Cargando…

Syndecan-1-Dependent Regulation of Heparanase Affects Invasiveness, Stem Cell Properties, and Therapeutic Resistance of Caco2 Colon Cancer Cells

The heparan sulfate proteoglycan Syndecan-1 binds cytokines, morphogens and extracellular matrix components, regulating cancer stem cell properties and invasiveness. Syndecan-1 is modulated by the heparan sulfate-degrading enzyme heparanase, but the underlying regulatory mechanisms are only poorly u...

Descripción completa

Detalles Bibliográficos
Autores principales: Katakam, Sampath Kumar, Pelucchi, Paride, Cocola, Cinzia, Reinbold, Rolland, Vlodavsky, Israel, Greve, Burkhard, Götte, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240066/
https://www.ncbi.nlm.nih.gov/pubmed/32477959
http://dx.doi.org/10.3389/fonc.2020.00774
_version_ 1783536807484325888
author Katakam, Sampath Kumar
Pelucchi, Paride
Cocola, Cinzia
Reinbold, Rolland
Vlodavsky, Israel
Greve, Burkhard
Götte, Martin
author_facet Katakam, Sampath Kumar
Pelucchi, Paride
Cocola, Cinzia
Reinbold, Rolland
Vlodavsky, Israel
Greve, Burkhard
Götte, Martin
author_sort Katakam, Sampath Kumar
collection PubMed
description The heparan sulfate proteoglycan Syndecan-1 binds cytokines, morphogens and extracellular matrix components, regulating cancer stem cell properties and invasiveness. Syndecan-1 is modulated by the heparan sulfate-degrading enzyme heparanase, but the underlying regulatory mechanisms are only poorly understood. In colon cancer pathogenesis, complex changes occur in the expression pattern of Syndecan-1 and heparanase during progression from well-differentiated to undifferentiated tumors. Loss of Syndecan-1 and increased expression of heparanase are associated with a change in phenotypic plasticity and an increase in invasiveness, metastasis and dedifferentiation. Here we investigated the regulatory and functional interplay of Syndecan-1 and heparanase employing siRNA-mediated silencing and plasmid-based overexpression approaches in the human colon cancer cell line Caco2. Heparanase expression and activity were upregulated in Syndecan-1 depleted cells. This increase was linked to an upregulation of the transcription factor Egr1, which regulates heparanase at the promoter level. Inhibitor experiments demonstrated an impact of focal adhesion kinase, Wnt and ROCK-dependent signaling on this process. siRNA-depletion of Syndecan-1, and upregulation of heparanase increased the colon cancer stem cell phenotype based on sphere formation assays and phenotypic marker analysis (Side-population, NANOG, KLF4, NOTCH, Wnt, and TCF4 expression). Syndecan-1 depletion increased invasiveness of Caco2 cells in vitro in a heparanase-dependent manner. Finally, upregulated expression of heparanase resulted in increased resistance to radiotherapy, whereas high expression of enzymatically inactive heparanase promoted chemoresistance to paclitaxel and cisplatin. Our findings provide a new avenue to target a stemness-associated signaling axis as a therapeutic strategy to reduce metastatic spread and cancer recurrence.
format Online
Article
Text
id pubmed-7240066
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-72400662020-05-29 Syndecan-1-Dependent Regulation of Heparanase Affects Invasiveness, Stem Cell Properties, and Therapeutic Resistance of Caco2 Colon Cancer Cells Katakam, Sampath Kumar Pelucchi, Paride Cocola, Cinzia Reinbold, Rolland Vlodavsky, Israel Greve, Burkhard Götte, Martin Front Oncol Oncology The heparan sulfate proteoglycan Syndecan-1 binds cytokines, morphogens and extracellular matrix components, regulating cancer stem cell properties and invasiveness. Syndecan-1 is modulated by the heparan sulfate-degrading enzyme heparanase, but the underlying regulatory mechanisms are only poorly understood. In colon cancer pathogenesis, complex changes occur in the expression pattern of Syndecan-1 and heparanase during progression from well-differentiated to undifferentiated tumors. Loss of Syndecan-1 and increased expression of heparanase are associated with a change in phenotypic plasticity and an increase in invasiveness, metastasis and dedifferentiation. Here we investigated the regulatory and functional interplay of Syndecan-1 and heparanase employing siRNA-mediated silencing and plasmid-based overexpression approaches in the human colon cancer cell line Caco2. Heparanase expression and activity were upregulated in Syndecan-1 depleted cells. This increase was linked to an upregulation of the transcription factor Egr1, which regulates heparanase at the promoter level. Inhibitor experiments demonstrated an impact of focal adhesion kinase, Wnt and ROCK-dependent signaling on this process. siRNA-depletion of Syndecan-1, and upregulation of heparanase increased the colon cancer stem cell phenotype based on sphere formation assays and phenotypic marker analysis (Side-population, NANOG, KLF4, NOTCH, Wnt, and TCF4 expression). Syndecan-1 depletion increased invasiveness of Caco2 cells in vitro in a heparanase-dependent manner. Finally, upregulated expression of heparanase resulted in increased resistance to radiotherapy, whereas high expression of enzymatically inactive heparanase promoted chemoresistance to paclitaxel and cisplatin. Our findings provide a new avenue to target a stemness-associated signaling axis as a therapeutic strategy to reduce metastatic spread and cancer recurrence. Frontiers Media S.A. 2020-05-14 /pmc/articles/PMC7240066/ /pubmed/32477959 http://dx.doi.org/10.3389/fonc.2020.00774 Text en Copyright © 2020 Katakam, Pelucchi, Cocola, Reinbold, Vlodavsky, Greve and Götte. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Katakam, Sampath Kumar
Pelucchi, Paride
Cocola, Cinzia
Reinbold, Rolland
Vlodavsky, Israel
Greve, Burkhard
Götte, Martin
Syndecan-1-Dependent Regulation of Heparanase Affects Invasiveness, Stem Cell Properties, and Therapeutic Resistance of Caco2 Colon Cancer Cells
title Syndecan-1-Dependent Regulation of Heparanase Affects Invasiveness, Stem Cell Properties, and Therapeutic Resistance of Caco2 Colon Cancer Cells
title_full Syndecan-1-Dependent Regulation of Heparanase Affects Invasiveness, Stem Cell Properties, and Therapeutic Resistance of Caco2 Colon Cancer Cells
title_fullStr Syndecan-1-Dependent Regulation of Heparanase Affects Invasiveness, Stem Cell Properties, and Therapeutic Resistance of Caco2 Colon Cancer Cells
title_full_unstemmed Syndecan-1-Dependent Regulation of Heparanase Affects Invasiveness, Stem Cell Properties, and Therapeutic Resistance of Caco2 Colon Cancer Cells
title_short Syndecan-1-Dependent Regulation of Heparanase Affects Invasiveness, Stem Cell Properties, and Therapeutic Resistance of Caco2 Colon Cancer Cells
title_sort syndecan-1-dependent regulation of heparanase affects invasiveness, stem cell properties, and therapeutic resistance of caco2 colon cancer cells
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240066/
https://www.ncbi.nlm.nih.gov/pubmed/32477959
http://dx.doi.org/10.3389/fonc.2020.00774
work_keys_str_mv AT katakamsampathkumar syndecan1dependentregulationofheparanaseaffectsinvasivenessstemcellpropertiesandtherapeuticresistanceofcaco2coloncancercells
AT pelucchiparide syndecan1dependentregulationofheparanaseaffectsinvasivenessstemcellpropertiesandtherapeuticresistanceofcaco2coloncancercells
AT cocolacinzia syndecan1dependentregulationofheparanaseaffectsinvasivenessstemcellpropertiesandtherapeuticresistanceofcaco2coloncancercells
AT reinboldrolland syndecan1dependentregulationofheparanaseaffectsinvasivenessstemcellpropertiesandtherapeuticresistanceofcaco2coloncancercells
AT vlodavskyisrael syndecan1dependentregulationofheparanaseaffectsinvasivenessstemcellpropertiesandtherapeuticresistanceofcaco2coloncancercells
AT greveburkhard syndecan1dependentregulationofheparanaseaffectsinvasivenessstemcellpropertiesandtherapeuticresistanceofcaco2coloncancercells
AT gottemartin syndecan1dependentregulationofheparanaseaffectsinvasivenessstemcellpropertiesandtherapeuticresistanceofcaco2coloncancercells