The heparan sulfate proteoglycan syndecan‐1 regulates colon cancer stem cell function via a focal adhesion kinase—Wnt signaling axis. (25th May 2020)

• Record Type: Journal Article
• Authors: Kumar Katakam, Sampath; Tria, Valeria; Sim, Wey‐Cheng; 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
• Is Part Of: FEBS journal. Volume 288:Number 2(2021)
• Page Start: 486
• Page End: 506
• Publication Date: 2020-05-25
• Subjects: extracellular matrix -- glycosaminoglycan -- syndecans -- tumor‐initiating cells -- xenograft; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.15356
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : 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 . Abstract : Loss of Sdc‐1 in colon cancer cells activates β1‐integrin and focal adhesion kinase, which in turn induces TCF4 expression, promoting a FAK: Wnt signaling axis. This enhances the cancer stem cell phenotype and drives an epithelial–mesenchymal transition‐like state with an increase in invasion, tumor growth in vivo, and enhanced resistance to chemo‐ and radiation therapy.