En este trabajo hemos establecido por primera vez el papel de la edición del ARN en cáncer de tiroides. En particular, hemos demostrado que la edición en el ARN es un proceso que se encuentra incrementado en cáncer de tiroides, y que la principal enzima encargada de este proceso, denominada ADAR1 (double-stranded RNA-specific adenosine deaminase), actúa como un oncogén. Además, hemos descrito que uno de los mecanismos de acción de ADAR1 es la edición del miR-200b, un importante supresor tumoral que disminuye los niveles de la proteína de transición epitelio mesénquima ZEB1. Finalmente, los resultados obtenidos describen nuevas aplicaciones terapéuticas que podrían establecer las bases de futuros tratamientos para el cáncer de tiroides.
Resumen
Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double-stranded RNA. A-to-I editing of RNA is a widespread posttranscriptional process that has recently emerged as an important mechanism in cancer biology. A-to-I editing levels are high in several human cancers, including thyroid cancer, but ADAR1 editase-dependent mechanisms governing thyroid cancer progression are unexplored. To address the importance of RNA A-to-I editing in thyroid cancer, we examined the role of ADAR1. Loss-of-function analysis showed that ADAR1 suppression profoundly repressed proliferation, invasion, and migration in thyroid tumor cell models. These observations were validated in an in vivo xenograft model, which showed that ADAR1-silenced cells had a diminished ability to form tumors. RNA editing of miRNAs has the potential to markedly alter target recognition. According to TCGA data, the tumor suppressor miR-200b is overedited in thyroid tumors, and its levels of editing correlate with a worse progression-free survival and disease stage. We confirmed miR-200b overediting in thyroid tumors and we showed that edited miR-200b has weakened activity against its target gene ZEB1 in thyroid cancer cells, likely explaining the reduced aggressiveness of ADAR1-silenced cells. We also found that RAS, but not BRAF, modulates ADAR1 levels, an effect mediated predominantly by PI3K and in part by MAPK. Lastly, pharmacological inhibition of ADAR1 activity with the editing inhibitor 8-azaadenosine reduced cancer cell aggressiveness. Overall, our data implicate ADAR1-mediated A-to-I editing as an important pathway in thyroid cancer progression, and highlight RNA editing as a potential therapeutic target in thyroid cancer.
Sobre el grupo investigador
Nuestro grupo, dirigido por la doctora Pilar Santisteban, se centra en el estudio de los mecanismos moleculares implicados en el desarrollo y progresión del cáncer de tiroides, estudiando el mecanismo de acción de oncogenes y vías de señalización. Este trabajo se ha realizado en colaboración con el grupo del Dr. Frank Slack de la universidad de Harvard (Boston, EEUU), donde la autora principal ha realizado parte de esta investigación.
Referencia del artículo
Oncogene. 2020 Apr;39(18):3738-3753.
https://doi.org/10.1038/s41388-020-1248-x