Survivin Modulates Squamous Cell Carcinoma-Derived Stem-Like Cell Proliferation, Viability and Tumor Formation in Vivo

Int J Mol Sci. 2016 Jan 12;17(1):89. doi: 10.3390/ijms17010089.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AC133 Antigen
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Carcinogenesis / genetics*
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cell Culture Techniques
  • Cell Proliferation
  • Cell Survival
  • Gene Expression Regulation, Neoplastic*
  • Glycoproteins / genetics
  • Glycoproteins / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors
  • Inhibitor of Apoptosis Proteins / genetics*
  • Inhibitor of Apoptosis Proteins / metabolism
  • Integrin alphaV / genetics
  • Integrin alphaV / metabolism
  • Integrin beta1 / genetics
  • Integrin beta1 / metabolism
  • Keratinocytes / metabolism*
  • Keratinocytes / pathology
  • Mice
  • Mice, SCID
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism
  • Peptides / genetics
  • Peptides / metabolism
  • Primary Cell Culture
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • Signal Transduction
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • Survivin
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • AC133 Antigen
  • Antigens, CD
  • BIRC5 protein, human
  • Glycoproteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Inhibitor of Apoptosis Proteins
  • Integrin alphaV
  • Integrin beta1
  • NOTCH1 protein, human
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • PROM1 protein, human
  • Peptides
  • Prom1 protein, mouse
  • RNA, Small Interfering
  • Receptor, Notch1
  • Survivin
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A