The Aryl Hydrocarbon Receptor is a Repressor of Inflammation-associated Colorectal Tumorigenesis in Mouse

Díaz-Díaz, Carol J.; Ronnekleiv-Kelly, Sean; Nukaya, Manabu; Geiger, Peter; Balbo, Silvia; Dator, Romel P; Megna, Bryant; Carney, Patrick R.; Bradfield, Christopher A.; Kennedy, Gregory D.

doi:10.1097/sla.0000000000001874

Cited by 80 publications

(68 citation statements)

References 32 publications

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“…Although dioxin is classified as a human carcinogen- acting through the AhR- there is controversy for the role of the AhR in cancer development. In some studies, the AhR acts as a potent tumor suppressor, recently being shown to repress melanoma growth55, liver carcinogenesis56 and inflammation-associated colorectal tumorigenesis57. Genetic variations in AHR are also implicated in lung cancer susceptibility amongst smokers, where such variation may affect AhR protein expression and/or activity585960.…”

Section: Discussionmentioning

confidence: 99%

Aryl hydrocarbon receptor (AhR)-dependent regulation of pulmonary miRNA by chronic cigarette smoke exposure

Rogers

Souza

Zago

et al. 2017

Sci Rep

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The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor historically known for its toxic responses to man-made pollutants such as dioxin. More recently, the AhR has emerged as a suppressor of inflammation, oxidative stress and apoptosis from cigarette smoke by mechanisms that may involve the regulation of microRNA. However, little is known about the AhR regulation of miRNA expression in the lung in response to inhaled toxicants. Therefore, we exposed Ahr−/− and Ahr+/− mice to cigarette smoke for 4 weeks and evaluated lung miRNA expression by PCR array. There was a dramatic regulation of lung miRNA by the AhR in the absence of exogenous ligand. In response to cigarette smoke, there were more up-regulated miRNA in Ahr−/− mice compared to Ahr+/− mice, including the cancer-associated miRNA miR-96. There was no significant change in the expression of the AhR regulated proteins HuR and cyclooxygenase-2 (COX-2). There were significant increases in the anti-oxidant gene sulfiredoxin 1 (Srxn1) and FOXO3a- predicted targets of miR-96. Collectively, these data support a prominent role for the AhR in regulating lung miRNA expression. Further studies to elucidate a role for these miRNA may further uncover novel biological function for the AhR in respiratory health and disease.

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Section: Discussionmentioning

confidence: 99%

Aryl hydrocarbon receptor (AhR)-dependent regulation of pulmonary miRNA by chronic cigarette smoke exposure

Rogers

Souza

Zago

et al. 2017

Sci Rep

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“…Disease models in which AHR modulation has been suggested as a possible target include, for instance, cancer, Crohn's disease, ulcerative colitis, diabetes, MS and inflammatory skin conditions such as atopic dermatitis (Benson and Shepherd 2011, Díaz-Díaz, et al 2016, Furumatsu, et al 2011, Haas, et al 2016, Jin, et al 2014, Kerkvliet, et al 2009, Quintana, et al 2010, Singh, et al 2007, Van Den Bogaard, et al 2013 . Although the mechanisms of action of the parent compounds of C1 and C3, laquinimod and tasquinimod, are not yet fully elucidated, they are recognised as immunomodulatory compounds (Raymond, et al 2014, Varrin-Doyer, et al 2014.…”

Section: Accepted Manuscriptmentioning

confidence: 98%

“…These impacts are particularly related to immunomodulation (Zhu, et al 2014). Appropriate activation of AHR, devoid of TCDD-like toxicity, could thus lead to novel therapeutics for treatment of, for instance, cancer, multiple sclerosis (MS), inflammatory skin diseases, Crohn's disease and colitis (Arsenescu, et al 2011, Benson and Shepherd 2011, Díaz-Díaz, et al 2016, Furumatsu, et al 2011, Haas, et al 2016, Jin, et al 2014, Quintana, et al 2008, Van Den Bogaard, et al 2013.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Toxicological characterisation of two novel selective aryl hydrocarbon receptor modulators in Sprague-Dawley rats

Mahiout

Lindén

Esteban

et al. 2017

Toxicology and Applied Pharmacology

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The aryl hydrocarbon receptor (AHR) mediates the toxicity of dioxins, but also plays important physiological roles. Selective AHR modulators, which elicit some effects imparted by this receptor without causing the marked toxicity of dioxins, are presently under intense scrutiny. Two novel such compounds are IMA-08401 (N-acetyl-N-phenyl-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide) and IMA-07101 (N-acetyl-N-(4-trifluoromethylphenyl)-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide). They represent, as diacetyl prodrugs, AHR-active metabolites of the drug compounds laquinimod and tasquinimod, respectively, which are intended for the treatment of autoimmune diseases and cancer. Here, we toxicologically assessed the novel compounds in Sprague-Dawley rats, after a single dose (8.75-92.5mg/kg) and 5-day repeated dosing at the highest doses achievable (IMA-08401: 100mg/kg/day; and IMA-07101: 75mg/kg/day). There were no overt clinical signs of toxicity, but body weight gain was marginally retarded, and the treatments induced minimal hepatic extramedullary haematopoiesis. Further, both the absolute and relative weights of the thymus were significantly decreased. Cyp1a1 gene expression was substantially increased in all tissues examined. The hepatic induction profile of other AHR battery genes was distinct from that caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The only marked alterations in serum clinical chemistry variables were a reduction in triglycerides and an increase in 3-hydroxybutyrate. Liver and kidney retinol and retinyl palmitate concentrations were affected largely in the same manner as reported for TCDD. In vitro, the novel compounds activated CYP1A1 effectively in H4IIE cells. Altogether, these novel compounds appear to act as potent activators of the AHR, but lack some major characteristic toxicities of dioxins. They therefore represent promising new selective AHR modulators.

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“…The loss of AhR by crossing APC Min/+ with AhR −/− mice enhances intestinal tumor formation and treatment of APC Min/+ mice with AhR ligands [e.g., cruciferous vegetable-derived I3C and DIM] inhibits tumor formation [221]. Similar results indicating that AhR is a repressor of inflammation-associated colon cancer have also been recently described [230]. Collectively, these findings clearly demonstrate that the AhR and its dietary and microbial-derived ligands have a profound impact on gastrointestinal homeostasis and tumorigenesis.…”

Section: Dietary Mediators Of Colon Tumorigenesismentioning

confidence: 55%

Shaping functional gut microbiota using dietary bioactives to reduce colon cancer risk

Seidel

Azcarate‐Peril

Chapkin

et al. 2017

Seminars in Cancer Biology

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Colon cancer is a multifactorial disease associated with a variety of lifestyle factors. Alterations in the gut microbiota and the intestinal metabolome are noted during colon carcinogenesis, implicating them as critical contributors or results of the disease process. Diet is a known determinant of health, and as a modifier of the gut microbiota and its metabolism, a critical element in maintenance of intestinal health. This review summarizes recent evidence demonstrating the role and responses of the intestinal microbiota during colon tumorigenesis and the ability of dietary bioactive compounds and probiotics to impact colon health from the intestinal lumen to the epithelium and systemically. We first describe changes to the intestinal microbiome, metabolome, and epithelium associated with colon carcinogenesis. This is followed by a discussion of recent evidence indicating how specific classes of dietary bioactives, prebiotics, or probiotics affect colon carcinogenesis. Lastly, we briefly address the prospects of using multiple ‘omics’ techniques to integrate the effects of diet, host, and microbiota on colon tumorigenesis with the goal of more fully appreciating the interconnectedness of these systems and thus, how these approaches can be used to advance personalized nutrition strategies and nutrition research.

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The Aryl Hydrocarbon Receptor is a Repressor of Inflammation-associated Colorectal Tumorigenesis in Mouse

Cited by 80 publications

References 32 publications

Aryl hydrocarbon receptor (AhR)-dependent regulation of pulmonary miRNA by chronic cigarette smoke exposure

Aryl hydrocarbon receptor (AhR)-dependent regulation of pulmonary miRNA by chronic cigarette smoke exposure

Toxicological characterisation of two novel selective aryl hydrocarbon receptor modulators in Sprague-Dawley rats

Shaping functional gut microbiota using dietary bioactives to reduce colon cancer risk

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