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Validation d'outils moléculaires pour la cancérologie clinique : Etude de l'expression des récepteurs aux rétinoïdes dans les cancers bronchiques

Abstract : Retinoid Receptors are involved in development and cell homeostasis. Alterations of their expressions have been observed in lung cancer. However, retinoid chemoprevention trials in populations at risk to develop such tumours have failed. Therefore, the pertinence of new clinical trials using second generation retinoids requires prior better understanding of the molecular mechanisms involved in the retinoid signalling. This is our aim when validating extensively research tools, focused on the Retinoic Acid Receptor ß, whose major role in lung cancer is documented. Biocomputing was used to draw in silico an updated RARß genomic organisation. Features of a putative P1'-RARß promoter were investigated experimentally. Specific measures realised, with qRT-PCR Syber Green assays and a triplex of Taqman probes, were extensively validated to establish Retinoid Receptors mRNAs reference values for normal human bronchial epithelial cells. Relative expressions of the different RRs mRNA isoforms were further quantified in lung tumour samples and in several cancer cell lines. Finally, an antibody recognising all the RARß protein isoforms, was generated and extensively validated by western-blot and immunoprecipitation. No promoter-like activity was found for P1'-RARß. P2-RARß mRNA increase signs the normal differentiation of the human bronchial epithelium while a significant decrease is observed in most lung cancer cell lines. Accordingly, it is also, along with RXRß, down-regulated in lung tumours. When using nuclear extracts of BEAS-2B and normal lung cells, only the P2-long RARß2 protein isoform was recognised by our antibody. Rigorous samples processing and extensive biocomputing, were the key factors for this study. mRNA reference values and validated tools are now available to advance researches on retinoid signalling in the lung.
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Submitted on : Thursday, March 29, 2018 - 11:35:26 AM
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Stéphane Poulain. Validation d'outils moléculaires pour la cancérologie clinique : Etude de l'expression des récepteurs aux rétinoïdes dans les cancers bronchiques. Biologie cellulaire. Université Henri Poincaré - Nancy 1, 2009. Français. ⟨NNT : 2009NAN10038⟩. ⟨tel-01748456⟩



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