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.
View: Text | PDF
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

×

Figure 7

miR181ab1 promotes 2D and 3D proliferation in lung and pancreas epithelial cells.

Options: View larger image (or click on image) Download as PowerPoint
miR181ab1 promotes 2D and 3D proliferation in lung and pancreas epitheli...
(A) miR181a and miR181b expression by quantitative PCR in 3KT cells transduced with the different Mir181a1 and Mir181b1 constructs (n = 3). (B) Cell proliferation of the same cells as in A assessed by MTS (n = 5–8) and compared using ANOVA. (C) 3D culture of the same cells as in A. Left: Representative images of organoids on day 4. Scale bars: 100 μm. Right: Proliferation of organoids measured by CellTiterGLO on day 4 relative to day 1 after seeding (n = 3) and compared by ANOVA. (D) miR181a and miR181b expression in human pancreatic ductal cells (H6c7) transduced with the different Mir181a1 and Mir181b1 constructs (n = 3). (E) Cell proliferation of the same H6c7 cells as in D assessed by MTS (n = 4–12) and compared by ANOVA. (F) 3D culture of the same H6c7 cells as in D. Left: Representative images of organoids on day 3. Scale bars: 100 μm. Right: Proliferation of organoids measured by CellTiterGLO on day 4 relative to day 1 after seeding (n = 3) and compared by ANOVA and Dunnett’s multiple-comparisons test.