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

Abstract

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.

Immunohistochemical Characteristics of Surfactant Proteins A, B, C and D in Inflammatory and Tumorigenic Lung Lesions of F344 Rats

“…Some studies have suggested that SP-A might have a role in suppressing lung cancer progression, and SP-A expression by tumor cells leads to recruitment and activation of NK cells and tumor-associated macrophages 19 . In another study, activating mutations of the Kras gene at codon 12 were reported in 47% of lesions induced by DHPN in the F344 rat 8 . Overexpression of oncogenic Kras leads to activation of the NF-κB pathway, which appears to be required for the development of tumors in a mouse model of lung adenocarcinoma 30 .…”

“…It has been reported that activating mutations of the Kras gene at codon 12 are detected in almost 50% of rat lung neoplastic lesions induced by a carcinogen 8 . Furthermore, we previously examined the lung toxicity of fine particles of various materials in an in vivo bioassay using an IT approach 5 , 7 , 9 .…”

Pulmonary tumors associated with the JC virus T-antigen in a transgenic mouse model

“…In this case, an EGFR mutation was detected, while a K-ras mutation was not detected. While it is unclear how mutations of EGFR and other molecular alterations are related to the mechanisms involved in pulmonary tumorigenesis in mice, both genetic and epigenetic factors are known to be important for tumorigenesis (39). In this case, it is impossible to resolve the mechanism of the phenomenon based on only one tumor.…”

Ablating all three retinoblastoma family members in mouse lung leads to neuroendocrine tumor formation

“…In an attempt to provide further clarification to these possible oncogenic inputs required, we performed chemical carcinogenesis using two well known lung carcinogens, DHPN and urethane, that cause Kras activation [19, 20, 22]. We observed that under our experimental conditions DHPN is insufficient to cause tumor development in control mice, probably due to the mixed background of the strain used [44], although a potential role of p107 deficiency can not be discarded at present.…”

“…DHPN, a potent mutagen and a wide-spectrum carcinogen in rodents induces lung tumors when given in drinking water [16–18]. Mutational activation of Kras has been described in these rodent lung tumors [19, 20]. Urethane (ethyl carbamate), a component of various food products and cigarette smoke, induces the formation of lung tumors in animal models.…”