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The heparan sulfate proteoglycan syndecan‐1 regulates colon cancer stem cell function via a focal adhesion kinase—Wnt signaling axis
Author(s) -
Kumar Katakam Sampath,
Tria Valeria,
Sim WeyCheng,
Yip George W.,
Molgora Stefano,
Karnavas Theodoros,
Elghonaimy Eslam A.,
Pelucchi Paride,
Piscitelli Eleonora,
Ibrahim Sherif Abdelaziz,
Zucchi Ileana,
Reinbold Rolland,
Greve Burkhard,
Götte Martin
Publication year - 2021
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.15356
Subject(s) - wnt signaling pathway , lgr5 , cancer stem cell , stem cell , cancer research , biology , cd44 , microbiology and biotechnology , syndecan 1 , sodium butyrate , focal adhesion , signal transduction , cell , cell culture , genetics
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 .