title: Survivin Modulates Squamous Cell Carcinoma-Derived Stem-Like Cell Proliferation, Viability and Tumor Formation in Vivo.
abstract: Squamous Cell Carcinoma-derived Stem-like Cells (SCC-SC) originate from alterations in keratinocyte stem cells (KSC) gene expression and sustain tumor development, invasion and recurrence. Since survivin, a KSC marker, is highly expressed in SCC-SC, we evaluate its role in SCC-SC cell growth and SCC models. Survivin silencing by siRNA decreases clonal growth of SCC keratinocytes and viability of total, rapidly adhering (RAD) and non-RAD (NRAD) cells from primary SCC. Similarly, survivin silencing reduces the expression of stem cell markers (OCT4, NOTCH1, CD133, β₁-integrin), while it increases the level of differentiation markers (K10, involucrin). Moreover, survivin silencing improves the malignant phenotype of SCC 3D-reconstruct, as demonstrated by reduced epidermal thickness, lower Ki-67 positive cell number, and decreased expression of MMP9 and psoriasin. Furthermore, survivin depletion by siRNA in Ras(G12V)-IκBα-derived tumors leads to smaller tumor formation characterized by lower mitotic index and reduced expression of the tumor-associated marker HIF1α, VEGF and CD51. Therefore, our results indicate survivin as a key gene in regulating SCC cancer stem cell formation and cSCC development.
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, via del Pozzo 71, 41124 Modena, Italy. roberta.lotti@studenti.unimore.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Lotti
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, via del Pozzo 71, 41124 Modena, Italy. elisabetta.palazzo@unimore.it.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Palazzo
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, via del Pozzo 71, 41124 Modena, Italy. tiziana.petrachi@virgilio.it.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Petrachi
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, via del Pozzo 71, 41124 Modena, Italy. katiuscia.dallaglio@yahoo.it.
authors.forename: Katiuscia
authors.initials: K
authors.lastname: Dallaglio
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, via del Pozzo 71, 41124 Modena, Italy. annalisa.saltari@unimore.it.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Saltari
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, via del Pozzo 71, 41124 Modena, Italy. francesca.truzzi@unimore.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Truzzi
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, via del Pozzo 71, 41124 Modena, Italy. marika.quadri@unimore.it.
authors.forename: Marika
authors.initials: M
authors.lastname: Quadri
authors.affiliation: Ospedale Civile di Sassuolo, Via Francesco Ruini 2, 41049 Sassuolo (MO), Italy. mar.puviani@ospedalesassuolo.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Puviani
authors.affiliation: Department of Laboratories and Pathologic Anatomy, University of Modena and Reggio Emilia, Via del Pozzo 71, 41124 Modena, Italy. antonino.maiorana@unimore.it.
authors.forename: Antonino
authors.initials: A
authors.lastname: Maiorana
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, via del Pozzo 71, 41124 Modena, Italy. alessandra.marconi@unimore.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Marconi
authors.affiliation: Laboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, via del Pozzo 71, 41124 Modena, Italy. carlo.pincelli@unimore.it.
authors.forename: Carlo
authors.initials: C
authors.lastname: Pincelli
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D039564:Integrin alphaV / Q000235:genetics / Q000378:metabolism; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; C107489:BIRC5 protein, human; D006023:Glycoproteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051034:Inhibitor of Apoptosis Proteins; D039564:Integrin alphaV; D019012:Integrin beta1; C497761:NOTCH1 protein, human; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D000077022:Survivin; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: differentiation; rapidly adhering cells; skin; squamous cell carcinoma; stem cells; survivin; tumor formation; tumorigenesis; β1-integrin