期刊
FEBS JOURNAL
卷 288, 期 2, 页码 486-506出版社
WILEY
DOI: 10.1111/febs.15356
关键词
extracellular matrix; glycosaminoglycan; syndecans; tumor-initiating cells; xenograft
资金
- Deutsche Forschungsgemeinschaft DFG International Research Training Group 'Molecular and Cellular GlycoSciences' [GRK 1549]
- German-Israeli Foundation [I-1004-202.15/2008]
- EU H2020 MSCA-RISE-2014 [645756 GLYCANC]
- N.O.B.E.L. Grant
- Cariplo Progetti-Internazionali [2008-2015]
- MUIR-FIRB
- InterOmics Flag Project
- National Medical Research Council, Singapore [NMRC/CSA/0041/2012]
- [RBAP11BYNP]
The downregulation of Sdc-1 in colon cancer is associated with increased invasiveness, metastasis, and potential tumor-initiating cell phenotype. Sdc-1 depletion enhances cancer stem cell properties and resistance to chemotherapy, while also promoting invasive growth of cancer cells.
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 beta 1-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 .
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