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Impaired AKT signaling and lung tumorigenesis by PIERCE1 ablation in KRAS-mutant non-small cell lung cancer

KRAS-mutant non-small cell lung cancer (NSCLC) is a major lung cancer subtype that leads to many cancer-related deaths worldwide. Although numerous studies on KRAS-mutant type NSCLC have been conducted, new oncogenic or tumor suppressive genes need to be detected because a large proportion of NSCLC...

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Autores principales: Roh, Jae-il, Lee, Jaehoon, Sung, Young-Hoon, Oh, Jahyun, Hyeon, Do Young, Kim, Yujin, Lee, Seungeon, Devkota, Sushil, Kim, Hye Jeong, Park, Bomin, Nam, Taewook, Song, Yaechan, Kim, Yonghwan, Hwang, Daehee, Lee, Han-Woong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471098/
https://www.ncbi.nlm.nih.gov/pubmed/32728173
http://dx.doi.org/10.1038/s41388-020-01399-5
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author Roh, Jae-il
Lee, Jaehoon
Sung, Young-Hoon
Oh, Jahyun
Hyeon, Do Young
Kim, Yujin
Lee, Seungeon
Devkota, Sushil
Kim, Hye Jeong
Park, Bomin
Nam, Taewook
Song, Yaechan
Kim, Yonghwan
Hwang, Daehee
Lee, Han-Woong
author_facet Roh, Jae-il
Lee, Jaehoon
Sung, Young-Hoon
Oh, Jahyun
Hyeon, Do Young
Kim, Yujin
Lee, Seungeon
Devkota, Sushil
Kim, Hye Jeong
Park, Bomin
Nam, Taewook
Song, Yaechan
Kim, Yonghwan
Hwang, Daehee
Lee, Han-Woong
author_sort Roh, Jae-il
collection PubMed
description KRAS-mutant non-small cell lung cancer (NSCLC) is a major lung cancer subtype that leads to many cancer-related deaths worldwide. Although numerous studies on KRAS-mutant type NSCLC have been conducted, new oncogenic or tumor suppressive genes need to be detected because a large proportion of NSCLC patients does not respond to currently used therapeutics. Here, we show the tumor-promoting function of a cell cycle-related protein, PIERCE1, in KRAS-mutant NSCLC. Mechanistically, PIERCE1 depletion inhibits cell growth and AKT phosphorylation (pAKT) at S473, which is particularly observed in KRAS-mutant lung cancers. Analyses of AKT-related genes using microarray, immunoblotting, and real-time quantitative PCR indicated that PIERCE1 negatively regulates the gene expression of the AKT suppressor, TRIB3, through the CHOP pathway, which is a key regulatory pathway for TRIB3 expression. Similarly, in vivo analyses of PIERCE1 depletion in the KRAS mutation-related lung cancer mouse models revealed the suppressive effect of PIERCE1 knockout in urethane- and KRAS(G12D)-induced lung tumorigenesis with decreased pAKT levels observed in the tumors. Tissue microarrays of human lung cancers indicated the expression of PIERCE1 in 83% of lung cancers and its correlation with pAKT expression. Thus, we illustrate how PIERCE1 depletion may serve as a therapeutic strategy against KRAS-mutant NSCLC and propose the clinical benefit of PIERCE1.
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spelling pubmed-74710982020-09-16 Impaired AKT signaling and lung tumorigenesis by PIERCE1 ablation in KRAS-mutant non-small cell lung cancer Roh, Jae-il Lee, Jaehoon Sung, Young-Hoon Oh, Jahyun Hyeon, Do Young Kim, Yujin Lee, Seungeon Devkota, Sushil Kim, Hye Jeong Park, Bomin Nam, Taewook Song, Yaechan Kim, Yonghwan Hwang, Daehee Lee, Han-Woong Oncogene Article KRAS-mutant non-small cell lung cancer (NSCLC) is a major lung cancer subtype that leads to many cancer-related deaths worldwide. Although numerous studies on KRAS-mutant type NSCLC have been conducted, new oncogenic or tumor suppressive genes need to be detected because a large proportion of NSCLC patients does not respond to currently used therapeutics. Here, we show the tumor-promoting function of a cell cycle-related protein, PIERCE1, in KRAS-mutant NSCLC. Mechanistically, PIERCE1 depletion inhibits cell growth and AKT phosphorylation (pAKT) at S473, which is particularly observed in KRAS-mutant lung cancers. Analyses of AKT-related genes using microarray, immunoblotting, and real-time quantitative PCR indicated that PIERCE1 negatively regulates the gene expression of the AKT suppressor, TRIB3, through the CHOP pathway, which is a key regulatory pathway for TRIB3 expression. Similarly, in vivo analyses of PIERCE1 depletion in the KRAS mutation-related lung cancer mouse models revealed the suppressive effect of PIERCE1 knockout in urethane- and KRAS(G12D)-induced lung tumorigenesis with decreased pAKT levels observed in the tumors. Tissue microarrays of human lung cancers indicated the expression of PIERCE1 in 83% of lung cancers and its correlation with pAKT expression. Thus, we illustrate how PIERCE1 depletion may serve as a therapeutic strategy against KRAS-mutant NSCLC and propose the clinical benefit of PIERCE1. Nature Publishing Group UK 2020-07-29 2020 /pmc/articles/PMC7471098/ /pubmed/32728173 http://dx.doi.org/10.1038/s41388-020-01399-5 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Roh, Jae-il
Lee, Jaehoon
Sung, Young-Hoon
Oh, Jahyun
Hyeon, Do Young
Kim, Yujin
Lee, Seungeon
Devkota, Sushil
Kim, Hye Jeong
Park, Bomin
Nam, Taewook
Song, Yaechan
Kim, Yonghwan
Hwang, Daehee
Lee, Han-Woong
Impaired AKT signaling and lung tumorigenesis by PIERCE1 ablation in KRAS-mutant non-small cell lung cancer
title Impaired AKT signaling and lung tumorigenesis by PIERCE1 ablation in KRAS-mutant non-small cell lung cancer
title_full Impaired AKT signaling and lung tumorigenesis by PIERCE1 ablation in KRAS-mutant non-small cell lung cancer
title_fullStr Impaired AKT signaling and lung tumorigenesis by PIERCE1 ablation in KRAS-mutant non-small cell lung cancer
title_full_unstemmed Impaired AKT signaling and lung tumorigenesis by PIERCE1 ablation in KRAS-mutant non-small cell lung cancer
title_short Impaired AKT signaling and lung tumorigenesis by PIERCE1 ablation in KRAS-mutant non-small cell lung cancer
title_sort impaired akt signaling and lung tumorigenesis by pierce1 ablation in kras-mutant non-small cell lung cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471098/
https://www.ncbi.nlm.nih.gov/pubmed/32728173
http://dx.doi.org/10.1038/s41388-020-01399-5
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