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ALDH1B1 Is Crucial for Colon Tumorigenesis by Modulating Wnt/β-Catenin, Notch and PI3K/Akt Signaling Pathways

In the normal human colon, aldehyde dehydrogenase 1B1 (ALDH1B1) is expressed only at the crypt base, along with stem cells. It is also highly expressed in the human colonic adenocarcinomas. This pattern of expression corresponds closely to that observed for Wnt/β-catenin signaling activity. The pres...

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Autores principales: Singh, Surendra, Arcaroli, John, Chen, Ying, Thompson, David C., Messersmith, Wells, Jimeno, Antonio, Vasiliou, Vasilis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423958/
https://www.ncbi.nlm.nih.gov/pubmed/25950950
http://dx.doi.org/10.1371/journal.pone.0121648
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author Singh, Surendra
Arcaroli, John
Chen, Ying
Thompson, David C.
Messersmith, Wells
Jimeno, Antonio
Vasiliou, Vasilis
author_facet Singh, Surendra
Arcaroli, John
Chen, Ying
Thompson, David C.
Messersmith, Wells
Jimeno, Antonio
Vasiliou, Vasilis
author_sort Singh, Surendra
collection PubMed
description In the normal human colon, aldehyde dehydrogenase 1B1 (ALDH1B1) is expressed only at the crypt base, along with stem cells. It is also highly expressed in the human colonic adenocarcinomas. This pattern of expression corresponds closely to that observed for Wnt/β-catenin signaling activity. The present study examines the role of ALDH1B1 in colon tumorigenesis and signalling pathways mediating its effects. In a 3-dimensional spheroid growth model and a nude mouse xenograft tumor model, shRNA-induced suppression of ALDH1B1 expression decreased the number and size of spheroids formed in vitro and the size of xenograft tumors formed in vivo by SW 480 cells. Six binding elements for Wnt/β-catenin signalling transcription factor binding elements (T-cell factor/ lymphoid enhancing factor) were identified in the human ALDH1B1 gene promoter (3 kb) but shown by dual luciferase reporter assay to not be necessary for ALDH1B1 mRNA expression in colon adenocarcinoma cell lines. We examined Wnt-reporter activity and protein/mRNA expression for Wnt, Notch and PI3K/Akt signaling pathways. Wnt/β-catenin, Notch and PI3K/Akt-signaling pathways were down-regulated in SW 480 cells in which ALDH1B1 expression had been suppressed. In summary, our data demonstrate that ALDH1B1 may promote colon cancer tumorigenesis by modulating the Wnt/β-catenin, Notch and PI3K/Akt signaling pathways. Selective targeting of ALDH1B1 may represent a novel means to prevent or treat colon cancer.
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spelling pubmed-44239582015-05-13 ALDH1B1 Is Crucial for Colon Tumorigenesis by Modulating Wnt/β-Catenin, Notch and PI3K/Akt Signaling Pathways Singh, Surendra Arcaroli, John Chen, Ying Thompson, David C. Messersmith, Wells Jimeno, Antonio Vasiliou, Vasilis PLoS One Research Article In the normal human colon, aldehyde dehydrogenase 1B1 (ALDH1B1) is expressed only at the crypt base, along with stem cells. It is also highly expressed in the human colonic adenocarcinomas. This pattern of expression corresponds closely to that observed for Wnt/β-catenin signaling activity. The present study examines the role of ALDH1B1 in colon tumorigenesis and signalling pathways mediating its effects. In a 3-dimensional spheroid growth model and a nude mouse xenograft tumor model, shRNA-induced suppression of ALDH1B1 expression decreased the number and size of spheroids formed in vitro and the size of xenograft tumors formed in vivo by SW 480 cells. Six binding elements for Wnt/β-catenin signalling transcription factor binding elements (T-cell factor/ lymphoid enhancing factor) were identified in the human ALDH1B1 gene promoter (3 kb) but shown by dual luciferase reporter assay to not be necessary for ALDH1B1 mRNA expression in colon adenocarcinoma cell lines. We examined Wnt-reporter activity and protein/mRNA expression for Wnt, Notch and PI3K/Akt signaling pathways. Wnt/β-catenin, Notch and PI3K/Akt-signaling pathways were down-regulated in SW 480 cells in which ALDH1B1 expression had been suppressed. In summary, our data demonstrate that ALDH1B1 may promote colon cancer tumorigenesis by modulating the Wnt/β-catenin, Notch and PI3K/Akt signaling pathways. Selective targeting of ALDH1B1 may represent a novel means to prevent or treat colon cancer. Public Library of Science 2015-05-07 /pmc/articles/PMC4423958/ /pubmed/25950950 http://dx.doi.org/10.1371/journal.pone.0121648 Text en © 2015 Singh et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Singh, Surendra
Arcaroli, John
Chen, Ying
Thompson, David C.
Messersmith, Wells
Jimeno, Antonio
Vasiliou, Vasilis
ALDH1B1 Is Crucial for Colon Tumorigenesis by Modulating Wnt/β-Catenin, Notch and PI3K/Akt Signaling Pathways
title ALDH1B1 Is Crucial for Colon Tumorigenesis by Modulating Wnt/β-Catenin, Notch and PI3K/Akt Signaling Pathways
title_full ALDH1B1 Is Crucial for Colon Tumorigenesis by Modulating Wnt/β-Catenin, Notch and PI3K/Akt Signaling Pathways
title_fullStr ALDH1B1 Is Crucial for Colon Tumorigenesis by Modulating Wnt/β-Catenin, Notch and PI3K/Akt Signaling Pathways
title_full_unstemmed ALDH1B1 Is Crucial for Colon Tumorigenesis by Modulating Wnt/β-Catenin, Notch and PI3K/Akt Signaling Pathways
title_short ALDH1B1 Is Crucial for Colon Tumorigenesis by Modulating Wnt/β-Catenin, Notch and PI3K/Akt Signaling Pathways
title_sort aldh1b1 is crucial for colon tumorigenesis by modulating wnt/β-catenin, notch and pi3k/akt signaling pathways
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423958/
https://www.ncbi.nlm.nih.gov/pubmed/25950950
http://dx.doi.org/10.1371/journal.pone.0121648
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