The Mir181ab1 cluster promotes KRAS-driven oncogenesis and progression in lung and pancreas.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31874105.
- Also identified by DOI 10.1172/JCI129012 and PMC identifier 7108928.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Carcinogenesis
- Lung Neoplasms
- MicroRNAs
- Multigene Family
- Neoplasms, Experimental
- Pancreatic Neoplasms
- Proto-Oncogene Proteins p21(ras)
- RNA, Neoplasm