Detalle Publicación


The miR181ab1 cluster promotes KRAS-driven oncogenesis and progression in lung and pancreas

Autores: Valencia Leoz, Karmele; Erice, O.; Kostyrko, K.; Hausmann, S.; Guruceaga Martínez, Elisabet; Tathireddy, A.; Flores, N. M.; Sayles, L. C.; Lee, A. G.; Fragoso, R.; Sun, T. Q.; Vallejo Blanco, Adrián; Román Moreno, Marta; Entrialgo Cadierno, Rodrigo; Miguéliz Basterra, Itziar; Razquin Erro, Nerea; Fortes, Puri; Lecanda Cordero, Fernando; Lu, J.; Ponz Sarvisé, Mariano; Chen, C. Z.; Mazur, P. K.; Sweet-Cordero, A. (Autor de correspondencia); Vicent Cambra, Silvestre (Autor de correspondencia)
ISSN: 0021-9738
Volumen: 130
Número: 4
Páginas: 1879 - 1895
Fecha de publicación: 2020
Few therapies are currently available for patients with KRAS-driven cancers, highlighting the need to identify new molecular targets that modulate central downstream effector pathways. Here we found the miRNA cluster mir181ab1 as a key modulator of KRAS-driven oncogenesis. Ablation of Mir181ab1 in genetically-engineered mouse models of Kras-driven lung and pancreatic cancer was deleterious to tumor initiation and progression. Expression of both resident miRNAs in the Mir181ab1 cluster, miR181a1 and miR181b1, was necessary to rescue the Mir181ab1-loss phenotype underscoring their non-redundant role. In human cancer cells, depletion of miR181ab1 impaired proliferation and 3D growth, whereas overexpression provided a proliferative advantage. Lastly, we unveiled miR181ab1-regulated genes responsible for this phenotype. These studies identified what we believe to be a previously unknown role for miR181ab1 as a potential therapeutic target in two highly aggressive and difficult to treat KRAS-mutated cancers.