1. The Mir181ab1 cluster promotes KRAS-driven oncogenesis and progression in lung and pancreas
- Author
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Valencia, Karmele, Erice, Oihane, Kostyrko, Kaja, Hausmann, Simone, Guruceaga, Elizabeth, Tathireddy, Anuradha, Flores, Natasha M., Sayles, Leanne C., Lee, Alex G., Fragoso, Rita, Sun, Tian-Qiang, Vallejo, Adrian, Roman, Marta, Entrialgo-Cadierno, Rodrigo, Migueliz, Itziar, Razquin, Nerea, Fortes, Puri, Lecanda, Fernando, Lu, Jun, Ponz-Sarvise, Mariano, Chen, Chang-Zheng, Mazur, Pawel K., Sweet-Cordero, E. Alejandro, and Vicent, Silvestre
- Subjects
Thermo Fisher Scientific Inc. ,Genetic engineering ,Genetically modified organisms ,MicroRNA ,B cells ,Pancreatic cancer -- Development and progression ,Carcinogenesis -- Development and progression ,Scientific equipment industry ,Genetic research ,Cancer cells ,Genes ,Tumors ,Cancer patients ,Health care industry - Abstract
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., Introduction KRAS is one of the most commonly mutated oncogenes in human cancer (1) and is a key oncogenic driver in many lung and most pancreatic cancers (2-5). KRAS induces [...]
- Published
- 2020
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