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PP2A Deficiency Enhances Carcinogenesis of Lgr5(+) Intestinal Stem Cells Both in Organoids and In Vivo
In most cancers, cellular origin and the contribution of intrinsic and extrinsic factors toward transformation remain elusive. Cell specific carcinogenesis models are currently unavailable. To investigate cellular origin in carcinogenesis, we developed a tumorigenesis model based on a combination of...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017129/ https://www.ncbi.nlm.nih.gov/pubmed/31905853 http://dx.doi.org/10.3390/cells9010090 |
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author | Yen, Yu-Ting Chien, May Lai, Yung-Chih Chen, Dao-Peng Chuong, Cheng-Ming Hung, Mien-Chie Hung, Shih-Chieh |
author_facet | Yen, Yu-Ting Chien, May Lai, Yung-Chih Chen, Dao-Peng Chuong, Cheng-Ming Hung, Mien-Chie Hung, Shih-Chieh |
author_sort | Yen, Yu-Ting |
collection | PubMed |
description | In most cancers, cellular origin and the contribution of intrinsic and extrinsic factors toward transformation remain elusive. Cell specific carcinogenesis models are currently unavailable. To investigate cellular origin in carcinogenesis, we developed a tumorigenesis model based on a combination of carcinogenesis and genetically engineered mouse models. We show in organoids that treatment of any of three carcinogens, DMBA, MNU, or PhIP, with protein phosphatase 2A (PP2A) knockout induced tumorigenesis in Lgr5(+) intestinal lineage, but not in differentiated cells. These transformed cells increased in stem cell signature, were upregulated in EMT markers, and acquired tumorigenecity. A mechanistic approach demonstrated that tumorigenesis was dependent on Wnt, PI3K, and RAS-MAPK activation. In vivo combination with carcinogen and PP2A depletion also led to tumor formation. Using whole-exome sequencing, we demonstrate that these intestinal tumors display mutation landscape and core driver pathways resembling human intestinal tumor in The Cancer Genome Atlas (TCGA). These data provide a basis for understanding the interplay between extrinsic carcinogen and intrinsic genetic modification and suggest that PP2A functions as a tumor suppressor in intestine carcinogenesis. |
format | Online Article Text |
id | pubmed-7017129 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-70171292020-02-28 PP2A Deficiency Enhances Carcinogenesis of Lgr5(+) Intestinal Stem Cells Both in Organoids and In Vivo Yen, Yu-Ting Chien, May Lai, Yung-Chih Chen, Dao-Peng Chuong, Cheng-Ming Hung, Mien-Chie Hung, Shih-Chieh Cells Article In most cancers, cellular origin and the contribution of intrinsic and extrinsic factors toward transformation remain elusive. Cell specific carcinogenesis models are currently unavailable. To investigate cellular origin in carcinogenesis, we developed a tumorigenesis model based on a combination of carcinogenesis and genetically engineered mouse models. We show in organoids that treatment of any of three carcinogens, DMBA, MNU, or PhIP, with protein phosphatase 2A (PP2A) knockout induced tumorigenesis in Lgr5(+) intestinal lineage, but not in differentiated cells. These transformed cells increased in stem cell signature, were upregulated in EMT markers, and acquired tumorigenecity. A mechanistic approach demonstrated that tumorigenesis was dependent on Wnt, PI3K, and RAS-MAPK activation. In vivo combination with carcinogen and PP2A depletion also led to tumor formation. Using whole-exome sequencing, we demonstrate that these intestinal tumors display mutation landscape and core driver pathways resembling human intestinal tumor in The Cancer Genome Atlas (TCGA). These data provide a basis for understanding the interplay between extrinsic carcinogen and intrinsic genetic modification and suggest that PP2A functions as a tumor suppressor in intestine carcinogenesis. MDPI 2019-12-30 /pmc/articles/PMC7017129/ /pubmed/31905853 http://dx.doi.org/10.3390/cells9010090 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Yen, Yu-Ting Chien, May Lai, Yung-Chih Chen, Dao-Peng Chuong, Cheng-Ming Hung, Mien-Chie Hung, Shih-Chieh PP2A Deficiency Enhances Carcinogenesis of Lgr5(+) Intestinal Stem Cells Both in Organoids and In Vivo |
title | PP2A Deficiency Enhances Carcinogenesis of Lgr5(+) Intestinal Stem Cells Both in Organoids and In Vivo |
title_full | PP2A Deficiency Enhances Carcinogenesis of Lgr5(+) Intestinal Stem Cells Both in Organoids and In Vivo |
title_fullStr | PP2A Deficiency Enhances Carcinogenesis of Lgr5(+) Intestinal Stem Cells Both in Organoids and In Vivo |
title_full_unstemmed | PP2A Deficiency Enhances Carcinogenesis of Lgr5(+) Intestinal Stem Cells Both in Organoids and In Vivo |
title_short | PP2A Deficiency Enhances Carcinogenesis of Lgr5(+) Intestinal Stem Cells Both in Organoids and In Vivo |
title_sort | pp2a deficiency enhances carcinogenesis of lgr5(+) intestinal stem cells both in organoids and in vivo |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017129/ https://www.ncbi.nlm.nih.gov/pubmed/31905853 http://dx.doi.org/10.3390/cells9010090 |
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