The Mir181ab1 cluster promotes KRAS-driven oncogenesis and progression in lung and pancreas
Karmele Valencia, … , E. Alejandro Sweet-Cordero, Silvestre Vicent
Karmele Valencia, … , E. Alejandro Sweet-Cordero, Silvestre Vicent
Published December 24, 2019
Citation Information: J Clin Invest. 2020;130(4):1879-1895. https://doi.org/10.1172/JCI129012.
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Research Article Oncology

The Mir181ab1 cluster promotes KRAS-driven oncogenesis and progression in lung and pancreas

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.

Authors

Karmele Valencia, Oihane Erice, Kaja Kostyrko, Simone Hausmann, Elizabeth Guruceaga, Anuradha Tathireddy, Natasha M. Flores, Leanne C. Sayles, Alex G. Lee, Rita Fragoso, Tian-Qiang Sun, Adrian Vallejo, Marta Roman, Rodrigo Entrialgo-Cadierno, Itziar Migueliz, Nerea Razquin, Puri Fortes, Fernando Lecanda, Jun Lu, Mariano Ponz-Sarvise, Chang-Zheng Chen, Pawel K. Mazur, E. Alejandro Sweet-Cordero, Silvestre Vicent

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Figure 10

miR181ab1 targets involved in human KRAS-driven cancer.

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miR181ab1 targets involved in human KRAS-driven cancer. (A) Graph repres...
(A) Graph representing biological processes enriched in KLA wt/wt with regard to KLA mut/mut adCre–treated cells by Ingenuity Pathways Analysis (IPA). (B) Kaplan-Meier plots of lung adenocarcinoma (LUAD) patients from TCGA stratified based on median expression of the 10-gene miR181ab1 signature (log-rank test). Left: Mutant-KRAS LUAD patients. Right: Wild-type KRAS LUAD patients. Putative miR181ab1 targets in human cancer were selected if a seed sequence was predicted to exist in the 3′UTR by at least 3 prediction algorithms. (C) Kaplan-Meier plot of pancreatic ductal adenocarcinoma (PDAC) patients from ICGC based on the 10-gene miR181ab1-target signature (log-rank test). (D) Luciferase assay of KLA wt/wt adCre–treated cells that were transfected with a psiCheck vector encoding the wild-type functional 3′UTR of Nexmif or a seed-mutated (mut) version that impedes miR181ab1 binding (n = 3). Renilla results are normalized to firefly luciferase signal and compared by t test. (E) Nexmif expression assessed by quantitative PCR in control- (GFP) and Nexmif-overexpressing KLA cells (n = 3) compared by t test. (F) Cell proliferation analysis by MTS of control- (GFP) and Nexmif-overexpressing KLA cells (n = 6) compared by t test. (G) Clonogenic analysis of the same cells as in F (n = 3) compared by t test. (H) Proposed model of miR181ab1 regulation and function in the context of mutant-KRAS oncogenesis.