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MicroRNA-155 deletion promotes tumorigenesis in the azoxymethane-dextran sulfate sodium model of colon cancer
- Source :
- American journal of physiology. Gastrointestinal and liver physiology. 310(6)
- Publication Year :
- 2015
-
Abstract
- Clinical studies have linked microRNA-155 (miR-155) expression in the tumor microenvironment to poor prognosis. However, whether miR-155 upregulation is predictive of a pro- or antitumorigenic response is unclear, as the limited preclinical data available remain controversial. We examined miR-155 expression in tumor tissue from colon cancer patients. Furthermore, we investigated the role of this microRNA in proliferation and apoptosis, inflammatory processes, immune cell populations, and transforming growth factor-β/SMAD signaling in a chemically induced (azoxymethane-dextran sulfate sodium) mouse model of colitis-associated colon cancer. We found a higher expression of miR-155 in the tumor region than in nontumor colon tissue of patients with colon cancer. Deletion of miR-155 in mice resulted in a greater number of polyps/adenomas, an increased symptom severity score, a higher grade of epithelial dysplasia, and a decrease in survival. Surprisingly, these findings were associated with an increase in apoptosis in the normal mucosa, but there was no change in proliferation. The protumorigenic effects of miR-155 deletion do not appear to be driven solely by dysregulation of inflammation, as both genotypes had relatively similar levels of inflammatory mediators. The enhanced tumorigenic response in miR-155−/− mice was associated with alterations in macrophages and neutrophils, as markers for these populations were decreased and increased, respectively. Furthermore, we demonstrated a greater activation of the transforming growth factor-β/SMAD pathway in miR-155−/− mice, which was correlated with the increased tumorigenesis. Given the multiple targets of miR-155, careful evaluation of its role in tumorigenesis is necessary prior to any consideration of its potential as a biomarker and/or therapeutic target in colon cancer.
- Subjects :
- 0301 basic medicine
Physiology
Colorectal cancer
Azoxymethane
Inflammation
Apoptosis
Smad Proteins
Biology
medicine.disease_cause
Transfection
miR-155
03 medical and health sciences
chemistry.chemical_compound
Mice
Downregulation and upregulation
Transforming Growth Factor beta
Physiology (medical)
microRNA
medicine
Animals
Humans
Intestinal Mucosa
Cell Proliferation
Tumor microenvironment
Hepatology
Dextran Sulfate
Gastroenterology
medicine.disease
Mice, Inbred C57BL
MicroRNAs
030104 developmental biology
chemistry
Immunology
Colonic Neoplasms
Cancer research
Carcinogens
Call for Papers
medicine.symptom
Carcinogenesis
Biomarkers
Gene Deletion
Signal Transduction
Subjects
Details
- ISSN :
- 15221547
- Volume :
- 310
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- American journal of physiology. Gastrointestinal and liver physiology
- Accession number :
- edsair.doi.dedup.....2a4d34d72f69dd40778815f012fa6a66