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.
Highlights
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 [2,3,4,5]
We identified MiR181ab1 as a miRNA cluster upregulated by oncogenic KRAS and used multiple genetically engineered mouse models (GEMMs) to demonstrate a role for this cluster in both initiation and maintenance of lung and pancreatic cancer
We extended these results to human cells where we show that miR181ab1 plays an important role in early and late stages of KRAS-driven oncogenesis
Summary
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 [2,3,4,5]. Prior work has identified genes that are transcriptionally regulated as a consequence of KRAS activation [6,7,8,9,10], fostering strategies for the discovery of critical transcriptional regulators within the KRAS signaling pathway [11, 12]. The study of miRNA function is an alternative strategy to yield molecular insights necessary for the development of novel therapies against KRAS-driven tumors. Fewer studies have focused on miRNAs with a pro-oncogenic role in the context of mutant-KRAS tumorigenesis [14, 15, 32, 33], in contrast with the wealth of information about tumor-suppressive miRNAs reported to downregulate KRAS expression [34, 35]. Efforts to develop inhibitory strategies against members of the MiR181ab cluster as a possible therapeutic opportunity in KRAS-mutated tumors
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