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.
Keywords:
differentiation; rapidly adhering cells; skin; squamous cell carcinoma; stem cells; survivin; tumor formation; tumorigenesis; β1-integrin.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AC133 Antigen
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Animals
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Antigens, CD / genetics
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Antigens, CD / metabolism
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Carcinogenesis / genetics*
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Carcinogenesis / metabolism
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Carcinogenesis / pathology
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Carcinoma, Squamous Cell / genetics*
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology
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Cell Culture Techniques
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Cell Proliferation
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Cell Survival
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Gene Expression Regulation, Neoplastic*
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Glycoproteins / genetics
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Glycoproteins / metabolism
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Inhibitor of Apoptosis Proteins / antagonists & inhibitors
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Inhibitor of Apoptosis Proteins / genetics*
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Inhibitor of Apoptosis Proteins / metabolism
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Integrin alphaV / genetics
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Integrin alphaV / metabolism
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Integrin beta1 / genetics
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Integrin beta1 / metabolism
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Keratinocytes / metabolism*
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Keratinocytes / pathology
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Mice
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Mice, SCID
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Neoplasm Transplantation
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Neoplastic Stem Cells / metabolism*
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Neoplastic Stem Cells / pathology
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Octamer Transcription Factor-3 / genetics
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Octamer Transcription Factor-3 / metabolism
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Peptides / genetics
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Peptides / metabolism
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Primary Cell Culture
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptor, Notch1 / genetics
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Receptor, Notch1 / metabolism
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Signal Transduction
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Skin Neoplasms / genetics*
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Skin Neoplasms / metabolism
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Skin Neoplasms / pathology
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Survivin
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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AC133 Antigen
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Antigens, CD
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BIRC5 protein, human
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Glycoproteins
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Inhibitor of Apoptosis Proteins
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Integrin alphaV
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Integrin beta1
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NOTCH1 protein, human
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Octamer Transcription Factor-3
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POU5F1 protein, human
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PROM1 protein, human
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Peptides
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Prom1 protein, mouse
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RNA, Small Interfering
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Receptor, Notch1
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Survivin
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VEGFA protein, human
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Vascular Endothelial Growth Factor A