1. Molecular analysis of the Ink4a/Rb1-Arf/Tp53 pathways in radon-induced rat lung tumors
- Author
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Kristell Bastide, Jean-François Bernaudin, Christophe Joubert, Bernard Malfoy, Sylvie Chevillard, Bruno Lectard, Marie-Noëlle Guilly, Céline Levalois, Laboratoire de Cancérologie Expérimentale (LCE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Dynamique de l'information génétique : bases fondamentales et cancer (DIGBFC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Service d'Histologie-Biologie tumorale [Hôpital Tenon], Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay
- Subjects
Cancer Research ,Pathology ,Lung Neoplasms ,Rats, Inbred WF ,MESH: Rats, Sprague-Dawley ,Polymerase Chain Reaction ,Retinoblastoma Protein ,MESH: Carcinogens, Environmental ,Loss of heterozygosity ,Rats, Sprague-Dawley ,0302 clinical medicine ,MESH: DNA Methylation ,CDKN2A ,Tumor Suppressor Protein p14ARF ,MESH: Animals ,RNA, Neoplasm ,MESH: Tumor Suppressor Protein p53 ,Regulation of gene expression ,0303 health sciences ,integumentary system ,biology ,Arf ,MESH: Gene Expression Regulation, Neoplastic ,Ink4a ,Immunohistochemistry ,3. Good health ,Gene Expression Regulation, Neoplastic ,MESH: Neoplasms, Experimental ,Oncology ,Tp53 mutation ,Radon ,030220 oncology & carcinogenesis ,MESH: Cyclin-Dependent Kinase Inhibitor p16 ,DNA methylation ,MESH: Rats, Inbred WF ,Mdm2 ,biological phenomena, cell phenomena, and immunity ,Lung cancer ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,MESH: Mutation ,Tumor suppressor gene ,MESH: Rats ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,03 medical and health sciences ,medicine ,Animals ,Rb1 ,MESH: Tumor Suppressor Protein p14ARF ,neoplasms ,Cyclin-Dependent Kinase Inhibitor p16 ,030304 developmental biology ,MESH: Rats, Inbred F344 ,Cancer ,MESH: Immunohistochemistry ,MESH: Polymerase Chain Reaction ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Neoplasms, Experimental ,MESH: Retinoblastoma Protein ,DNA Methylation ,medicine.disease ,MESH: RNA, Neoplasm ,Carcinogens, Environmental ,Rats, Inbred F344 ,MESH: Lung Neoplasms ,Rats ,Mutation ,biology.protein ,Cancer research ,Rat ,Tumor Suppressor Protein p53 ,MESH: Radon - Abstract
International audience; 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.
- Published
- 2008
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