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FEBS J. 2019 Jul 15. doi: 10.1111/febs.14998. [Epub ahead of print]

Vitamin D differentially regulates colon stem cells in patient-derived normal and tumor organoids.

Author information

1
Departments of Cancer Biology and Biochemistry, Instituto de Investigaciones Biomédicas 'Alberto Sols', Spanish National Research Council (CSIC)-Autonomous University of Madrid (UAM) and IdiPAZ, Madrid, Spain.
2
Biomedical Research Networking Centres-Oncology (CIBERONC), Madrid, Spain.
3
Departments of Pathology and Surgery, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain.
4
Institute for Research in Biomedicine Barcelona (IRB), Barcelona, Spain.
5
DKTK, German Cancer Consortium, Research Group, Institute of Pathology, Ludwig-Maximilians University, Munich, Germany German Cancer Research Centre (DKFZ), Heidelberg, Germany.
6
Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
7
Department of Pathology, La Paz University Hospital-IdiPAZ, Madrid, Spain.
8
University of Cantabria-IDIVAL, Santander, Spain.
9
Colorectal Unit, Department of Surgery, La Paz University Hospital-IdiPAZ, Madrid, Spain.
10
Biomedical Research Networking Centres-Respiratory Diseases (CIBERES), Madrid, Spain.
11
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain.
12
ICREA, Passeig Lluís Companys 23, 08010, Barcelona, Spain.

Abstract

Intestine is a major target of vitamin D and several studies indicate an association between vitamin D deficiency and inflammatory bowel diseases (IBD), but also increased colorectal cancer (CRC) risk and mortality. However, the putative effects of 1α,25-dihydroxyvitamin D3 (calcitriol), the active vitamin D metabolite, on human colonic stem cells are unknown. Here we show by immunohistochemistry and RNAscope in situ hybridization that vitamin D receptor (VDR) is unexpectedly expressed in LGR5+ colon stem cells in human tissue and in normal and tumor organoid cultures generated from patient biopsies. Interestingly, normal and tumor organoids respond differentially to calcitriol with profound and contrasting changes in their transcriptomic profiles. In normal organoids, calcitriol upregulates stemness-related genes, such as LGR5, SMOC2, LRIG1, MSI1, PTK7, and MEX3A, and inhibits cell proliferation. In contrast, in tumor organoids calcitriol has little effect on stemness-related genes while it induces a differentiated phenotype, and variably reduces cell proliferation. Concordantly, electron microscopy showed that calcitriol does not affect the blastic undifferentiated cell phenotype in normal organoids but it induces a series of differentiated features in tumor organoids. Our results constitute the first demonstration of a regulatory role of vitamin D on human colon stem cells, indicating a homeostatic effect on colon epithelium with relevant implications in IBD and CRC.

KEYWORDS:

colon cancer; colon stem cells; organoids; stemness genes; vitamin D

PMID:
31306552
DOI:
10.1111/febs.14998

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