Identification of gene expression changes from colitis to CRC in the mouse CAC model

Xin Li; Yuyan Gao; Ming Yang; Qi Zhao; Guangyu Wang; Yan Mei Yang; Yue Yang; Hui Liu; Yanqiao Zhang

doi:10.1371/journal.pone.0095347

Identification of gene expression changes from colitis to CRC in the mouse CAC model

PLoS One. 2014 Apr 17;9(4):e95347. doi: 10.1371/journal.pone.0095347. eCollection 2014.

Authors

Xin Li¹, Yuyan Gao², Ming Yang³, Qi Zhao³, Guangyu Wang³, Yan Mei Yang⁴, Yue Yang⁴, Hui Liu⁵, Yanqiao Zhang³

Affiliations

¹ Department of Gastrointestinal Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Department of Respiratory Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
² Department of Radiation Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
³ Department of Gastrointestinal Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
⁴ Cancer Research Institute, Harbin Medical University, Harbin, Heilongjiang, China.
⁵ School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China.

Abstract

A connection between colorectal carcinogenesis and inflammation is well known, but the underlying molecular mechanisms have not been elucidated. Chemically induced colitis-associated cancer (CAC) is an outstanding mouse model for studying the link between inflammation and cancer. Additionally, the CAC model is used for examining novel diagnostic, prognostic, and predictive markers for use in clinical practice. Here, a CAC model was established in less than 100 days using azoxymethane (AOM) with dextran sulfate sodium salt (DSS) in BALB/c mice. We examined the mRNA expression profiles of three groups: control untreated mice (K), DSS-induced chronic colitis mice (D), and AOM/DSS-induced CAC (AD) mice. We identified 6301 differentially expressed genes (DEGs) among the three groups, including 93 persistently upregulated genes and 139 persistently downregulated genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the most persistent DEGs were significantly enriched in metabolic or inflammatory components in the tumor microenvironment. Furthermore, several associated DEGs were identified as potential DEGs by protein-protein interaction (PPI) network analysis. We selected 14 key genes from the DEGs and potential DEGs for further quantitative real-time PCR (qPCR) verification. Six persistently upregulated, 3 persistently downregulated DEGs, and the other 3 genes showed results consistent with the microarray data. We demonstrated the regulation of 12 key genes specifically involved in Wnt signaling, cytokine and cytokine receptor interactions, homeostasis, and tumor-associated metabolism during colitis-associated CRC. Our results suggest that a close relationship between metabolic and inflammatory mediators of the tumor microenvironment is present in CAC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Azoxymethane / toxicity
Colitis / chemically induced
Colitis / metabolism*
Colorectal Neoplasms / chemically induced
Colorectal Neoplasms / metabolism*
Dextran Sulfate / toxicity
Disease Models, Animal
Female
Gene Expression Regulation, Neoplastic*
Genome-Wide Association Study
Mice
Mice, Inbred BALB C
Protein Binding

Substances

Dextran Sulfate
Azoxymethane

Grants and funding

This work was supported by a grant from the Ministry of Public Health, China, a grant from the Nature Science Foundation of China(81172265). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.