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 5

Effect of Mir181ab1 loss in mutant Kras–driven cancer cells.

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Effect of Mir181ab1 loss in mutant Kras–driven cancer cells. (A) Cell pr...
(A) Cell proliferation of KLA cells, plated after 48 hours of adCre or adEmpty (adE) treatment, assessed by MTS (n = 5) and compared by t test. (B) 3D culture of KLA cells previously treated with adCre or adE for 48 hours. Left: Representative KLA organoid images on day 4 after seeding. Scale bars: 100 μm. Middle: KLA organoid size quantification on day 4 after seeding (n = 29–45) compared by t test. Right: Proliferation of KLA organoids measured by CellTiterGLO (n = 3) and compared by Mann-Whitney U test. (C) Left: Average tumor volume of allografts from mouse KLA cells previously treated with adE or adCre for 48 hours (n = 6 per group) and compared by t test. Right: Representative images of KLA tumors in the presence and absence of Mir181ab1. (D) Cell proliferation of KPC miR181wt and miR181ko cells assessed by MTS (n = 6) and compared by t test. (E) Left: Representative images of KPC miR181wt and miR181ko organoids on day 4. Scale bars: 100 μm. Middle: Organoid size quantification on day 4 after seeding (n = 16) and compared by t test. Right: Proliferation of KPC miR181wt and miR181ko organoids measured by CellTiterGLO (n = 3) and compared by Mann-Whitney U test. (F) Left: Average tumor volume of allografts from mouse KPC miR181wt and miR181ko cells (n = 8 per group) and compared by t test. Right: Representative images of KPC miR181wt and miR181ko tumors. Proliferation assays (A, B, D, and E) are representative of 3 independent experiments.