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Etude fonctionnelle de la voie micro-ARN dans la biologie des cellules tumorales

Abstract : MicroRNAs (miRNAs) are 20-22 nucleotides RNAs, transcribed from the genome, which regulate gene expression by base-pairing to target mRNAs, thus inhibiting their translation and/or leading to their degradation. In cancers, miRNAs expression is strongly deregulated. A majority of miRNAs is diminished in tumoral tissues compared to normal tissues, and a causal link has been established between global inhibition of the miRNA pathway and tumorigenesis. In addition, miRNAs acting like tumor suppressors or oncogenes have been described. In this context of growing evidences implicating miRNAs in neoplasic diseases, this work aimed to investigate the role played by miRNA pathway in the biology of tumoral cells. In order to identify tumoral cells depending on endogenous oncogenic miRNAs to proliferate or survive, we developed a strategy of global inhibition of miRNAs biogenesis by targeting Drosha or DGCR8, the two components of the “microprocessor”, the nuclear miRNA maturation complex. This strategy allowed us to identify tumoral cell lines in which microprocessor inhibition led to a sustained growth arrest. We took advantage of this miRNA pathway dependency to screen for individual miRNAs able to complement the observed growth defect. This complementation screen allowed us to identify individual miRNAs able to sustain growth in those tumoral cells. This strategy also highlighted functional differences between homologous miRNAs or between miRNAs from the same family. The search for targets regulated by those miRNAs allowed us to develop hypothesis concerning the potential targets involved in the observed phenotype. By using this approach, we demonstrated that the tumor suppressor PTEN was involved in the growth arrest induced by microprocessor inhibition. The strategy of global miRNA pathway inhibition followed by phenotypic complementation by individual miRNAs allows overcoming the high sequence and function redundancy of miRNAs. We thus think it could be applied more generally to the study of other cellular processes regulated by miRNAs.
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https://tel.archives-ouvertes.fr/tel-00656609
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Submitted on : Wednesday, January 4, 2012 - 3:42:29 PM
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  • HAL Id : tel-00656609, version 1

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Delphine Peric. Etude fonctionnelle de la voie micro-ARN dans la biologie des cellules tumorales. Sciences agricoles. Université Paris Sud - Paris XI, 2011. Français. ⟨NNT : 2011PA112328⟩. ⟨tel-00656609⟩

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