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The Mir181ab1 cluster promotes KRAS-driven oncogenesis and progression in lung and pancreas

2019; American Society for Clinical Investigation; Volume: 130; Issue: 4 Linguagem: Inglês

10.1172/jci129012

1558-8238

Karmele Valencia, Oihane Erice, Kaja Kostyrko, Simone Hausmann, Elizabeth Guruceaga, Anuradha Tathireddy, Natasha Flores, Leanne C. Sayles, Alex G. Lee, Rita Fragoso, Tian-Qiang Sun, Adrián Vallejo, Marta Román, Rodrigo Entrialgo‐Cadierno, Itziar Miguéliz, Nerea Razquin, Puri Fortes, Fernando Lecanda, Jun Lü, Mariano Ponz‐Sarvisé, Chang‐Zheng Chen, Paweł K. Mazur, E. Alejandro Sweet‐Cordero, Silvestre Vicent,

RNA Research and Splicing

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 that the microRNA (miRNA) cluster including miR181ab1 is 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 nonredundant 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 2 highly aggressive and difficult to treat KRAS-mutated cancers.