Enhancement of lung carcinogenesis initiated with 4-(N-hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone by Ogg1 gene deficiency in female, but not male, mice

Igarashi, Maki; Watanabe, Masao; Yoshida, Midori; Sugaya, Kimio; Endo, Yuichi; Miyajima, Nozomi; Abe, Masayoshi; Sugano, Sumio; Nakae, Dai

doi:10.2131/jts.34.163

Cited by 17 publications

(14 citation statements)

References 48 publications

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“…The mutational spectra of NNK-treated MGMT−/− lungs revealed an increase in G:C to A:T changes accompanied by a shift from CpG to GpG sites [31]. 8-hydroxyguanine DNA glycosylase 1 (Ogg1) gene encodes an enzyme that repairs an oxidative DNA injury 8-oxoguanine (8-oxoG), whose deficiency results in the development of lung adenomas and preneoplastic atypical hypreplasias in knockout mice treated with NNK [32]. …”

Section: Transgenic Animal Model Of Nnk-mediated Lung Carcinomamentioning

confidence: 99%

NNK-Induced Lung Tumors: A Review of Animal Model

Zheng

Takano

2011

Journal of Oncology

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The incidence of lung adenocarcinoma has been remarkably increasing in recent years due to the introduction of filter cigarettes and secondary-hand smoking because the people are more exposed to higher amounts of nitrogen oxides, especially 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK), which is widely applied in animal model of lung tumors. In NNK-induced lung tumors, genetic mutation, chromosome instability, gene methylation, and activation of oncogenes have been found so as to disrupt the expression profiles of some proteins or enzymes in various cellular signal pathways. Transgenic animal with specific alteration of lung cancer-related molecules have also been introduced to clarify the molecular mechanisms of NNK in the pathogenesis and development of lung tumors. Based on these animal models, many antioxidant ingredients and antitumor chemotherapeutic agents have been proved to suppress the NNK-induced lung carcinogenesis. In the future, it is necessary to delineate the most potent biomarkers of NNK-induced lung tumorigenesis, and to develop efficient methods to fight against NNK-associated lung cancer using animal models.

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Section: Transgenic Animal Model Of Nnk-mediated Lung Carcinomamentioning

confidence: 99%

NNK-Induced Lung Tumors: A Review of Animal Model

Zheng

Takano

2011

Journal of Oncology

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“…In the mouse, it is well known that females are generally more sensitive to chemical lung carcinogenesis, such as that induced by NNK, than males (16). It is hypothesized that the difference is due to difference in the amount of sex hormones such as testosterone and estradiol.…”

Section: Introductionmentioning

confidence: 99%

Gender-dependent effects of gonadectomy on lung carcinogenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female and male A/J mice

et al. 2013

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The present study was conducted to investigate the effects of gonadectomy on lung carcinogenesis in female and male mice, and to determine an association between sex hormone and lung carcinogenesis. Female and male A/J mice were divided into gonadectomized and unoperated control groups and all animals were treated intraperitoneally with 1 or 2 injections of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) at the dose of 2 mg/mouse. The mice were sacrificed 18 or 56 weeks after surgery. Serum levels of estradiol in females and testosterone in males were confirmed to be decreased by gonadectomy. Lung white nodules were detected in all mice of all groups. In the control groups of 18- and 56-week studies, the multiplicities of lung nodules in females were significantly greater than in males. In males in the 56-week study, the multiplicity of macroscopical lung nodules, bronchiolo-alveolar hyperplasias, adenomas and tumors (adenomas and adenocarcinomas) showed significant increase with castration. In females in the 18-week study, the multiplicity of adenomas decreased significantly by ovariectomy. Based on the results of the present study, female A/J mice were confirmed to be more susceptible to NNK-induced lung carcinogenesis than males. Furthermore, it was suggested that the process is inhibited by testosterone and accelerated by estradiol. These findings indicate the possibility that sex hormones play important roles in determining sex differences in lung carcinogenesis in the A/J mice initiated by NNK.

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“…Egfr mutations of rodent lung carcinogenesis have only been reported under special conditions, such as X-ray irradiation (16), and in genetically engineered animals with Ogg1 gene deficiency (17). To our knowledge, this is the first demonstration of an Egfr mutation in chemical lung carcinogenesis in a nongenetically engineered animal.…”

Section: Discussionmentioning

confidence: 87%

“…Such mutations are more frequently observed in asian, adenocarcinoma and female patients, and in patients with a never-smoking history (9,(11)(12)(13)(14)(15). However, in animal lung carcinogenesis models, there have been very few reports of mutations within the TK domain of Egfr (16,17). in human nSclc patients, survival and response to Egfr-TK inhibitors correlate with Egfr mutations, high Egfr copy number, overexpression of eGFr protein and Kras mutations (13,18).…”

Section: Introductionmentioning

confidence: 99%

Molecular analysis of carcinogen-induced rodent lung tumors: Involvement of microRNA expression and Krαs or Egfr mutations

Yamakawa

Kuno²,

Hashimoto³

et al. 2009

Mol Med Rep

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Abstract. Genetic and epigenetic alterations play a key role in lung carcinogenesis, and a high frequency of Kras and epidermal growth factor receptor (Egfr) mutations have been observed in human lung cancers. recent evidence indicates that the expression of specific microRNAs (miRNAs) may be involved. in rodent lung carcinogenesis models, Kras mutations are frequently observed, whereas genetic alteration of the Egfr gene is generally rare. Since little is known regarding the involvement of mirnas in rodent lung carcinogenesis, the present study of mirna expression levels in the liver and lung during 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (nnK)-and 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeiQx)-induced lung tumorigenesis in a/J mice was conducted. in addition, incidences of Egfr and Kras gene mutations in rat and mouse lung tumors induced by the chemical carcinogens nnK, MeiQx and n-bis(2-hydroxypropyl)nitrosamine (dHPn) were examined. Three mirnas, let-7a, mir-34c and mir-125a-5p, were selected for attention. in rat lung tumors, one silent mutation was detected in the Egfr gene exon 20 (aac→aaT; n772). activating mutations of the Kras gene at codon 12 were detected in neoplastic lesions induced by nnK (5/6, 83%), MeiQx (1/1, 100%) and dHPn (7/15, 47%), all resulting in G/c→a/T transitions. nnK or MeiQx administration reduced the expression of mir-125a-5p (MeiQx alone group, 86.3%; MeiQx + nnK group, 83.6%; p<0.05, at day 15) and let-7a (MeiQx + nnK group, 56.3%; p<0.001, at day 22) in the liver. mir-34c was up-regulated 3.5-fold with nnK treatment as compared to the control group (p<0.001). These findings raise the possibility that aberrant expression of mirna is involved in lung tumorigenesis, at least in its early stages.

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Enhancement of lung carcinogenesis initiated with 4-(N-hydroxymethylnitrosamino)-1-(3-pyridyl)-1-butanone by Ogg1 gene deficiency in female, but not male, mice

Cited by 17 publications

References 48 publications

NNK-Induced Lung Tumors: A Review of Animal Model

NNK-Induced Lung Tumors: A Review of Animal Model

Gender-dependent effects of gonadectomy on lung carcinogenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female and male A/J mice

Molecular analysis of carcinogen-induced rodent lung tumors: Involvement of microRNA expression and Krαs or Egfr mutations

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