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Retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer
Retinoic acid (RA) signaling is an important and conserved pathway that regulates cellular proliferation and differentiation. Furthermore, perturbed RA signaling is implicated in cancer initiation and progression. However, the mechanisms by which RA signaling contributes to homeostasis, malignant tr...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633980/ https://www.ncbi.nlm.nih.gov/pubmed/34877501 http://dx.doi.org/10.1016/j.isci.2021.103444 |
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author | Wester, Roelof A. van Voorthuijsen, Lisa Neikes, Hannah K. Dijkstra, Jelmer J. Lamers, Lieke A. Frölich, Siebren van der Sande, Maarten Logie, Colin Lindeboom, Rik G.H. Vermeulen, Michiel |
author_facet | Wester, Roelof A. van Voorthuijsen, Lisa Neikes, Hannah K. Dijkstra, Jelmer J. Lamers, Lieke A. Frölich, Siebren van der Sande, Maarten Logie, Colin Lindeboom, Rik G.H. Vermeulen, Michiel |
author_sort | Wester, Roelof A. |
collection | PubMed |
description | Retinoic acid (RA) signaling is an important and conserved pathway that regulates cellular proliferation and differentiation. Furthermore, perturbed RA signaling is implicated in cancer initiation and progression. However, the mechanisms by which RA signaling contributes to homeostasis, malignant transformation, and disease progression in the intestine remain incompletely understood. Here, we report, in agreement with previous findings, that activation of the Retinoic Acid Receptor and the Retinoid X Receptor results in enhanced transcription of enterocyte-specific genes in mouse small intestinal organoids. Conversely, inhibition of this pathway results in reduced expression of genes associated with the absorptive lineage. Strikingly, this latter effect is conserved in a human organoid model for colorectal cancer (CRC) progression. We further show that RXR motif accessibility depends on progression state of CRC organoids. Finally, we show that reduced RXR target gene expression correlates with worse CRC prognosis, implying RA signaling as a putative therapeutic target in CRC. |
format | Online Article Text |
id | pubmed-8633980 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-86339802021-12-06 Retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer Wester, Roelof A. van Voorthuijsen, Lisa Neikes, Hannah K. Dijkstra, Jelmer J. Lamers, Lieke A. Frölich, Siebren van der Sande, Maarten Logie, Colin Lindeboom, Rik G.H. Vermeulen, Michiel iScience Article Retinoic acid (RA) signaling is an important and conserved pathway that regulates cellular proliferation and differentiation. Furthermore, perturbed RA signaling is implicated in cancer initiation and progression. However, the mechanisms by which RA signaling contributes to homeostasis, malignant transformation, and disease progression in the intestine remain incompletely understood. Here, we report, in agreement with previous findings, that activation of the Retinoic Acid Receptor and the Retinoid X Receptor results in enhanced transcription of enterocyte-specific genes in mouse small intestinal organoids. Conversely, inhibition of this pathway results in reduced expression of genes associated with the absorptive lineage. Strikingly, this latter effect is conserved in a human organoid model for colorectal cancer (CRC) progression. We further show that RXR motif accessibility depends on progression state of CRC organoids. Finally, we show that reduced RXR target gene expression correlates with worse CRC prognosis, implying RA signaling as a putative therapeutic target in CRC. Elsevier 2021-11-15 /pmc/articles/PMC8633980/ /pubmed/34877501 http://dx.doi.org/10.1016/j.isci.2021.103444 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Wester, Roelof A. van Voorthuijsen, Lisa Neikes, Hannah K. Dijkstra, Jelmer J. Lamers, Lieke A. Frölich, Siebren van der Sande, Maarten Logie, Colin Lindeboom, Rik G.H. Vermeulen, Michiel Retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer |
title | Retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer |
title_full | Retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer |
title_fullStr | Retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer |
title_full_unstemmed | Retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer |
title_short | Retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer |
title_sort | retinoic acid signaling drives differentiation toward the absorptive lineage in colorectal cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633980/ https://www.ncbi.nlm.nih.gov/pubmed/34877501 http://dx.doi.org/10.1016/j.isci.2021.103444 |
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