title: Syndecan-1 (CD138) contributes to prostate cancer progression by stabilizing tumour-initiating cells.
abstract: Increasing evidence suggests that tumour-initiating cells (TICs) contribute to the development of prostate cancer. Here, we identified syndecan-1 as a key molecule maintaining the stability of prostate cancer TICs. Holoclones harbouring the biological properties of stemness were derived from single-cell cultures of the PC3 human prostate cancer cell line. These holoclones over-expressed syndecan-1, but showed reduced expression of NADPH oxidase (NOX) and synthesis of hydrogen peroxide and oxygen radicals. Stable RNA-mediated silencing of syndecan-1 gene expression up-regulated NOX-dependent generation of reactive oxygen species and reduced the survival of holoclones in vitro. Syndecan-1 down-regulation also strongly reduced the number of CD133(+)/CD44(+) primitive cancer cells and tumour growth in vivo. Interestingly, syndecan-1 gene knockdown significantly enhanced the tumour-suppressive effects of docetaxel by inhibiting the docetaxel-induced increase in CD133(+)/CD44(+) cells in vivo. In the transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model of prostate cancer, early intervention with a syndecan-1 inhibitor (OGT2115) or syndecan-1 RNAi reduced the incidence of adenocarcinoma and the number of c-kit(+)/CD44(+) cells in cancer foci. Finally, we found that syndecan-1 immunopositivity in prostate cancer cells was significantly associated with biochemical recurrence after radical prostatectomy. Taken together, our results show that syndecan-1 contributes to prostatic carcinogenesis by maintaining TICs and may be a target molecule for therapy.
authors.affiliation: Department of Pathology, Nara Medical University School of Medicine, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Shimada
authors.forename: Satoshi
authors.initials: S
authors.lastname: Anai
authors.forename: Tomomi
authors.initials: T
authors.lastname: Fujii
authors.forename: Nobumichi
authors.initials: N
authors.lastname: Tanaka
authors.forename: Kiyohide
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Noboru
authors.initials: N
authors.lastname: Konishi
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D003131:Combined Modality Therapy; D018450:Disease Progression; D000077143:Docetaxel; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D017382:Reactive Oxygen Species / Q000378:metabolism; D012008:Recurrence; D053668:Syndecan-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; C508241:SDC1 protein, human; D053668:Syndecan-1; D043823:Taxoids; D000077143:Docetaxel; D019255:NADPH Oxidases
keywords: ROS; holoclone; syndecan-1; tumour-initiating cells