Unraveling RNA regulatory mechanisms in thyroid cancer

• Autores: Julia Ramírez Moya
• Directores de la Tesis: Pilar Santisteban (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2021
• Idioma: inglés
• Número de páginas: 228
• Títulos paralelos:
  • Identificación de mecanismos de regulación del RNA en cáncer de tiroides
• Tribunal Calificador de la Tesis: Ana Aranda Iriarte (presid.), Francisco Portillo Pérez (secret.), Mercedes Robledo Batanero (voc.), M. Inmaculada Ibáñez de Caceres (voc.), Caroline Serrano Do Nascimento (voc.)
• Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
• Materias:
  • Ciencias de la vida
    • Biología molecular
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • RNA networks are fundamental in the control of gene regulation, and recent years have witnessed a strong interest in non-coding RNAs, such as microRNAs (miRNAs). These products of the noncoding genome have key regulatory roles in cellular biology, and their aberrant expression/function is associated with numerous diseases, including cancer. In the present thesis, we identified novel RNA regulatory mechanisms important for thyroid tumorigenesis, the most common endocrine cancer. We show that miRNA dysregulation is a common event in this cancer, and involves not only individual changes in the expression of miRNAs, but also disruption of the biogenesis machinery and/or modifications to miRNA sequences by RNA editing. We explored the role and mechanisms of action of the most upregulated miRNA in thyroid cancer, miR-146b, and describe three novel targets that help explain miR-146b-induced cell aggressiveness: PTEN, E-cadherin and DICER1. We also demonstrate that all three proteins have tumor-suppressive activity in thyroid cancer. Specifically, miR-146b induces hyperactivation of the oncogenic PI3K pathway by inhibiting PTEN, promotes cell motility by suppressing E-cadherin, and triggers the global reduction of the miRNA network by downregulating DICER1. Importantly, these events are frequent in thyroid tumors. We also investigated the involvement of the high adenosine-toinosine (A-to-I) RNA editing levels in thyroid tumors and how this process adds complexity to the post-transcriptional regulation of gene expression. We demonstrate that ADAR1, the enzyme responsible for A-to-I RNA editing in human thyroid cells, induces tumorigenesis both in vitro and in vivo. This process is dependent, at least in part, on the overediting of the seed sequence of the tumor-suppressor miR-200b, impairing its ability to inhibit its target ZEB1. Our results highlight potential therapeutic approaches based on miRNA inhibition, restoring global miRNA levels via the DICER1 pathway, and suppressing RNA editing, overall providing a basis for new thyroid cancer treatments