Interplay of Syndecan-1 and Heparanase in Cancer Stem Cell Function

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Abstract

The heparan sulfate proteoglycan Syndecan-1 binds growth factors, morphogens, chemokines and extracellular matrix components, thereby regulating cancer cell proliferation, motility and invasiveness. In colon cancer pathogenesis, complex changes occur in the expression pattern of Syndecan-1 during progression from well-differentiated to undifferentiated tumors. Loss of Syndecan-1 is associated with a change in phenotypic plasticity with an increase in invasiveness, metastasis and dedifferentiation. Empirical evidence shows that this change in phenotypic plastiticty allows cells to dynamically enter into a stem-cell-like-state. In this study, we investigated the role of Syndecan-1 in a potential colon cancer stem cell-function employing an siRNA approach in the human colon cancer cell lines Caco2 and HT-29. We demonstrate thas siRNA-depletion of Syndecan-1 increased the stem cell phenotype based on sphere formation assays, xenografting studies and phenotypic marker analysis (Side-population, ALDH activity, CD133 FACS). Moreover, Syndecan-1 depletion increased invasiveness of Caco2 cells in a matrigel invasion chamber assay. Mechanistically, decreased expression of Syndecan-1 was associated in an upregulation of the activated form of beta-integrin, and to increased activation of focal adhesion kinase (FAK), suggesting that Syndecan-1 was implicated in integrin-mediated actin remodeling. Importantly, Wnt signaling was increased upon Syndecan-1 siRNA delpetion as revealed by TOP Flash assays and qPCR, resulting in upregulation of the transcription factor TCF4 and a strenghtening of the FAK:WNT signaling axis. Notably, we also observed an upregulation of the heparan sulfate-degrading enzyme heparanase (HPSE) in Syndecan-1 depleted cells. Increased HPSE-expression could be linked to an upregulation of the transcription factor Egr1, which regulated HPSE at the promoter level. The enhanced stem cell phenotype in Syndecan-1-depleted cells could be blocked by pharmacological inhibitors of FAK and HPSE, suggesting a functional interplay of these molecular pathways. We conclude that reduced Syndecan-1 expression 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.

Speakers from the University of Münster

Götte, Martin

Department of Gynecology and Obstetrics