The heparan sulfate proteoglycan syndecan-1 regulates colon cancer stem cell function via a focal adhesion kinase-Wnt signaling axis.
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.
['Kumar Katakam|Sampath|S|', 'Tria|Valeria|V|', 'Sim|Wey-Cheng|WC|', 'Yip|George W|GW|', 'Molgora|Stefano|S|', 'Karnavas|Theodoros|T|', 'Elghonaimy|Eslam A|EA|', 'Pelucchi|Paride|P|', 'Piscitelli|Eleonora|E|', 'Ibrahim|Sherif Abdelaziz|SA|', 'Zucchi|Ileana|I|', 'Reinbold|Rolland|R|', 'Greve|Burkhard|B|', 'Götte|Martin|M|0000-0003-2360-2496']
D000071916:AC133 Antigen D000080924:Aldehyde Dehydrogenase 1 Family D000818:Animals D052160:Benzothiazoles D018938:Caco-2 Cells D002465:Cell Movement D049109:Cell Proliferation D003110:Colonic Neoplasms D000071858:Epithelial Cell Adhesion Molecule D051417:Focal Adhesion Kinase 1 D015972:Gene Expression Regulation, Neoplastic D019073:HT29 Cells D006801:Humans D007211:Indoles D019012:Integrin beta1 D051741:Kruppel-Like Transcription Factors D051379:Mice D000071317:Nanog Homeobox Protein D014411:Neoplastic Stem Cells D009842:Oligopeptides D034741:RNA, Small Interfering D043562:Receptors, G-Protein-Coupled D051876:Sex-Determining Region Y Protein D018874:Spheroids, Cellular D013449:Sulfonamides D053668:Syndecan-1 D058118:Transcription Factor 7-Like 2 Protein D047368:Tumor Burden D060449:Wnt Signaling Pathway D023041:Xenograft Model Antitumor Assays
tumor-initiating cells xenograft extracellular matrix glycosaminoglycan syndecans