Dataset Information

The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc ^Min/+ mice.

ABSTRACT:

Background

Intestinal tumorigenesis is promoted by myeloid differentiation primary response gene 88 (MyD88) activation in response to the components of microbiota in Apc ^Min/+ mice. Microbiota also contains double-stranded RNA (dsRNA), a ligand for TLR3, which activates the toll-like receptor adaptor molecule 1 (TICAM-1, also known as TRIF) pathway.

Methods

We established Apc ^Min/+ Ticam1 ^-/- mice and their survival was compared to survival of Apc ^Min/+ Myd88 ^-/- and wild-type (WT) mice. The properties of polyps were investigated using immunofluorescence staining and RT-PCR analysis.

Results

We demonstrate that TICAM-1 is essential for suppression of polyp formation in Apc ^Min/+ mice. TICAM-1 knockout resulted in shorter survival of mice compared to WT mice or mice with knockout of MyD88 in the Apc ^Min/+ background. Polyps were more frequently formed in the distal intestine of Apc ^Min/+ Ticam1 ^-/- mice than in Apc ^Min/+ mice. Infiltration of immune cells such as CD11b⁺ and CD8?⁺ cells into the polyps was detected histologically. CD11b and CD8? mRNAs were increased in polyps of Apc ^Min/+ Ticam1 ^-/- mice compared to Apc ^Min/+ mice. Gene expression of inducible nitric oxide synthase (iNOS), interferon (IFN)-?, CXCL9 and IL-12p40 was increased in polyps of Apc ^Min/+ Ticam1 ^-/- mice. mRNA and protein expression of c-Myc, a critical transcription factor for inflammation-associated polyposis, were increased in polyps of Apc ^Min/+ Ticam1 ^-/- mice. A Lactobacillus strain producing dsRNA was detected in feces of Apc ^Min/+ mice.

Conclusion

These results imply that the TLR3/TICAM-1 pathway inhibits polyposis through suppression of c-Myc expression and supports long survival in Apc ^Min/+ mice.

SUBMITTER: Ono J

PROVIDER: S-EPMC5646017 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Publications

The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc <sup>Min/+</sup> mice.

Ono Junya J Shime Hiroaki H Takaki Hiromi H Takashima Ken K Funami Kenji K Yoshida Sumito S Takeda Yohei Y Matsumoto Misako M Kasahara Masanori M Seya Tsukasa T

Journal of biomedical science 20171017 1

<h4>Background</h4>Intestinal tumorigenesis is promoted by myeloid differentiation primary response gene 88 (MyD88) activation in response to the components of microbiota in Apc <sup>Min/+</sup> mice. Microbiota also contains double-stranded RNA (dsRNA), a ligand for TLR3, which activates the toll-like receptor adaptor molecule 1 (TICAM-1, also known as TRIF) pathway.<h4>Methods</h4>We established Apc <sup>Min/+</sup> Ticam1 <sup>-/-</sup> mice and their survival was compared to survival of Apc ...[more]

PMID: 29041928

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Project description:Colorectal cancer (CRC) incidence is rising globally. Hence, preventing this disease is a high priority. With this aim, we determined the CRC prevention potential of the TRAIL-inducing small molecule ONC201/TIC10 using a preclinical model representing high-risk familial adenomatous polyposis (FAP) patients, Apc min/+ mice. Prior to the efficacy study, optimal and non-toxic doses of ONC201 were determined by testing five different doses of ONC201 (0-100 mg/kg body weight (BW); twice weekly by oral gavage) in C57BL/6J mice (n=6/group) for 6 weeks. BW gain, organ weights and histopathology, blood profiling, and the plasma liver enzyme profile suggested no toxicities of ONC201 at doses up to 100 mg/kg BW. For efficacy determination, beginning at six weeks of age, groups of Apc min/+ male and female mice (n≥20) treated with colon carcinogen azoxymethane (AOM) (AOM-Apc min/+) were administered ONC201 (0, 25, and 50 mg/kg BW) as above up to 20 weeks of age. At termination, efficacy was determined by comparing the incidence and multiplicity of intestinal tumors between vehicle- and drug-treated groups. ONC201 showed a strong suppressive effect against the development of both large and small intestinal tumors in male and female mice. Apc min/+ mice treated with ONC201 (50 mg/kg BW) showed >50% less colonic tumor incidence (P<0.0002) than controls. Colonic tumor multiplicity was also significantly reduced by 68% in male mice (0.44 ± 0.11 in treated vs. 1.4 ± 0.14 in controls; P<0.0001) and by 75% in female mice (0.30 ± 0.10 in treated vs. 1.19 ± 0.19 in controls; P<0.0003) with ONC201 treatment (50 mg/kg BW). Small intestinal polyps were reduced by 68% in male mice (11.40 ± 1.19 in treated vs. 36.08 ± 2.62 in controls; P<0.0001) and female mice (9.65 ± 1.15 in treated vs. 29.24 ± 2.51 in controls; P<0.0001). Molecular analysis of the tumors suggested an increase in TRAIL, DR5, cleaved caspases 3/7/8, Fas-associated death domain protein (FADD), and p21 (WAF1) in response to drug treatment. Serum analysis indicated a decrease in pro-inflammatory serum biomarkers, such as IL1β, IL6, TNFα, G-CSF, and GM-CSF, in the ONC201-treated mice compared with controls. Our data demonstrated excellent chemopreventive potential of orally administered ONC201 against intestinal tumorigenesis in the AOM-Apc min/+ mouse model.

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Dataset Information

The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc ^Min/+ mice.

Background

Methods

Results

Conclusion

Publications

The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc <sup>Min/+</sup> mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc Min/+ mice.

Background

Methods

Results

Conclusion

Publications

The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc <sup>Min/+</sup> mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

The TLR3/TICAM-1 signal constitutively controls spontaneous polyposis through suppression of c-Myc in Apc ^Min/+ mice.