title: MicroRNA-155 deletion promotes tumorigenesis in the azoxymethane-dextran sulfate sodium model of colon cancer.
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.
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina;
authors.forename: Kandy T
authors.initials: KT
authors.lastname: Velázquez
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina;
authors.forename: Reilly T
authors.initials: RT
authors.lastname: Enos
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina;
authors.forename: Jamie L
authors.initials: JL
authors.lastname: McClellan
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina;
authors.forename: Taryn L
authors.initials: TL
authors.lastname: Cranford
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina; Center for Colon Cancer Research, University of South Carolina, Columbia, South Carolina.
authors.forename: Ioulia
authors.initials: I
authors.lastname: Chatzistamou
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina;
authors.forename: Udai P
authors.initials: UP
authors.lastname: Singh
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina;
authors.forename: Mitzi
authors.initials: M
authors.lastname: Nagarkatti
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina;
authors.forename: Prakash S
authors.initials: PS
authors.lastname: Nagarkatti
authors.affiliation: Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, South Carolina; and.
authors.forename: Daping
authors.initials: D
authors.lastname: Fan
authors.affiliation: Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina; Center for Colon Cancer Research, University of South Carolina, Columbia, South Carolina angela.murphy@uscmed.sc.edu.
authors.forename: E Angela
authors.initials: EA
authors.lastname: Murphy
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001397:Azoxymethane; D015415:Biomarkers; D002273:Carcinogens; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D016264:Dextran Sulfate; D017353:Gene Deletion; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000235:genetics; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: D015415:Biomarkers; D002273:Carcinogens; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D016264:Dextran Sulfate; D001397:Azoxymethane
keywords: TGFβ/SMAD signaling pathway; colon cancer; immune cell markers; inflammation; miR-155