ABSTRACT
Adenocarcinomas (AC), squamous cell carcinomas (SCC) and adenosquamous carcinomas (ASC) are three histological subtypes of non-small-cell lung carcinomas (NSCLC). ASC are morphologically mixed tumours that contain the two cell components AC and SCC. To understand if they are a "simple" mix of AC and SCC or if they present molecular specificities, as compared with the molecular characterization of both components, we performed a comparative transcriptome analysis on a series of nine ASC, five AC and five SCC induced in rats by radon exposure. We found that 72, 40 and 39 genes were differentially expressed when comparing AC_SCC, ASC_SCC and AC_ASC, respectively. Moreover, when classifying the three histological subtypes, using genes that discriminated AC and SCC, we observed that all ASC were classified as intermediate between the AC and SCC, some being closer to AC, others to SCC. These results indicated that, regarding gene expression, ASC could be considered as a mix of AC and SCC, both in various proportions. However, they also exhibit molecular specificities since we found specific genes discriminating ASC_SCC and AC_ASC. In conclusion, the ASC mixed lung tumours are more complex than simple mixes of AC and SCC components. Neuroendocrine differentiation and ERK proliferation pathways seemed preferentially deregulated in ASC compared to AC and SCC respectively, pathways that are worthy of being explored because they could partially explain the high clinical aggressiveness of ASC.
Subject(s)
Adenocarcinoma/genetics , Carcinoma, Adenosquamous/genetics , Carcinoma, Squamous Cell/genetics , Lung Neoplasms/genetics , Lung/metabolism , Adenocarcinoma/chemically induced , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Animals , Carcinoma, Adenosquamous/chemically induced , Carcinoma, Adenosquamous/metabolism , Carcinoma, Adenosquamous/pathology , Carcinoma, Squamous Cell/chemically induced , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , Cell Transformation, Neoplastic , DNA Mutational Analysis , GATA6 Transcription Factor/genetics , GATA6 Transcription Factor/metabolism , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Genes, ras/genetics , Lung/pathology , Lung Neoplasms/chemically induced , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , MAP Kinase Signaling System/genetics , Microarray Analysis , Mucin-1/genetics , Mucin-1/metabolism , Radon/toxicity , Rats , Rats, Sprague-Dawley , Receptor, Notch2/genetics , Receptor, Notch2/metabolismABSTRACT
Inhalation of radon is closely associated with an increased risk of lung cancers. While the involvement of Ink4a in lung tumor development has been widely described, the tumor suppressor gene has not been studied in radon-induced lung tumors. In this study, loss of heterozygosity (LOH) analysis of the Cdkn2a locus, common to the Ink4a and Arf genes, was performed on 33 radon-induced rat lung tumors and showed a DNA loss in 50% of cases. The analysis of p16(Ink4a) protein expression by immunohistochemistry revealed that 50% of the tumors were negative for this protein. Looking for the origin of this lack of expression, we observed a low frequency of homozygous deletion (6%), a lack of mutation, an absence of correlation between promoter methylation and Ink4a mRNA expression and no correlation between LOH and protein expression. However, a tendency for an inverse correlation between p16(Ink4a) and pRb protein expression was observed. The expressions of p19Arf, Mmd2 and Mdm4 were not deregulated and only 14% of the tumors were mutated for Tp53. These results indicated that Ink4a/Cdk4/Rb1 pathway deregulation, more than Arf/Mdm2/Tp53 pathway, has a major role in the development of these tumors through p16(Ink4a) deregulation. However, all known mechanisms of inactivation of the pathway do not play a recurrent role in these tumors and the actual origin of the lack of p16(Ink4a) protein expression remains to be established.
