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Updated: Nov 4, 2025
Investigating Target Gene Function in a CD40 Agonistic Antibody-induced Colitis Model using CRISPR/Cas9-based Technologies
Published on: June 2, 2021
Transcriptome analysis of potential candidate genes and molecular pathways in colitis-associated colorectal cancer of
Ahmed Hammad1, Zhao-Hong Zheng2, Akhileshwar Namani1,3
1Department of Biochemistry and Department of Thoracic Surgery of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, People's Republic of China.
Background:
The 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.
Methods:
Azoxymethane/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.
Results:
Persistent 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.
Conclusion:
These 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.
Insights
Mitogen-activated protein kinase phosphatase-1 (MKP-1) plays a key role in colorectal cancer (CRC) development. MKP-1 knockout mice showed altered pathways crucial for cancer progression and metastasis.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Mitogen-activated protein kinase phosphatase-1 (MKP-1) is a nuclear phosphatase regulating innate immune responses and pro-inflammatory cytokine biosynthesis.
- Overexpression and functional disturbances of MKP-1 are observed in colorectal cancer (CRC), suggesting its involvement in cancer development.
- The precise molecular mechanisms of MKP-1's influence on CRC progression remain unclear.
Purpose of the Study:
- To investigate the role of MKP-1 in colorectal cancer (CRC) progression.
- To explore molecular mechanisms by which MKP-1 influences CRC development using global gene expression profiling.
- To analyze transcriptome data from MKP-1 knockout (KO) mice.
Main Methods:
- Utilized Azoxymethane/dextran sodium sulfate (AOM/DSS) mouse models for CRC development.
- Performed global gene expression profiling via RNA sequencing (RNA-seq) in wild-type and MKP-1 KO mice.
- Conducted comprehensive bioinformatics analyses including Gene Ontology (GO), KEGG pathway analysis, and protein-protein interaction (PPI) network analysis.
Main Results:
- Identified persistent differentially expressed genes (DEGs) in adenoma and carcinoma stages, and between wild-type and MKP-1 KO mice.
- MKP-1 knockout modulated key cancer-associated molecular processes: cell adhesion, ion transport, extracellular matrix organization, and responses to drugs, hypoxia, and toxins.
- Protein-protein interaction network analysis revealed nine hub genes strongly associated with CRC development and metastasis.
Conclusions:
- MKP-1 and its identified hub genes are implicated in colorectal cancer (CRC) development, prognosis, and treatment outcomes.
- Findings suggest a critical role for MKP-1 in colitis-associated tumorigenesis.
- Further research is warranted to elucidate the specific pathways and therapeutic potential.
