Lotti Roberta, Palazzo Elisabetta, Petrachi Tiziana, Dallaglio Katiuscia, Saltari Annalisa, Truzzi Francesca, Quadri Marika, Puviani Mario, Maiorana Antonino, Marconi Alessandra, Pincelli Carlo
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.
Ospedale Civile di Sassuolo, Via Francesco Ruini 2, 41049 Sassuolo (MO), Italy.
Int J Mol Sci. 2016 Jan 12;17(1):89. doi: 10.3390/ijms17010089.
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.
鳞状细胞癌来源的干细胞（SCC-SC）起源于角质形成干细胞（KSC）基因表达的改变，并维持肿瘤的发展、侵袭和复发。由于KSC标志物survivin在SCC-SC中高表达，我们评估了其在SCC-SC细胞生长和SCC模型中的作用。通过siRNA沉默survivin可降低SCC角质形成细胞的克隆生长以及原发性SCC中总细胞、快速黏附（RAD）细胞和非RAD（NRAD）细胞的活力。同样，沉默survivin可降低干细胞标志物（OCT4、NOTCH1、CD133、β₁整合素）的表达，同时增加分化标志物（K10、兜甲蛋白）的水平。此外，沉默survivin可改善SCC三维重建的恶性表型，表现为表皮厚度降低、Ki-67阳性细胞数量减少以及MMP9和银屑蛋白表达降低。此外，在Ras（G12V）-IκBα衍生的肿瘤中，通过siRNA耗尽survivin会导致肿瘤形成减小，其特征为有丝分裂指数降低以及肿瘤相关标志物HIF1α、VEGF和CD51的表达减少。因此，我们的结果表明survivin是调节SCC癌干细胞形成和皮肤鳞状细胞癌（cSCC）发展的关键基因。
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