The Mir181ab1 cluster promotes KRAS-driven oncogenesis and progression in lung and pancreas
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
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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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 1

Systemic Mir181ab1 ablation impairs Kras-driven lung cancer.

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Systemic Mir181ab1 ablation impairs Kras-driven lung cancer. (A) Represe...
(A) Representative H&E-stained sections of K181+/+ and K181–/– lungs 20 weeks after adCre infection. Scale bars: 5 mm. (B) Average tumor area percentage in K181+/+ (n = 9) and K181–/– (n = 8) groups compared by t test. (C) Mean number of tumors per mouse in K181+/+ (n = 9) and K181–/– (n = 8) mice compared by t test. (D) Average tumor size in K181+/+ (n = 632) and K181–/– (n = 222) groups compared by Mann-Whitney U test. (E) Left: Average percentage of Ki67+ cells in tumors from K181+/+ (n = 9) and K181–/– (n = 8) mice compared by t test. Right: Immunohistochemistry for Ki67 expression in representative sections. Scale bars: 200 μm and 50 μm (insets). (F) Kaplan-Meier plot of K181+/+ (n = 23, median survival = 151.5 days) and K181–/– (n = 19, median survival = 217 days) mice (log-rank test).