate (AOM/DSS) treatment for 6 weeks induced adenoma stage in WT and KO mice compared to normal WT colon, representing the early stage of tumorigenesis
Summary
Colorectal cancer (CRC) is the third most common malignancies worldwide [1], with more than 1.2 million new cases diagnosed annually [2]. CRC developed through a multistep process from normal epithelium to adenoma and adenocarcinoma, which can eventually metastasize to different organs [5]; it was shown that the transition of CRC cells from early stages to late stages (metastasis) is associated with a significant change in the cellular gene expression profile [6]. These genetic alterations have led to the emergence of the novel strategies for personalized medicine programs [7, 8]. We performed global gene expression profiling of Mkp-1 KO mice using RNA sequencing (RNA-seq) to explore the role of Mkp-1 in CRC progression using transcriptome analysis
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