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

Roberta Lotti,Annalisa Saltari,Elisabetta Palazzo,Marika Quadri,Mario Puviani,Francesca Truzzi,Tiziana Petrachi,Alessandra Marconi,Carlo Pincelli,Antonino Maiorana,Katiuscia Dallaglio

doi:10.3390/ijms17010089

Roberta Lotti, Annalisa Saltari + Show 9 more

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https://doi.org/10.3390/ijms17010089

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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.

Highlights

Cutaneous squamous cell carcinoma represents one of the most frequent skin cancers, and together with the basal cell carcinoma (BCC), account for over 1 million new cancers annually in the United States [1]
The oncogenic transformation of the keratinocyte stem cells (KSC), due to genetic or epigenetic alterations [5], gives origin to the SCC-derived Stem-like Cells (SCC-SC), which are responsible for the development of papillomas and Cutaneous squamous cell carcinoma (cSCC) [4]
We had previously demonstrated that survivin expression, which identifies KSC in vitro, is higher in rapidly adhering (RAD) keratinocytes with respect to NRAD and cSCC bulk cells [22]

Summary

Introduction

Cutaneous squamous cell carcinoma (cSCC) represents one of the most frequent skin cancers, and together with the basal cell carcinoma (BCC), account for over 1 million new cancers annually in the United States [1]. Surgical resection is curative in 95% of patients with early diagnosis and leads to complete eradication of the tumor. This neoplasia may display aggressive histopathologic behavior and undergo relapse and/or perineural or lymphovascular invasion, suggesting that further studies on the mechanisms underlying cSCCs formation are needed. CSCC develop from the graft of v-rasHa or v-rasHa–IκBα transformed keratinocytes onto nude mice [7,8,9], and the slow-cycling, quiescent, poorly differentiated (stem cells), but not the rapidly proliferating transit amplifying cells, give rise to more aggressive and invasive tumor [6,10], acting, once transformed, as cancer stem cells

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