The heparan sulfate proteoglycan syndecan-1 regulates colon cancer stem cell function via a focal adhesion kinase-Wnt signaling axis.
AC133 Antigen
/ genetics
Aldehyde Dehydrogenase 1 Family
/ genetics
Animals
Benzothiazoles
/ pharmacology
Caco-2 Cells
Cell Movement
/ drug effects
Cell Proliferation
/ drug effects
Colonic Neoplasms
/ drug therapy
Epithelial Cell Adhesion Molecule
/ genetics
Focal Adhesion Kinase 1
/ antagonists & inhibitors
Gene Expression Regulation, Neoplastic
HT29 Cells
Humans
Indoles
/ pharmacology
Integrin beta1
/ genetics
Kruppel-Like Transcription Factors
/ genetics
Mice
Nanog Homeobox Protein
/ genetics
Neoplastic Stem Cells
/ drug effects
Oligopeptides
/ pharmacology
RNA, Small Interfering
/ genetics
Receptors, G-Protein-Coupled
/ genetics
Sex-Determining Region Y Protein
/ genetics
Spheroids, Cellular
/ drug effects
Sulfonamides
/ pharmacology
Syndecan-1
/ antagonists & inhibitors
Transcription Factor 7-Like 2 Protein
/ genetics
Tumor Burden
/ drug effects
Wnt Signaling Pathway
/ drug effects
Xenograft Model Antitumor Assays
extracellular matrix
glycosaminoglycan
syndecans
tumor-initiating cells
xenograft
Journal
The FEBS journal
ISSN: 1742-4658
Titre abrégé: FEBS J
Pays: England
ID NLM: 101229646
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
06
03
2019
revised:
23
04
2020
accepted:
01
05
2020
pubmed:
6
5
2020
medline:
22
6
2021
entrez:
6
5
2020
Statut:
ppublish
Résumé
In colon cancer, downregulation of the transmembrane heparan sulfate proteoglycan syndecan-1 (Sdc-1) is associated with increased invasiveness, metastasis, and dedifferentiation. As Sdc-1 modulates signaling pathways relevant to stem cell function, we tested the hypothesis that it may regulate a tumor-initiating cell phenotype. Sdc-1 small-interfering RNA knockdown in the human colon cancer cell lines Caco2 and HT-29 resulted in an increased side population (SP), enhanced aldehyde dehydrogenase 1 activity, and higher expression of CD133, LGR5, EPCAM, NANOG, SRY (sex-determining region Y)-box 2, KLF2, and TCF4/TCF7L2. Sdc-1 knockdown enhanced sphere formation, cell viability, Matrigel invasiveness, and epithelial-to-mesenchymal transition-related gene expression. Sdc-1-depleted HT-29 xenograft growth was increased compared to controls. Decreased Sdc-1 expression was associated with an increased activation of β1-integrins, focal adhesion kinase (FAK), and wingless-type (Wnt) signaling. Pharmacological FAK and Wnt inhibition blocked the enhanced stem cell phenotype and invasive growth. Sequential flow cytometric SP enrichment substantially enhanced the stem cell phenotype of Sdc-1-depleted cells, which showed increased resistance to doxorubicin chemotherapy and irradiation. In conclusion, Sdc-1 depletion cooperatively enhances activation of integrins and FAK, which then generates signals for increased invasiveness and cancer stem cell properties. Our findings may provide a novel concept to target a stemness-associated signaling axis as a therapeutic strategy to reduce metastatic spread and cancer recurrence. DATABASES: The GEO accession number of the Affymetrix transcriptomic screening is GSE58751.
Substances chimiques
AC133 Antigen
0
Benzothiazoles
0
EPCAM protein, human
0
Epithelial Cell Adhesion Molecule
0
IWP-2 compound
0
Indoles
0
Integrin beta1
0
Itgb1 protein, human
0
KLF2 protein, human
0
Kruppel-Like Transcription Factors
0
LGR5 protein, human
0
N-methyl-N-(3-((2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino)-methyl)-pyridin-2-yl)-methanesulfonamide
0
NANOG protein, human
0
Nanog Homeobox Protein
0
Oligopeptides
0
PROM1 protein, human
0
RNA, Small Interfering
0
Receptors, G-Protein-Coupled
0
SDC1 protein, human
0
SRY protein, human
0
Sex-Determining Region Y Protein
0
Sulfonamides
0
Syndecan-1
0
TCF7L2 protein, human
0
Transcription Factor 7-Like 2 Protein
0
arginyl-glycyl-aspartic acid
78VO7F77PN
Aldehyde Dehydrogenase 1 Family
EC 1.2.1
Focal Adhesion Kinase 1
EC 2.7.10.2
PTK2 protein, human
EC 2.7.10.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
486-506Informations de copyright
© 2020 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
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