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 9

Regulation of the Mir181ab1 cluster.

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Regulation of the Mir181ab1 cluster. (A) miR181a and miR181b expression ...
(A) miR181a and miR181b expression assessed by quantitative PCR in mouse lung cancer (KLA) and pancreatic cancer (KPC) cells treated with 10 ng/mL TGF-β for 3 hours (n = 3) and compared by t test. (B) Schematic representation of the strategy to unveil transcription factors potentially regulating miR181ab1 expression. (C) Gata3 expression assessed by quantitative PCR in the same cell lines as in A (n = 3) compared by t test. Error bars correspond to SD. (D) GATA3 expression assessed by quantitative PCR in 3KT cells expressing a control gene (LacZ) or a mutated version of KRAS (G12D) (n = 3) compared by t test.