Expression of NR1I3 in mouse lung tumors induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanone

Fukumasu, Heidge; Cordeiro, Yonara de Gouveia; Rochetti, Arina Lázaro; Barra, Camila Neri; Sámora, T.S.; Strefezzi, Ricardo de Francisco; Dagli, M.L.

doi:10.1590/1414-431x20144210

Cited by 6 publications

(4 citation statements)

References 21 publications

(31 reference statements)

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“…In this context, activation of the CAR may be reducing tissue inflammation by accelerating mucosal repair and restitution. On the other hand, CAR expression was recently reported in tumour‐associated macrophages in the airways, suggesting its activation may regulate inflammation (Fukumasu et al, ). While these findings have yet to be confirmed by others, it is apparent that additional studies are required to determine whether the CAR plays a direct role in modulating mucosal immune cell function.…”

Section: Discussionmentioning

confidence: 99%

Constitutive androstane receptor regulates the intestinal mucosal response to injury

Hudson

Flannigan

Erickson

et al. 2017

British J Pharmacology

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Background and Purpose The pathogenesis of the inflammatory bowel diseases (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), involves aberrant interactions between a genetically susceptible individual, their microbiota and environmental factors. Alterations in xenobiotic receptor expression and function are associated with increased risk for IBD. Here, we have assessed the role of the constitutive androstane receptor (CAR), a xenobiotic receptor closely related to the pregnane X receptor, in the regulation of intestinal mucosal homeostasis. Experimental Approach CAR expression was assessed in intestinal mucosal biopsies obtained from CD and UC patients, and in C57/Bl6 mice exposed to dextran sulphate sodium (DSS; 3.5% w/v in drinking water) to evoke intestinal inflammation and tissue damage. CAR‐deficient mice were exposed to DSS and mucosal healing assessed. Modulation of wound healing by CAR was assessed in vitro. The therapeutic potential of CAR activation was evaluated, using 3,3′,5,5′‐tetrachloro‐1,4‐bis(pyridyloxy)benzene (TCPOBOP), a selective rodent CAR agonist. Key Results CAR expression was reduced in CD and UC samples, compared with expression in healthy controls. This was reproduced in our DSS studies, where CAR expression was reduced in colitic mice. CAR‐deficient mice exhibited reduced healing following DSS exposure. In vitro, CAR activation accelerated intestinal epithelial wound healing by enhancing cell migration. Lastly, treating mice with TCPOBOP, following induction of colitis, enhanced mucosal healing. Conclusion and Implications Our results support the notion that xenobiotic sensing is altered during intestinal inflammation, and suggest that CAR activation may prove effective in enhancing mucosal healing in patients with IBD.

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Section: Discussionmentioning

confidence: 99%

Constitutive androstane receptor regulates the intestinal mucosal response to injury

Hudson

Flannigan

Erickson

et al. 2017

British J Pharmacology

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“…For the immunohistochemistry experiments, the tumors were harvested, fixed in formalin and embedded in paraffin (Life Technologies), and conventional immunohistochemistry sections were prepared. Detection was performed using the SP method in accordance with standard procedures ( 15 ). Positive expression was regarded as the presence of yellow-brown particles in cytoplasm or nucleus.…”

Section: Methodsmentioning

confidence: 99%

Hypoxia-inducible factor-1α and Wnt/β-catenin signaling pathways promote the invasion of hypoxic gastric cancer cells

Liu

Ding

et al. 2015

Molecular Medicine Reports

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The present study aimed to examine the association between hypoxia-inducible factor (HIF)-1α and the Wnt/β-catenin signaling pathway in a hypoxic environment. The study also aimed to explore the possible mechanisms underlying the invasion of hypoxic gastric cancer cells in vitro and in vivo. The pcDNA™ 6.2-GW/EmGFP-miR-β-catenin plasmid was transfected into SGC-7901 gastric cancer cells, resulting in cells with stable suppression of β-catenin expression. The biological characteristics of the control, liposome, negative control, β-catenin knockdown, hypoxia and hypoxia β-catenin knockdown groups were tested using an invasion assay. The differences in the invasive capacity of the control, negative control and liposome groups were not statistically significant. However, the hypoxia group demonstrated a significantly enhanced invasive capacity, as compared with that in the control group (P<0.05). In the hypoxia β-catenin knockdown group, reduced cell penetration and diminished invasive behavior was observed (P<0.05). In the hypoxia and double (chemical + physical) hypoxia groups, HIF-1α, β-catenin, urokinase-type plasminogen activator (uPA) and matrix metalloproteinase (MMP-7) protein and mRNA expression levels were elevated. In response to knockdown of β-catenin expression, HIF-1α, β-catenin, uPA and MMP-7 protein as well as mRNA expression levels were significantly reduced in the hypoxia β-catenin knockdown and the double hypoxia β-catenin knockdown groups. In an in vivo experiment, the growth rate of xenograft tumors of hypoxic and control cells was high alongside increased HIF-1α, β-catenin, uPA and MMP-7 levels according to western blot and immunohistochemical analyses, while growth and protein levels of tumors from hypoxic β-catenin knockdown cells were significantly lower and those of β-catenin knockdown cells were lowest. In conclusion, these results suggested that HIF-1α activation was able to regulate the Wnt/β-catenin pathway, and that HIF-1α may be controlled by the Wnt/β-catenin pathway. A potential mechanism underlying SGC-7901 tumorigenicity is the activation of the Wnt/β-catenin signaling pathway, which activates uPA and MMP-7 expression and contributes to the enhanced invasion of hypoxic cancer cells.

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“…CAR expression is reduced in CD133 + brain tumor stem cells, and its activation by CITCO induces its own expression and inhibits stem cell proliferation [265]. In a mouse model of lung carcinogenesis, macrophages and type I and II pneumocytes express CAR, whereas fibroblasts and endothelial cells do not [266]. Moreover, the number of CAR-positive tumor cells was lower in malignant than benign tumor lesions [266].…”

Section: Cancermentioning

confidence: 99%

“…In a mouse model of lung carcinogenesis, macrophages and type I and II pneumocytes express CAR, whereas fibroblasts and endothelial cells do not [266]. Moreover, the number of CAR-positive tumor cells was lower in malignant than benign tumor lesions [266]. CAR mRNA expression is downregulated in hepatoblastoma and can be used as a predictor to assign unknown samples to the healthy or hepatoblastoma group with 100% accuracy [267].…”

Section: Cancermentioning

confidence: 99%

Regulation of CAR and PXR Expression in Health and Disease

Daujat-Chavanieu

Gerbal‐Chaloin

2020

Cells

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Pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are members of the nuclear receptor superfamily that mainly act as ligand-activated transcription factors. Their functions have long been associated with the regulation of drug metabolism and disposition, and it is now well established that they are implicated in physiological and pathological conditions. Considerable efforts have been made to understand the regulation of their activity by their cognate ligand; however, additional regulatory mechanisms, among which the regulation of their expression, modulate their pleiotropic effects. This review summarizes the current knowledge on CAR and PXR expression during development and adult life; tissue distribution; spatial, temporal, and metabolic regulations; as well as in pathological situations, including chronic diseases and cancers. The expression of CAR and PXR is modulated by complex regulatory mechanisms that involve the interplay of transcription factors and also post-transcriptional and epigenetic modifications. Moreover, many environmental stimuli affect CAR and PXR expression through mechanisms that have not been elucidated.

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Expression of NR1I3 in mouse lung tumors induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanone

Cited by 6 publications

References 21 publications

Constitutive androstane receptor regulates the intestinal mucosal response to injury

Constitutive androstane receptor regulates the intestinal mucosal response to injury

Hypoxia-inducible factor-1α and Wnt/β-catenin signaling pathways promote the invasion of hypoxic gastric cancer cells

Regulation of CAR and PXR Expression in Health and Disease

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