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J Clin Invest ; 130(4): 1879-1895, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31874105

RESUMO

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.


Assuntos
Carcinogênese/metabolismo , Neoplasias Pulmonares/metabolismo , MicroRNAs/metabolismo , Família Multigênica , Neoplasias Experimentais/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , RNA Neoplásico/metabolismo , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Pulmonares/genética , Camundongos , Camundongos Knockout , MicroRNAs/genética , Neoplasias Experimentais/genética , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA Neoplásico/genética
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