Epithelial calcineurin controls microbiota-dependent intestinal tumor development

Autor: John F. Baines, Sven Künzel, Triantafyllos Chavakis, Clemens Schafmayer, Esther Bosse, Giuseppina Luzzi, Jan Hendrik Egberts, Alexander Arlt, Andrea Ulbricht, Gijs R. van den Brink, Anne Strigli, Sebastian Zeissig, Jochen Hampe, Richard S. Blumberg, Thomas Becker, Kenneth Peuker, Arthur Kaser, Yvonne Zeissig, Stefan Schreiber, Marco Bianchi, Jun Wang, Stefanie Muff, Marijana Basic, André Bleich, Christoph Röcken
Přispěvatelé: Wang, Jun [0000-0002-8859-7707], Hampe, Jochen [0000-0002-2421-6127], Apollo - University of Cambridge Repository, Gastroenterology and Hepatology, AII - Amsterdam institute for Infection and Immunity, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Tytgat Institute for Liver and Intestinal Research, Peuker, K, Muff, S, Wang, J, Künzel, S, Bosse, E, Zeissig, Y, Luzzi, G, Basic, M, Strigli, A, Ulbricht, A, Kaser, A, Arlt, A, Chavakis, T, van den Brink, Gr, Schafmayer, C, Egberts J., H, Becker, T, Bianchi, MARCO EMILIO, Bleich, A, Röcken, C, Hampe, J, Schreiber, S, Baines, Jf, Blumberg, R, Zeissig, S.
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Genes
APC
Cell Survival
education
Blotting
Western
Electrophoretic Mobility Shift Assay
Biology
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
HT29 Cells
Mice
Intestinal mucosa
Cancer stem cell
RNA
Ribosomal
16S
Intestinal Neoplasms
cancer
Animals
Humans
Intestinal Mucosa
Transcription factor
In Situ Hybridization
Fluorescence
Cell Proliferation
NFATC Transcription Factors
Cell growth
Reverse Transcriptase Polymerase Chain Reaction
Calcineurin
NFAT
Epithelial Cells
General Medicine
Fecal Microbiota Transplantation
Flow Cytometry
HCT116 Cells
Prognosis
Immunohistochemistry
Cell biology
Gastrointestinal Microbiome
Intestines
Organoids
Disease Models
Animal
030104 developmental biology
inflammation
Tissue Array Analysis
Neoplastic Stem Cells
Colorectal Neoplasms
Zdroj: Nature Medicine
Nature medicine, 22(5), 506-515. Nature Publishing Group
ISSN: 1078-8956
DOI: 10.1038/nm.4072
Popis: Inflammation-associated pathways are active in intestinal epithelial cells (IECs) and contribute to the pathogenesis of colorectal cancer (CRC). Calcineurin, a phosphatase required for the activation of the nuclear factor of activated T cells (NFAT) family of transcription factors, shows increased expression in CRC. We therefore investigated the role of calcineurin in intestinal tumor development. We demonstrate that calcineurin and NFAT factors are constitutively expressed by primary IECs and selectively activated in intestinal tumors as a result of impaired stratification of the tumor-associated microbiota and toll-like receptor signaling. Epithelial calcineurin supports the survival and proliferation of cancer stem cells in an NFAT-dependent manner and promotes the development of intestinal tumors in mice. Moreover, somatic mutations that have been identified in human CRC are associated with constitutive activation of calcineurin, whereas nuclear translocation of NFAT is associated with increased death from CRC. These findings highlight an epithelial cell-intrinsic pathway that integrates signals derived from the commensal microbiota to promote intestinal tumor development.
Databáze: OpenAIRE
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