Long-term feeding of various fat diets modulates azoxymethane-induced colon carcinogenesis through Wnt/β-catenin signaling in rats

The Wnt signaling pathway plays an essential role in carcinogenesis, and the amount of fat intake and composition of dietary fatty acids are crucial factors for colon carcinogenesis. We investigated whether various dietary fats affected the Wnt signaling pathway of colon tumorigenesis in azoxymethane (AOM)-treated rats. Male Sprague-Dawley rats were given intraperitoneal injections of AOM and supplemented with 10% corn, olive, beef, and fish oil for 44 wk. Aberrant crypt foci (ACF) and tumors were examined at 12 and 44 wk. Normal appearing colon mucosal proliferation and apoptosis were evaluated by 5-bromo-2′-deoxyuridine (BrdU) incorporation and percentages of fragmented DNA, respectively. Expressions of β-catenin, cyclin D1, Wnt2, Wnt3, and Wnt5a of normal appearing colon mucosa were analyzed by Western blot analysis. Long-term dietary corn oil and beef tallow increased ACF, tumor incidence, and tumor numbers in AOM-treated rats. In contrast, both olive and fish oil inhibited them. Dietary corn oil and beef tallow increased BrdU incorporation and the expression of cytosolic β-catenin and cyclin D1 and decreased apoptosis in the colon mucosa. Expressions of Wnt2 and Wnt3 in rats fed with beef tallow and Wnt5a in rats fed with corn oil increased with or without AOM-treatment. BrdU-incorporated cells were often observed at the tops of crypts in rats fed with beef tallow, whereas this was not observed in rats fed with the other diet. Long-term high intake of corn oil and beef tallow enhanced cell proliferation through Wnt signaling and modulated the distribution of proliferating cells, which might contribute to promoting effects in colon tumorigenesis.

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Long-term effect of Wnt/β-catenin small molecule inhibitor CWP232291 on intestinal carcinogenesis in novel GEM model deficient in Smad4 and p53.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.594 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 594-594

Author(s):

Jun Won Park ◽

Jung Min Park ◽

Jeffrey E. Green ◽

Hark K. Kim

Keyword(s):

Wnt Signaling ◽

Small Molecule ◽

Target Genes ◽

Wnt Signaling Pathway ◽

Small Molecule Inhibitor ◽

Intestinal Tumors ◽

Intestinal Carcinogenesis ◽

Molecule Inhibitor ◽

Primary Mouse

594 Background: We have established and characterized a novel genetically-engineered mouse (GEM) model for colorectal cancer by performing intestinal epithelium-specific knockout of Smad4 and p53 under Villin promoter. CWP232291 (JW Pharmaceutical Corporation, Seoul, Korea) is a potent Wnt/ β-catenin small molecule inhibitor currently tested in several Phase I trials. We evaluated chemopreventive efficacy of long-term CWP232291 treatment for intestinal carcinogenesis in our novel GEM model. Methods: Three-week-old GEM mice were intraperitoneally injected BIW for 17 weeks with 100 mg/kg CWP232291 (n = 19) or vehicle normal saline (n = 27) and then sacrificed. Results: All Villin-Cre;Smad4F/F;Trp53F/F mice developed multiple spontaneous intestinal tumors with the high proliferative activity and the activation of Wnt signaling pathway (median adenocarcinoma-free survival, 5.4 months; incidence of adenocarcinoma, 75.9 %). Whereas, Villin-Cre;Smad4F/F or Villin-Cre;Trp53F/F micedidn’t develop any intestinal tumors until 20 weeks. A histological assessment showed that tumor-bearing mice were significantly reduced after CWP232291 treatment (CWP232291, 50.0% vs vehicle, 84.0%; P < 0.01). More importantly, CWP232291 showed significant decrease in the incidence of malignant tumors (CWP232291, 37.5% vs vehicle, 78.3%; P < 0.05). In addition, tumor multiplicity is significantly decreased in CWP232291-treated mice (CWP232291, 1.2 ± 0.4 vs vehicle, 2.8 ± 0.4, P < 0.01). Immunohistochemistry showed that CWP232291 treatment reduced β-catenin, myc and cyclin D1 levels in tumors. In-vivo limiting dilution assay using primary mouse cancer cells showed that the frequency of cancer stem cells (CSCs) was 1/3,223 for the untreated group and 1/48,069 for the CWP291-treated group (p < 0.001). Conclusions: These results showed that CWP232291 inhibited Wnt signaling and reduced the CSCs through down-regulation of β-catenin and Wnt target genes and exerted a chemopreventive effect in our GEM model. This suggests that CWP232291 may be a promising candidate for colorecal cancer chemoprevention and maintenance.

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Long-term ingestion of reduced glutathione suppressed an accelerating effect of beef tallow diet on colon carcinogenesis in rats

Journal of Gastroenterology ◽

10.1007/s00535-009-0101-3 ◽

2009 ◽

Vol 44 (10) ◽

pp. 1026-1035 ◽

Cited By ~ 7

Author(s):

Ryosuke Shiraishi ◽

Takehiro Fujise ◽

Tsukasa Kuroki ◽

Takashi Kakimoto ◽

Lujie Miao ◽

...

Keyword(s):

Beef Tallow ◽

Reduced Glutathione ◽

Colon Carcinogenesis ◽

Beef Tallow Diet

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Conjugated linoleic acid suppresses colon carcinogenesis in azoxymethane-pretreated rats with long-term feeding of diet containing beef tallow

Journal of Gastroenterology ◽

10.1007/s00535-010-0206-8 ◽

2010 ◽

Vol 45 (6) ◽

pp. 625-635 ◽

Cited By ~ 21

Author(s):

Ryosuke Shiraishi ◽

Ryuichi Iwakiri ◽

Takehiro Fujise ◽

Tsukasa Kuroki ◽

Takashi Kakimoto ◽

...

Keyword(s):

Linoleic Acid ◽

Conjugated Linoleic Acid ◽

Beef Tallow ◽

Colon Carcinogenesis

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Brewers’ rice induces apoptosis in azoxymethane-induced colon carcinogenesis in rats via suppression of cell proliferation and the Wnt signaling pathway

BMC Complementary and Alternative Medicine ◽

10.1186/1472-6882-14-304 ◽

2014 ◽

Vol 14 (1) ◽

Cited By ~ 10

Author(s):

Bee Ling Tan ◽

Norhaizan Mohd Esa ◽

Heshu Sulaiman Rahman ◽

Hazilawati Hamzah ◽

Roselina Karim

Keyword(s):

Cell Proliferation ◽

Wnt Signaling ◽

Signaling Pathway ◽

Wnt Signaling Pathway ◽

Colon Carcinogenesis

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Long-term, multilineage hematopoiesis occurs in the combined absence of β-catenin and γ-catenin

Blood ◽

10.1182/blood-2007-07-102558 ◽

2008 ◽

Vol 111 (1) ◽

pp. 142-149 ◽

Cited By ~ 161

Author(s):

Grégoire Jeannet ◽

Marina Scheller ◽

Léonardo Scarpellino ◽

Stéphane Duboux ◽

Noemie Gardiol ◽

...

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Wnt Signaling ◽

Ex Vivo ◽

Wnt Signaling Pathway ◽

Transcriptional Responses ◽

Differentiation Potential ◽

Hematopoietic Stem ◽

Canonical Wnt

The canonical Wnt signaling pathway plays key roles in stem-cell maintenance, progenitor cell expansion, and lineage decisions. Transcriptional responses induced by Wnt depend on the association of either β-catenin or γ-catenin with lymphoid enhancer factor/T cell factor transcription factors. Here we show that hematopoiesis, including thymopoiesis, is normal in the combined absence of β- and γ-catenin. Double-deficient hematopoietic stem cells maintain long-term repopulation capacity and multilineage differentiation potential. Unexpectedly, 2 independent ex vivo reporter gene assays show that Wnt signal transmission is maintained in double-deficient hematopoietic stem cells, thymocytes, or peripheral T cells. In contrast, Wnt signaling is strongly reduced in thymocytes lacking TCF-1 or in nonhematopoietic cells devoid of β-catenin. These data provide the first evidence that hematopoietic cells can transduce canonical Wnt signals in the combined absence of β- and γ-catenin.

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MODULATION OF THE WNT SIGNALING PATHWAY BY WISE ANTIBODY IMPROVES LONG-TERM KIDNEY TRANSPLANT OUTCOME IN A RAT RENAL TRANSPLANT MODEL

Transplantation Journal ◽

10.1097/00007890-201007272-00003 ◽

2010 ◽

Vol 90 ◽

pp. 2

Author(s):

X. Yuan ◽

S. Vonderfecht ◽

X. Ge ◽

J. Lee ◽

A. Jurisch ◽

...

Keyword(s):

Renal Transplant ◽

Wnt Signaling ◽

Signaling Pathway ◽

Kidney Transplant ◽

Wnt Signaling Pathway ◽

Transplant Outcome ◽

Transplant Model

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Brain Neutral Lipids and Phospholipids Are Modified by Long-Term Feeding of Beef Tallow vs. Corn Oil Diets

Journal of Nutrition ◽

10.1093/jn/126.6.1554 ◽

1996 ◽

Vol 126 (6) ◽

pp. 1554-1562 ◽

Cited By ~ 8

Author(s):

Ruth S. MacDonald ◽

Wen Zhang ◽

Jian-Ping Zhang ◽

Grace Y. Sun

Keyword(s):

Beef Tallow ◽

Corn Oil ◽

Neutral Lipids

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Liver Inflammation and Fibrosis Induced by Long-Term Exposure to Nano Titanium Dioxide (TiO2) Nanoparticles in Mice and Its Molecular Mechanism

Journal of Biomedical Nanotechnology ◽

10.1166/jbn.2020.2921 ◽

2020 ◽

Vol 16 (5) ◽

pp. 616-625

Author(s):

Fashui Hong ◽

Jianhui Ji ◽

Xiao Ze ◽

Yingjun Zhou ◽

Yuguan Ze

Keyword(s):

Titanium Dioxide ◽

Liver Fibrosis ◽

Wnt Signaling ◽

Signaling Pathway ◽

Hepatic Fibrosis ◽

Wnt Signaling Pathway ◽

Underlying Mechanism ◽

The Body ◽

Fibrotic Liver

Titanium dioxide (TiO2) and nano-sized titanium dioxide (nano-TiO2), which are used in food production, may be harmful to the body. Long-term exposure to nano-TiO2 can lead to hepatic injury; however, the effect of nano-TiO2 on liver fibrosis and the underlying mechanism remain unclear. The TGF-β/Smad/MAPK/Wnt signaling pathway is important for tissue fibrosis. In this study, mice were fed nano-TiO2 (2.5, 5, and 10 mg/kg body weight) for nine consecutive months to investigate its effect on liver fibrosis. Nano-TiO2 induced hepatic inflammatory cell infiltration and hepatic fibrosis and upregulated the expression of HIF-1α (+75-fold to +2.38-fold), Wnt3 (+12% to +135%), Wnt4 (1.33-fold to 6-fold), NF-κB (+3.13% to +34.38%), TGF-β1 (+1307-fold to +1.85-fold), TGF-β1R (+0.8-fold to 1.33-fold), Smad-2 (+0.58-fold to +1.58-fold), ILK (+0.43-fold to +1.19-fold), ECM (+1.82-fold to 2.36-fold), calpain 2 (+0.11-fold to +0.78-fold), α-SMA (+0.63-fold to +1.56-fold), c-Myc (+0.27-fold to +0.46-fold), and collagen I (+8% to +36%), and increased the phosphorylation level of p38MAPK (+66.67% to +153.33%) in inflammatory and fibrotic liver tissues, whereas it downregulated cyclin D (–6.25% to –43.75%) and decreased the phosphorylation levels of GSK-3β (–3.12% to –46.88%) and β-catenin (–19.57% to –45.65%). These results indicate that hepatic fibrosis induced by nano-TiO2 is mediated by the TGF-β/Smads/MAPK/Wnt signaling pathway. This study provides insight into the mechanism underlying hepatic toxicity induced by nano-TiO2 .

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