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 RasG12V-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.

HOXA9 inhibits HIF-1α-mediated glycolysis through interacting with CRIP2 to repress cutaneous squamous cell carcinoma development

“…Consistent with this, HIF-1α expression is lower in normal skin compared with cSCC tumors, wherein it is positively correlated with the ascending grades of cSCC 31 , 32 . In addition, HIF-1α also plays roles in the proliferation of cSCC stem-like cells 33 . However, the mechanism of HIF-1α being regulated and its relationship with HIF-1α-mediated glycolytic reprogramming in cSCC remain under explored.…”

Insights into the Regulation of Survivin Expression in Tumors

“…Therefore, GLI activity is not strictly dependent on the upstream SMO activation in tumor cells. Upregulated GLI proteins are associated with the invasive potential, epithelial-mesenchymal transition (EMT) and stemness of tumors [43,44]. Moreover, GLI2 is a direct activator of SOX2 transcription in telencephalic neuroepithelial cells and SOX2 expression decreases in the developing neuroepithelium of Gli2-deficient mice [4,45].…”

Effects of neuroblastoma breakpoint family member 1 (NBPF1) gene on Akt-p53-Cyclin D pathway and growth of cutaneous squamous carcinoma cells

“…Bcl-2 is a typical anti-apoptotic protein and Bcl-2 overexpression is common in SCC [19,20]. Survivin is associated with the immortality of cells, it is tumor-specific and is only expressed in tumors and embryonic tissues [21,22]. Previous studies have confirmed the existence of abnormal apoptosis in SCC and tumor apoptosis could be affected by many factors [23].…”