title: Deficiency of IL-17A, but not the prototypical Th17 transcription factor RORγt, decreases murine spontaneous intestinal tumorigenesis.
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 APC(MIN/+) 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 APC(MIN/+) mouse model, despite the fact that helper T cells from RORγt-deficient APC(MIN/+) mice do not secrete IL-17A when subjected to Th17-polarizing conditions and that Il17a expression is decreased in the intestine of RORγt-deficient APC(MIN/+) mice. Differential expression of Th17-associated cytokines between IL-17A-deficient and RORγt-deficient APC(MIN/+) mice may explain the difference in adenoma development.
authors.affiliation: Research Service, VA Boston Healthcare System, West Roxbury, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Mia
authors.initials: M
authors.lastname: Shapiro
authors.affiliation: Research Service, VA Boston Healthcare System, West Roxbury, MA, USA.|Harvard Medical School, Boston, MA, USA.
authors.forename: Bisweswar
authors.initials: B
authors.lastname: Nandi
authors.affiliation: Research Service, VA Boston Healthcare System, West Roxbury, MA, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Pai
authors.affiliation: Harvard Medical School, Boston, MA, USA.|Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: Mehmet K
authors.initials: MK
authors.lastname: Samur
authors.affiliation: Research Service, VA Boston Healthcare System, West Roxbury, MA, USA.|Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: Dheeraj
authors.initials: D
authors.lastname: Pelluru
authors.affiliation: Harvard Medical School, Boston, MA, USA.|Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Fulciniti
authors.affiliation: Research Service, VA Boston Healthcare System, West Roxbury, MA, USA.|Harvard Medical School, Boston, MA, USA.|Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: Rao H
authors.initials: RH
authors.lastname: Prabhala
authors.affiliation: Harvard Medical School, Boston, MA, USA.|Dana-Farber Cancer Center, Boston, MA, USA.|Medicine Service, VA Boston Healthcare System, West Roxbury, MA, USA.
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.affiliation: Harvard Medical School, Boston, MA, USA. jgold4@partners.org.|Surgery Service, VA Boston Healthcare System (112), 1400 VFW Parkway, West Roxbury, MA, 02132, USA. jgold4@partners.org.|Brigham and Women's Hospital, Boston, MA, USA. jgold4@partners.org.
authors.forename: Jason S
authors.identifier: http://orcid.org/0000-0002-2925-4755
authors.initials: JS
authors.lastname: Gold
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D008297:Male; D051379:Mice; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C508717:IL17A protein, human; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D014157:Transcription Factors
keywords: Adenoma; Carcinogenesis; Colorectal neoplasms; IL-17A; RORγt; Th17