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.