Referencia

Nature Genetics 41, 365 - 370 (2009) Published online: 15 February 2009 | doi:10.1038/ng.317

Autores

Sonia A. Melo(1), Santiago Ropero(1), Catia Moutinho(1), Lauri A Aaltonen(2), Hiroyuki Yamamoto(3), George A Calin(4), Simona Rossi(4), Agustin F Fernandez(1), Fatima Carneiro(5), Carla Oliveira(5), Bibiana Ferreira(1), Chang-Gong Liu(4), Alberto Villanueva(6), Gabriel Capella(6), Simo Schwartz Jr(7), Ramin Shiekhattar(8,9) & Manel Esteller(1,9,10)

Resumen

El artículo describe la alteración del gen TARBP2, presente en el 25% de los tumores de colon, estómago y útero de la ruta mutadora. El gen TARBP2 es clave en la regulación de muchos otros genes al tratarse del gen que fabrica los microRNAs, pequeñas moleculas de acido ribonucleico (ARN) que actuan como interruptores de la expresión genética. Es la primera vez que se demuestra la existencia de alteraciones en un gen de la cadena de montaje de los microRNAs en tumores humanos. La mutación descubierta inactiva el gen TARBP2 y se produce tanto en casos hereditarios de la enfermedad como en cánceres esporádicos. Además, las células que poseen esta alteración presentan una actividad aberrante de muchos otros genes debido a que TARBP2 actúa a modo de guardia de tráfico, regulando la actividad posterior de muchísimos otros genes.

Descripción

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by targeting messenger RNA (mRNA) transcripts. Recently, a miRNA expression profile of human tumors has been characterized by an overall miRNA downregulation (1, 2, 3). Explanations for this observation include a failure of miRNA post-transcriptional regulation (4), transcriptional silencing associated with hypermethylation of CpG island promoters (5, 6, 7) and miRNA transcriptional repression by oncogenic factors (8). Another possibility is that the enzymes and cofactors involved in miRNA processing pathways may themselves be targets of genetic disruption, further enhancing cellular transformation (9). However, no loss-of-function genetic alterations in the genes encoding these proteins have been reported. Here we have identified truncating mutations in TARBP2 (TAR RNA-binding protein 2), encoding an integral component of a DICER1-containing complex (10, 11) in sporadic and hereditary carcinomas with microsatellite instability (12, 13, 14). The presence of TARBP2 frameshift mutations causes diminished TRBP protein expression and a defect in the processing of miRNAs. The reintroduction of TRBP in the deficient cells restores the efficient production of miRNAs and inhibits tumor growth. Most important, the TRBP impairment is associated with a destabilization of the DICER1 protein. These results provide, for a subset of human tumors, an explanation for the observed defects in the expression of mature miRNAs.

1. Cancer Epigenetics Laboratory, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
2. Tumor Genomics Group, Academy of Finland and Genome-Scale Biology Research Program/Biomedicum, Department of Medical Genetics, University of Helsinki F-00014 Helsinki, Finland.
3. Sapporo Medical University, South 1, West 17, Chuo-ku, Sapporo 060-8556, Japan.
4. Experimental Therapeutics & Cancer Genetics, MD Anderson Cancer Center, Houston, Texas 77030, USA.
5. Medical Faculty of the University of Porto and Hospital S. João and Institute of Molecular Pathology and Immunology (IPATIMUP), 4200-465 Porto, Portugal.
6. Translational Research Laboratory, IDIBELL-Institut Catala d'Oncologia, 08907 Barcelona, Spain.
7. Molecular Biology and Biochemistry Research Center for Nanomedicine, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, 08035 Barcelona, Catalonia, Spain.
8. Center for Genomic Regulation, C/Dr. Aiguader 88, 08003 Barcelona, Catalonia, Spain.

Imágen artículo Noviembre

Sónia Melo realiza la tesis doctoral en el laboratorio de Epigenética del Cancer dirigido por el Dr Manel Esteller en el Instituto de Investigacion Biomédica de Bellvitge (IDIBELL) , Hospitalet, Barcelona. Su investigacion está centrada en las alteraciones genéticas y epigenéticas que afectan la actividad de los microRNAs en cáncer humano.

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