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AGO2 promotes tumor progression in KRAS-driven mouse models of non–small cell lung cancer
Lung cancer is the deadliest malignancy in the United States. Non–small cell lung cancer (NSCLC) accounts for 85% of cases and is frequently driven by activating mutations in the gene encoding the KRAS GTPase (e.g., KRASG12D). Our previous work demonstrated that Argonaute 2 (AGO2)—a component of the...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157917/ https://www.ncbi.nlm.nih.gov/pubmed/33972443 http://dx.doi.org/10.1073/pnas.2026104118 |
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author | Tien, Jean Ching-Yi Chugh, Seema Goodrum, Andrew E. Cheng, Yunhui Mannan, Rahul Zhang, Yuping Wang, Lisha Dommeti, Vijaya L. Wang, Xiaoming Xu, Alice Hon, Jennifer Kenum, Carson Su, Fengyun Wang, Rui Cao, Xuhong Shankar, Sunita Chinnaiyan, Arul M. |
author_facet | Tien, Jean Ching-Yi Chugh, Seema Goodrum, Andrew E. Cheng, Yunhui Mannan, Rahul Zhang, Yuping Wang, Lisha Dommeti, Vijaya L. Wang, Xiaoming Xu, Alice Hon, Jennifer Kenum, Carson Su, Fengyun Wang, Rui Cao, Xuhong Shankar, Sunita Chinnaiyan, Arul M. |
author_sort | Tien, Jean Ching-Yi |
collection | PubMed |
description | Lung cancer is the deadliest malignancy in the United States. Non–small cell lung cancer (NSCLC) accounts for 85% of cases and is frequently driven by activating mutations in the gene encoding the KRAS GTPase (e.g., KRASG12D). Our previous work demonstrated that Argonaute 2 (AGO2)—a component of the RNA-induced silencing complex (RISC)—physically interacts with RAS and promotes its downstream signaling. We therefore hypothesized that AGO2 could promote KRASG12D-dependent NSCLC in vivo. To test the hypothesis, we evaluated the impact of Ago2 knockout in the KPC (LSL-Kras (G12D/+);p53(f/f);Cre) mouse model of NSCLC. In KPC mice, intratracheal delivery of adenoviral Cre drives lung-specific expression of a stop-floxed KRASG12D allele and biallelic ablation of p53. Simultaneous biallelic ablation of floxed Ago2 inhibited KPC lung nodule growth while reducing proliferative index and improving pathological grade. We next applied the KP(Het)C model, in which the Clara cell–specific CCSP-driven Cre activates KRASG12D and ablates a single p53 allele. In these mice, Ago2 ablation also reduced tumor size and grade. In both models, Ago2 knockout inhibited ERK phosphorylation (pERK) in tumor cells, indicating impaired KRAS signaling. RNA sequencing (RNA-seq) of KPC nodules and nodule-derived organoids demonstrated impaired canonical KRAS signaling with Ago2 ablation. Strikingly, accumulation of pERK in KPC organoids depended on physical interaction of AGO2 and KRAS. Taken together, our data demonstrate a pathogenic role for AGO2 in KRAS-dependent NSCLC. Given the prevalence of this malignancy and current difficulties in therapeutically targeting KRAS signaling, our work may have future translational relevance. |
format | Online Article Text |
id | pubmed-8157917 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-81579172021-05-28 AGO2 promotes tumor progression in KRAS-driven mouse models of non–small cell lung cancer Tien, Jean Ching-Yi Chugh, Seema Goodrum, Andrew E. Cheng, Yunhui Mannan, Rahul Zhang, Yuping Wang, Lisha Dommeti, Vijaya L. Wang, Xiaoming Xu, Alice Hon, Jennifer Kenum, Carson Su, Fengyun Wang, Rui Cao, Xuhong Shankar, Sunita Chinnaiyan, Arul M. Proc Natl Acad Sci U S A Biological Sciences Lung cancer is the deadliest malignancy in the United States. Non–small cell lung cancer (NSCLC) accounts for 85% of cases and is frequently driven by activating mutations in the gene encoding the KRAS GTPase (e.g., KRASG12D). Our previous work demonstrated that Argonaute 2 (AGO2)—a component of the RNA-induced silencing complex (RISC)—physically interacts with RAS and promotes its downstream signaling. We therefore hypothesized that AGO2 could promote KRASG12D-dependent NSCLC in vivo. To test the hypothesis, we evaluated the impact of Ago2 knockout in the KPC (LSL-Kras (G12D/+);p53(f/f);Cre) mouse model of NSCLC. In KPC mice, intratracheal delivery of adenoviral Cre drives lung-specific expression of a stop-floxed KRASG12D allele and biallelic ablation of p53. Simultaneous biallelic ablation of floxed Ago2 inhibited KPC lung nodule growth while reducing proliferative index and improving pathological grade. We next applied the KP(Het)C model, in which the Clara cell–specific CCSP-driven Cre activates KRASG12D and ablates a single p53 allele. In these mice, Ago2 ablation also reduced tumor size and grade. In both models, Ago2 knockout inhibited ERK phosphorylation (pERK) in tumor cells, indicating impaired KRAS signaling. RNA sequencing (RNA-seq) of KPC nodules and nodule-derived organoids demonstrated impaired canonical KRAS signaling with Ago2 ablation. Strikingly, accumulation of pERK in KPC organoids depended on physical interaction of AGO2 and KRAS. Taken together, our data demonstrate a pathogenic role for AGO2 in KRAS-dependent NSCLC. Given the prevalence of this malignancy and current difficulties in therapeutically targeting KRAS signaling, our work may have future translational relevance. National Academy of Sciences 2021-05-18 2021-05-10 /pmc/articles/PMC8157917/ /pubmed/33972443 http://dx.doi.org/10.1073/pnas.2026104118 Text en Copyright © 2021 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Tien, Jean Ching-Yi Chugh, Seema Goodrum, Andrew E. Cheng, Yunhui Mannan, Rahul Zhang, Yuping Wang, Lisha Dommeti, Vijaya L. Wang, Xiaoming Xu, Alice Hon, Jennifer Kenum, Carson Su, Fengyun Wang, Rui Cao, Xuhong Shankar, Sunita Chinnaiyan, Arul M. AGO2 promotes tumor progression in KRAS-driven mouse models of non–small cell lung cancer |
title | AGO2 promotes tumor progression in KRAS-driven mouse models of non–small cell lung cancer |
title_full | AGO2 promotes tumor progression in KRAS-driven mouse models of non–small cell lung cancer |
title_fullStr | AGO2 promotes tumor progression in KRAS-driven mouse models of non–small cell lung cancer |
title_full_unstemmed | AGO2 promotes tumor progression in KRAS-driven mouse models of non–small cell lung cancer |
title_short | AGO2 promotes tumor progression in KRAS-driven mouse models of non–small cell lung cancer |
title_sort | ago2 promotes tumor progression in kras-driven mouse models of non–small cell lung cancer |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157917/ https://www.ncbi.nlm.nih.gov/pubmed/33972443 http://dx.doi.org/10.1073/pnas.2026104118 |
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