Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 130, Issue 4, Pages 1879-1895Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI129012
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Funding
- Swiss National Science Foundation [P300PB-174377]
- Deutsche Forschungsgemeinschaft Postdoctoral Fellowship
- ADA of the University of Navarra
- NIH [1R01AI073724, 1DP1 OD00643501, R00CA197816, P50CA070907, P30CA016672]
- UT STAR program
- Neuroendocrine Tumor Research Foundation
- American Association for Cancer Research
- Lung Cancer Research Foundation
- American Gastroenterological Association Research Foundation
- Andrew Sabin Family Foundation [RR160078]
- PHS grant (NCI) [4R01CA129562]
- FEDER/MINECO [SAF201346423-R, SAF2017-89944-R]
- European Commission [618312 KRASmiR FP7-PEOPLE-2013-CIG]
- Worldwide Cancer Research [16-0224]
- FEDER [RD12/0036/0040]
- La Caixa-FIMA agreement
- Asociacion de Novelda de ayuda a personas con cancer
- Mauge Burgos de la Iglesia's family
- [FSE/MINECO/FJCI2017-34233]
- [FPU15/00173]
- Swiss National Science Foundation (SNF) [P300PB_174377] Funding Source: Swiss National Science Foundation (SNF)
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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 30 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.
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