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K-Ras–Activated Cells Can Develop into Lung Tumors When Runx3-Mediated Tumor Suppressor Pathways Are Abrogated

K-RAS is frequently mutated in human lung adenocarcinomas (ADCs), and the p53 pathway plays a central role in cellular defense against oncogenic K-RAS mutation. However, in mouse lung cancer models, oncogenic K-Ras mutation alone can induce ADCs without p53 mutation, and loss of p53 does not have a...

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Autores principales: Lee, You-Soub, Lee, Ja-Yeol, Song, Soo-Hyun, Kim, Da-Mi, Lee, Jung-Won, Chi, Xin-Zi, Ito, Yoshiaki, Bae, Suk-Chul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Korean Society for Molecular and Cellular Biology 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604022/
https://www.ncbi.nlm.nih.gov/pubmed/33115981
http://dx.doi.org/10.14348/molcells.2020.0182
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author Lee, You-Soub
Lee, Ja-Yeol
Song, Soo-Hyun
Kim, Da-Mi
Lee, Jung-Won
Chi, Xin-Zi
Ito, Yoshiaki
Bae, Suk-Chul
author_facet Lee, You-Soub
Lee, Ja-Yeol
Song, Soo-Hyun
Kim, Da-Mi
Lee, Jung-Won
Chi, Xin-Zi
Ito, Yoshiaki
Bae, Suk-Chul
author_sort Lee, You-Soub
collection PubMed
description K-RAS is frequently mutated in human lung adenocarcinomas (ADCs), and the p53 pathway plays a central role in cellular defense against oncogenic K-RAS mutation. However, in mouse lung cancer models, oncogenic K-Ras mutation alone can induce ADCs without p53 mutation, and loss of p53 does not have a significant impact on early K-Ras–induced lung tumorigenesis. These results raise the question of how K-Ras–activated cells evade oncogene surveillance mechanisms and develop into lung ADCs. RUNX3 plays a key role at the restriction (R)-point, which governs multiple tumor suppressor pathways including the p14(ARF)–p53 pathway. In this study, we found that K-Ras activation in a very limited number of cells, alone or in combination with p53 inactivation, failed to induce any pathologic lesions for up to 1 year. By contrast, when Runx3 was inactivated and K-Ras was activated by the same targeting method, lung ADCs and other tumors were rapidly induced. In a urethane-induced mouse lung tumor model that recapitulates the features of K-RAS–driven human lung tumors, Runx3 was inactivated in both adenomas (ADs) and ADCs, whereas K-Ras was activated only in ADCs. Together, these results demonstrate that the R-point–associated oncogene surveillance mechanism is abrogated by Runx3 inactivation in AD cells and these cells cannot defend against K-Ras activation, resulting in the transition from AD to ADC. Therefore, K-Ras–activated lung epithelial cells do not evade oncogene surveillance mechanisms; instead, they are selected if they occur in AD cells in which Runx3 has been inactivated.
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spelling pubmed-76040222020-11-03 K-Ras–Activated Cells Can Develop into Lung Tumors When Runx3-Mediated Tumor Suppressor Pathways Are Abrogated Lee, You-Soub Lee, Ja-Yeol Song, Soo-Hyun Kim, Da-Mi Lee, Jung-Won Chi, Xin-Zi Ito, Yoshiaki Bae, Suk-Chul Mol Cells Research Article K-RAS is frequently mutated in human lung adenocarcinomas (ADCs), and the p53 pathway plays a central role in cellular defense against oncogenic K-RAS mutation. However, in mouse lung cancer models, oncogenic K-Ras mutation alone can induce ADCs without p53 mutation, and loss of p53 does not have a significant impact on early K-Ras–induced lung tumorigenesis. These results raise the question of how K-Ras–activated cells evade oncogene surveillance mechanisms and develop into lung ADCs. RUNX3 plays a key role at the restriction (R)-point, which governs multiple tumor suppressor pathways including the p14(ARF)–p53 pathway. In this study, we found that K-Ras activation in a very limited number of cells, alone or in combination with p53 inactivation, failed to induce any pathologic lesions for up to 1 year. By contrast, when Runx3 was inactivated and K-Ras was activated by the same targeting method, lung ADCs and other tumors were rapidly induced. In a urethane-induced mouse lung tumor model that recapitulates the features of K-RAS–driven human lung tumors, Runx3 was inactivated in both adenomas (ADs) and ADCs, whereas K-Ras was activated only in ADCs. Together, these results demonstrate that the R-point–associated oncogene surveillance mechanism is abrogated by Runx3 inactivation in AD cells and these cells cannot defend against K-Ras activation, resulting in the transition from AD to ADC. Therefore, K-Ras–activated lung epithelial cells do not evade oncogene surveillance mechanisms; instead, they are selected if they occur in AD cells in which Runx3 has been inactivated. Korean Society for Molecular and Cellular Biology 2020-10-31 2020-10-26 /pmc/articles/PMC7604022/ /pubmed/33115981 http://dx.doi.org/10.14348/molcells.2020.0182 Text en © The Korean Society for Molecular and Cellular Biology. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
spellingShingle Research Article
Lee, You-Soub
Lee, Ja-Yeol
Song, Soo-Hyun
Kim, Da-Mi
Lee, Jung-Won
Chi, Xin-Zi
Ito, Yoshiaki
Bae, Suk-Chul
K-Ras–Activated Cells Can Develop into Lung Tumors When Runx3-Mediated Tumor Suppressor Pathways Are Abrogated
title K-Ras–Activated Cells Can Develop into Lung Tumors When Runx3-Mediated Tumor Suppressor Pathways Are Abrogated
title_full K-Ras–Activated Cells Can Develop into Lung Tumors When Runx3-Mediated Tumor Suppressor Pathways Are Abrogated
title_fullStr K-Ras–Activated Cells Can Develop into Lung Tumors When Runx3-Mediated Tumor Suppressor Pathways Are Abrogated
title_full_unstemmed K-Ras–Activated Cells Can Develop into Lung Tumors When Runx3-Mediated Tumor Suppressor Pathways Are Abrogated
title_short K-Ras–Activated Cells Can Develop into Lung Tumors When Runx3-Mediated Tumor Suppressor Pathways Are Abrogated
title_sort k-ras–activated cells can develop into lung tumors when runx3-mediated tumor suppressor pathways are abrogated
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604022/
https://www.ncbi.nlm.nih.gov/pubmed/33115981
http://dx.doi.org/10.14348/molcells.2020.0182
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