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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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Detalles Bibliográficos
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
Descripción
Sumario: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.