TY - JOUR
T1 - The Mir181ab1 cluster promotes KRAS-driven oncogenesis and progression in lung and pancreas
AU - Valencia, Karmele
AU - Erice, Oihane
AU - Kostyrko, Kaja
AU - Hausmann, Simone
AU - Guruceaga, Elizabeth
AU - Tathireddy, Anuradha
AU - Flores, Natasha M.
AU - Sayles, Leanne C.
AU - Lee, Alex G.
AU - Fragoso, Rita
AU - Sun, Tian Qiang
AU - Vallejo, Adrian
AU - Roman, Marta
AU - Entrialgo-Cadierno, Rodrigo
AU - Migueliz, Itziar
AU - Razquin, Nerea
AU - Fortes, Puri
AU - Lecanda, Fernando
AU - Lu, Jun
AU - Ponz-Sarvise, Mariano
AU - Chen, Chang Zheng
AU - Mazur, Pawel K.
AU - Alejandro Sweet-Cordero, E.
AU - Vicent, Silvestre
N1 - Funding Information:
We thank all members of the Sweet-Cordero and Vicent labs for insightful discussions. OE was supported by FSE/MINECO/FJCI-2017-34233, KK by a Postdoc Mobility grant (P300PB-174377) from the Swiss National Science Foundation, SH by a Deutsche Forschungsgemeinschaft Postdoctoral Fellowship, AV by ADA of the University of Navarra, and MR by FPU15/00173. CZC was supported by NIH grants (1R01AI073724 and 1DP1 OD00643501). PKM is supported by NIH grants (R00CA197816, P50CA070907, and P30CA016672), the UT STAR program, Neuroendocrine Tumor Research Foundation, American Association for Cancer Research, Lung Cancer Research Foundation, American Gastroenterological Association Research Foundation, and is the Andrew Sabin Family Foundation Scientist and CPRIT Scholar (RR160078). EASC was funded by PHS grant 4R01CA129562 (NCI). SV was supported by FEDER/MINECO (SAF2013-46423-R and SAF2017-89944-R), the European Commission (618312 KRASmiR FP7-PEOPLE-2013-CIG), Worldwide Cancer Research (16-0224), FEDER (RD12/0036/0040), La Caixa-FIMA agreement, Asociacion de Novelda de ayuda a personas con cancer, and Mauge Burgos de la Iglesia's family.
Funding Information:
We thank all members of the Sweet-Cordero and Vicent labs for insightful discussions. OE was supported by FSE/MINECO/FJCI-2017-34233, KK by a Postdoc Mobility grant (P300PB-174377) from the Swiss National Science Foundation, SH by a Deutsche Forschungsgemeinschaft Postdoctoral Fellowship, AV by ADA of the University of Navarra, and MR by FPU15/00173. CZC was supported by NIH grants (1R01AI073724 and 1DP1 OD00643501). PKM is supported by NIH grants (R00CA197816, P50CA070907, and P30CA016672), the UT STAR program, Neuroendocrine Tumor Research Foundation, American Association for Cancer Research, Lung Cancer Research Foundation, American Gastroenterological Association Research Foundation, and is the Andrew Sabin Family Foundation Scientist and CPRIT Scholar (RR160078). EASC was funded by PHS grant 4R01CA129562 (NCI). SV was supported by FEDER/MINECO (SAF2013-46423-R and SAF2017-89944-R), the European Commission (618312 KRASmiR FP7-PEOPLE-2013-CIG), Worldwide Cancer Research (16-0224), FEDER (RD12/0036/0040), La Caixa-FI-MA agreement, Asociacion de Novelda de ayuda a personas con cancer, and Mauge Burgos de la Iglesia’s family.
Publisher Copyright:
Copyright: © 2020, Valencia et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI129012
DO - 10.1172/JCI129012
M3 - Article
C2 - 31874105
AN - SCOPUS:85082810120
SN - 0021-9738
VL - 130
SP - 1879
EP - 1895
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 4
ER -