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Published on: September 30, 2016
NOX4 promotes tumor progression through the MAPK-MEK1/2-ERK1/2 axis in colorectal cancer
Yu-Jie Xu1,2, Ya-Chang Huo1, Qi-Tai Zhao1
1Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
Background:
Metabolic reprogramming plays a key role in cancer progression and clinical outcomes; however, the patterns and primary regulators of metabolic reprogramming in colorectal cancer (CRC) are not well understood.
Aim:
To explore the role of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) in promoting progression of CRC.
Methods:
We evaluated the expression and function of dysregulated and survival-related metabolic genes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Consensus clustering was used to cluster CRC based on dysregulated metabolic genes. A prediction model was constructed based on survival-related metabolic genes. Sphere formation, migration, invasion, proliferation, apoptosis and clone formation was used to evaluate the biological function of NOX4 in CRC. mRNA sequencing was utilized to explore the alterations of gene expression NOX4 over-expression tumor cells. In vivo subcutaneous and lung metastasis mouse tumor model was used to explore the effect of NOX4 on tumor growth.
Results:
We comprehensively analyzed 3341 metabolic genes in CRC and identified three clusters based on dysregulated metabolic genes. Among these genes, NOX4 was highly expressed in tumor tissues and correlated with worse survival. In vitro, NOX4 overexpression induced clone formation, migration, invasion, and stemness in CRC cells. Furthermore, RNA-sequencing analysis revealed that NOX4 overexpression activated the mitogen-activated protein kinase-MEK1/2-ERK1/2 signaling pathway. Trametinib, a MEK1/2 inhibitor, abolished the NOX4-mediated tumor progression. In vivo, NOX4 overexpression promoted subcutaneous tumor growth and lung metastasis, whereas trametinib treatment can reversed the metastasis.
Conclusion:
Our study comprehensively analyzed metabolic gene expression and highlighted the importance of NOX4 in promoting CRC metastasis, suggesting that trametinib could be a potential therapeutic drugs of CRC clinical therapy targeting NOX4.
Insights
Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) promotes colorectal cancer (CRC) progression and metastasis. Targeting NOX4 with trametinib may offer a new therapeutic strategy for CRC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Metabolic reprogramming is crucial in colorectal cancer (CRC) but its regulators remain unclear.
- Understanding metabolic gene patterns is key to improving CRC patient outcomes.
Purpose of the Study:
- To investigate the role of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) in promoting CRC progression.
- To identify NOX4 as a potential therapeutic target in CRC.
Main Methods:
- Analyzed 3341 metabolic genes in CRC using bioinformatics and consensus clustering.
- Assessed NOX4 function in CRC cells through in vitro assays (proliferation, migration, invasion, stemness).
- Utilized mRNA sequencing and in vivo mouse models to evaluate NOX4's impact on tumor growth and metastasis.
Main Results:
- NOX4 was highly expressed in CRC tissues, correlating with poor survival.
- NOX4 overexpression enhanced CRC cell migration, invasion, and stemness.
- NOX4 activated the MAPK-MEK1/2-ERK1/2 pathway; trametinib inhibited NOX4-driven tumor progression and metastasis.
Conclusions:
- NOX4 plays a significant role in promoting CRC metastasis.
- NOX4 is a potential therapeutic target for CRC.
- Trametinib shows promise as a CRC therapy targeting NOX4.
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