Abstract
While inflammation has been associated with the development and progression of colorectal cancer, the exact role of the inflammatory Th17 pathway remains unclear. In this study, we aimed to determine the relative importance of IL-17A and the master regulator of the Th17 pathway, the transcription factor RORγt, in the sporadic intestinal neoplasia of APCMIN/+ mice and in human colorectal cancer. We show that levels of IL-17A are increased in human colon cancer as compared to adjacent uninvolved colon. Similarly, naïve helper T cells from colorectal cancer patients are more inducible into the Th17 pathway. Furthermore, IL-17A, IL-21, IL-22, and IL-23 are all demonstrated to be directly mitogenic to human colorectal cancer cell lines. Nevertheless, deficiency of IL-17A but not RORγt is associated with decreased spontaneous intestinal tumorigenesis in the APCMIN/+ mouse model, despite the fact that helper T cells from RORγt-deficient APCMIN/+ mice do not secrete IL-17A when subjected to Th17-polarizing conditions and that Il17a expression is decreased in the intestine of RORγt-deficient APCMIN/+ mice. Differential expression of Th17-associated cytokines between IL-17A-deficient and RORγt-deficient APCMIN/+ mice may explain the difference in adenoma development.
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Abbreviations
- ANCOVA:
-
Analysis of covariance for independent samples
- APC:
-
Adenomatous polyposis coli
- Apc :
-
Adenomatous polyposis coli gene
- ATCC:
-
American Type Culture Collection
- FAP:
-
Familial adenomatous polyposis
- HET:
-
Heterozygote
- IACUC:
-
Institutional Animal Care and Use Committee
- IBD:
-
Inflammatory bowel disease
- ILC:
-
Innate lymphoid cell
- ILC3:
-
Group 3 innate lymphoid cell
- IRB:
-
Institutional review board
- KO:
-
Knockout
- MIN:
-
Multiple intestinal neoplasia
- NKT cell:
-
Natural killer T cell
- qRT-PCR:
-
Quantitative real-time polymerase chain reaction
- siRNA:
-
Small interfering ribonucleic acid
- SPF:
-
Specific pathogen-free
- Treg:
-
Regulatory T cell
- VABHS:
-
VA Boston Healthcare System
- WT:
-
Wild type
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This work was supported by a United States Department of Veteran Affairs Office of Research and Development Career Development Award-2 (Jason S. Gold).
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Mia Shapiro and Bisweswar Nandi: Co-first authors.
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Shapiro, M., Nandi, B., Pai, C. et al. Deficiency of IL-17A, but not the prototypical Th17 transcription factor RORγt, decreases murine spontaneous intestinal tumorigenesis. Cancer Immunol Immunother 65, 13–24 (2016). https://doi.org/10.1007/s00262-015-1769-2
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DOI: https://doi.org/10.1007/s00262-015-1769-2