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Intestinal tumor suppression in Apc Min/+ mice by prostaglandin D 2 receptor PTGDR
Author(s) -
Tippin Brigette L.,
Kwong Alan M.,
Inadomi Michael J.,
Lee Oliver J.,
Park Jae Man,
Materi Alicia M.,
Buslon Virgilio S.,
Lin Amy M.,
Kudo Lili C.,
Karsten Stanislav L.,
French Samuel W.,
Narumiya Shuh,
Urade Yoshihiro,
Salido Eduardo,
Lin Henry J.
Publication year - 2014
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.251
Subject(s) - peroxisome proliferator activated receptor gamma , gene knockout , knockout mouse , receptor , prostaglandin , transgene , biology , genetically modified mouse , cancer research , endocrinology , medicine , chemistry , microbiology and biotechnology , peroxisome proliferator activated receptor , biochemistry , gene
Abstract Our earlier work showed that knockout of hematopoietic prostaglandin D synthase (HPGDS, an enzyme that produces prostaglandin D 2 ) caused more adenomas in Apc Min/+ mice. Conversely, highly expressed transgenic HPGDS allowed fewer tumors. Prostaglandin D 2 (PGD 2 ) binds to the prostaglandin D 2 receptor known as PTGDR (or DP1). PGD 2 metabolites bind to peroxisome proliferator‐activated receptor γ (PPARG). We hypothesized that Ptgdr or Pparg knockouts may raise numbers of tumors, if these receptors take part in tumor suppression by PGD 2 . To assess, we produced Apc Min/+ mice with and without Ptgdr knockouts (147 mice). In separate experiments, we produced Apc Min/+ mice expressing transgenic lipocalin‐type prostaglandin D synthase (PTGDS), with and without heterozygous Pparg knockouts (104 mice). Homozygous Ptgdr knockouts raised total numbers of tumors by 30–40% at 6 and 14 weeks. Colon tumors were not affected. Heterozygous Pparg knockouts alone did not affect tumor numbers in Apc Min/+ mice. As mentioned above, our Pparg knockout assessment also included mice with highly expressed PTGDS transgenes. Apc Min/+ mice with transgenic PTGDS had fewer large adenomas (63% of control) and lower levels of v‐myc avian myelocytomatosis viral oncogene homolog (MYC) mRNA in the colon. Heterozygous Pparg knockouts appeared to blunt the tumor‐suppressing effect of transgenic PTGDS. However, tumor suppression by PGD 2 was more clearly mediated by receptor PTGDR in our experiments. The suppression mechanism did not appear to involve changes in microvessel density or slower proliferation of tumor cells. The data support a role for PGD 2 signals acting through PTGDR in suppression of intestinal tumors.

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