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 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.