Aryl hydrocarbon receptor gene polymorphisms affect lung cancer risk

Kim, Jin Hee; Kim, Heon; Lee, Kye Young; Kang, Jeong Woo; Lee, Kwan-Hee; Park, So‐Yeon; Yoon, Ho-Il; Jheon, Sang Hoon; Sung, Sook Whan; Hong, Yun–Chul

doi:10.1016/j.lungcan.2006.11.010

Cited by 43 publications

(38 citation statements)

References 25 publications

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“…In humans, the expression change or mutation of AhR gene in human tissue has been studied as a potential factor related to risk or survival of cancer in lung or other sites (33,34). Haplotypes of AhR gene play an important role in the development of lung cancer (35). In the present study, the polymorphisms were found in introns of AhR; it is conceivable that these variants modify the metabolism of PAH through the regulation of AhR transcription.…”

Section: Ahr Gene Polymorphisms and Urinary 1-hydroxypyrenementioning

confidence: 66%

Association of Aryl Hydrocarbon Receptor Gene Polymorphisms and Urinary 1-Hydroxypyrene in Polycyclic Aromatic Hydrocarbon–Exposed Workers

Peng

Leng²,

Cheng³

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Polycyclic aromatic hydrocarbons (PAH) in coke oven emissions could cause lung cancer in human. Individual's genotype of the metabolic enzymes and early biological changes were known to be associated with the susceptibility of cancer development. Knowledge of metabolic gene polymorphisms, which affect on the urinary 1-hydroxypyrene (1-OHP), could benefit us in understanding the interindividual difference in the mechanism of PAH-induced carcinogenesis. In this study, we investigated the association of aryl hydrocarbon receptor (AhR) gene polymorphisms and urinary 1-OHP. One hundred forty-seven workers exposed to PAH and 69 nonexposure workers were recruited. Seven tagging single nucleotide polymorphisms in AhR gene were selected by pariwise r 2 method and minor allele frequency cutoff of 0.05 from Chinese genotype data in HapMap project. These seven tagging single nucleotide polymorphisms were genotyped by PCR-based methods. Multivariate analysis of covariance revealed that the levels of 1-OHP in PAH-exposed workers carrying genotype CT were lower than workers carrying wild genotype TT at loci rs10250822 and rs2282885 of AhR gene (P = 0.032 and 0.044, respectively). In PAH-exposed workers, the urinary 1-OHP levels showed a linear correlation (P trend = 0.041) with the genotypes at locus rs2282885, especially in low and moderate exposure groups. In contrast, no significant association was found between urinary 1-OHP level and AhR genotypes among nonexposed workers. Our findings indicated that polymorphisms of AhR gene were associated with the level of 1-OHP among PAH-exposed workers, suggesting that AhR-mediated signaling might contribute to individual susceptibility to PAH exposure. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1702 -8)

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Section: Ahr Gene Polymorphisms and Urinary 1-hydroxypyrenementioning

confidence: 66%

Association of Aryl Hydrocarbon Receptor Gene Polymorphisms and Urinary 1-Hydroxypyrene in Polycyclic Aromatic Hydrocarbon–Exposed Workers

Peng

Leng²,

Cheng³

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Therefore, we propose that the physiological role of the AhR is to act as a "brake" and curb inflammation. Interestingly there is a synergistic association between AhR gene polymorphisms and lung cancer risk (71). Loss of AhR expression and/or function via a genetic polymorphism may contribute to an individual's risk of developing lung cancer.…”

Section: Fibroblasts Ahrmentioning

confidence: 99%

The Aryl Hydrocarbon Receptor Attenuates Tobacco Smoke-induced Cyclooxygenase-2 and Prostaglandin Production in Lung Fibroblasts through Regulation of the NF-κB Family Member RelB

Baglole

Maggirwar

Gasiewicz

et al. 2008

Journal of Biological Chemistry

136

178

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Diseases such as chronic obstructive pulmonary disease and lung cancer caused by cigarette smoke affect millions of people worldwide. The aryl hydrocarbon receptor (AhR) is a ligandactivated transcription factor that influences responses to certain environmental pollutants such as tobacco smoke. However, the physiological function(s) of the AhR is unknown. Herein we propose that the physiologic role of the AhR is to limit inflammation. We show that lung fibroblasts from AhR ؊/؊ mice produce a heightened inflammatory response to cigarette smoke, typified by increased levels of cyclooxygenase-2 (COX-2) and prostaglandins (PGs), when compared with wild type (AhR ؉/؉ ) fibroblasts. This response was dependent on AhR expression as transient transfection of an AhR expression plasmid into AhR ؊/؊ fibroblasts significantly attenuated the smoke-induced COX-2 and PG production, confirming the anti-inflammatory role of the AhR. The AhR can interact with NF-B. However, the heightened inflammatory response observed in AhR ؊/؊ fibroblasts was not the result of NF-B (p50/p65) activation. Instead it was coupled with a loss of the NF-B family member RelB in AhR ؊/؊ fibroblasts. Taken together, these studies provide compelling evidence that AhR expression limits proinflammatory COX-2 and PG production by maintaining RelB expression. The association between RelB and AhR may represent a new therapeutic and more selective target with which to combat inflammation-associated diseases.Lung inflammation and diseases such as chronic obstructive pulmonary disease and cancer caused by cigarette smoke affect millions of people. The link between chronic inflammation, typified by heightened expression of cyclooxygenase-2 (COX-2; 2 also known as prostaglandin endoperoxide H synthase (PGHS-2)), and these diseases is well established (1-3). COX enzymes catalyze the transformation of arachidonic acid into prostaglandin (PG) H 2 (4, 5), which serves as a substrate for various synthases that generate PGs and thromboxanes (6). There are two COX isoforms. In most tissues, COX-1 is expressed constitutively (7), whereas COX-2 is rapidly up-regulated by a variety of inflammatory stimuli (5) such as interleukin (IL)-1 (8) and cigarette smoke (9).Cigarette smoke is a complex mixture containing more than 4800 compounds. Cigarette smoke and some of its components, such as benzo[a]pyrene (B[a]P), induce COX-2 expression in lymphocytes, epithelial cells, and fibroblasts (9 -11). Fibroblasts are the main cell type in the lung interstitium, are involved in tissue repair and remodeling (12), provide structural support to the alveolar compartment, and are an important target of cigarette smoke (9, 13-18). Importantly fibroblasts are one of the major cell types that express COX-2 and synthesize PGs in humans (19,20).Regulation of COX-2 expression involves several transcriptional regulators (5), including the aryl hydrocarbon receptor (AhR). The AhR is a ligand-activated transcription factor belonging to the basic helix-loop-helix/Per-Arnt-Sim transcription factor ...

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“…Although there is no direct evidence showing that the activation of AhR leads to NSCLC tumorigenesis, AhR has attracted increasing attention in this type of cancer. For example, overexpression of AhR has been detected in more than 50% of patients with NSCLC, and polymorphisms of AhR gene are implicated in the development of NSCLC (25)(26)(27)(28). Activation of AhR signaling upregulates several growth factors, and NSCLC cells require elevated AhR for sustained proliferation (29,30).…”

Section: Introductionmentioning

confidence: 99%

Activation of the Aryl Hydrocarbon Receptor Leads to Resistance to EGFR TKIs in Non–Small Cell Lung Cancer by Activating Src-mediated Bypass Signaling

Zhang

Gao

et al. 2018

Clinical Cancer Research

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Purpose: The aryl hydrocarbon receptor (AhR) has been generally recognized as a ligand-activated transcriptional factor that responds to xenobiotic chemicals. Recent studies have suggested that the expression of AhR varies widely across different cancer types and cancer cell lines, but its significance in cancer treatment has yet to be clarified. Experimental Design: AhR expression in non–small cell lung cancer (NSCLC) was determined by Western blotting and IHC staining. In vitro and in vivo functional experiments were performed to determine the effect of AhR on sensitivity to targeted therapeutics. A panel of biochemical assays was used to elucidate the underlying mechanisms. Results: A high AhR protein level indicated an unfavorable prognosis for lung adenocarcinoma. Inhibition of AhR signaling sensitized EGFR tyrosine kinase inhibitors (TKIs) in NSCLC cells that express high level of endogenous AhR protein. Notably, activation of AhR by pharmacologic and molecular approaches rendered EGFR-mutant cells resistant to TKIs by restoring PI3K/Akt and MEK/Erk signaling through activation of Src. In addition, we found that AhR acts as a protein adaptor to mediate Jak2–Src interaction, which does not require the canonical transcriptional activity of AhR. Conclusions: Our results reveal a transcription-independent function of AhR and indicate that AhR may act as a protein adaptor that recruits kinases bypassing EGFR and drives resistance to TKIs. Accordingly, targeting Src would be a strategy to overcome resistance to EGFR TKIs in AhR-activated NSCLC. Clin Cancer Res; 24(5); 1227–39. ©2017 AACR.

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Aryl hydrocarbon receptor gene polymorphisms affect lung cancer risk

Cited by 43 publications

References 25 publications

Association of Aryl Hydrocarbon Receptor Gene Polymorphisms and Urinary 1-Hydroxypyrene in Polycyclic Aromatic Hydrocarbon–Exposed Workers

Association of Aryl Hydrocarbon Receptor Gene Polymorphisms and Urinary 1-Hydroxypyrene in Polycyclic Aromatic Hydrocarbon–Exposed Workers

The Aryl Hydrocarbon Receptor Attenuates Tobacco Smoke-induced Cyclooxygenase-2 and Prostaglandin Production in Lung Fibroblasts through Regulation of the NF-κB Family Member RelB

Activation of the Aryl Hydrocarbon Receptor Leads to Resistance to EGFR TKIs in Non–Small Cell Lung Cancer by Activating Src-mediated Bypass Signaling

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