Expression of The Embryonic Stem Cell Transcription Factor SOX2 in Human Skin

Abstract

SOX2 is a gene located on chromosome 3q26.33 that encodes a transcription factor important to maintenance of embryonic neural crest stem cell pluripotency. We have identified rare SOX2-immunoreactive cells in normal human skin at or near the established stem cell niches. Three subsets of SOX2-positive cells were defined in these regions: those expressing only SOX2 and those that co-expressed SOX2 and either CK20 or microphthalmia-associated transcription factor , which are consistent with dichotomous differentiation of SOX2-expressing precursors along neuroendocrine (Merkel cell) or melanocytic lines , respectively. Examination of Merkel cell carcinomas confirmed nuclear SOX2 expression in this tumor type. In human patient melanoma , strong nuclear expression of SOX2 was noted in a subset of tumors , and the ability to detect SOX2 in lesional cells significantly correlated with primary tumor thickness in a survey cohort. To assess the potential role of SOX2 in melanoma growth , an in vivo tumorigenesis assay was used. Whereas SOX2 knockdown failed to influence proliferation of cultured melanoma cells in vitro , tumor xenografts generated with the SOX2-knockdown cell line showed significant decrease in mean tumor volume as compared with controls. In aggregate , these findings suggest that SOX2 is a novel biomarker for subpopulations of normal skin cells that reside in established stem cell niches and that might relate to Merkel cell and melanocyte ontogeny and tumorigenesis.

Sox2 is dispensable for primary melanoma and metastasis formation

“…In normal postnatal mouse skin, Sox2 was expressed in a subset of dermal papillae, consistent with previous findings in mouse and human 21,32 . Further, we did not detect (Figure 3c) 5 .…”

“…Although TMA studies have previously confirmed SOX2 expression in a subset of human melanomas 20,21 , our analysis of TCGA data did not reveal any correlation between SOX2 levels and disease outcome.…”

“…In a recent study, RNAi-mediated silencing of SOX2 led to reduced melanoma sphere self-renewal and tumor growth of xenotransplanted cells, supporting an important role of Sox2 in tumor initiation and tumor maintenance 22 . In other reports, however, knockdown of SOX2 did not affect proliferation of human melanoma cells 20,21,23 . Instead, SOX2 knockdown cells displayed reduced invasiveness, whereas SOX2 overexpression increased the invasion capacity of human melanoma cells 23 .…”

“…Of note, studies performed solely in vitro or in combination with xenotransplantation assays provided controversial results, either implicating SOX2 in melanoma cell proliferation or invasion, or also failing to reveal a crucial role in melanoma as in our experiments performed with CRISPR-Cas-mediated knock out cells [20][21][22][23][24] . While the discrepancies between our work and previously published data could potentially be explained by different experimental settings 37 , they could also reflect the heterogeneity of melanoma and, thus, leave open whether SOX2 might fulfill a role in some cases of human melanoma.…”

“…Tissue microarray (TMA) expression analysis revealed that SOX2 protein is expressed in around 50% of all human melanoma 20,21 . In a recent study, RNAi-mediated silencing of SOX2 led to reduced melanoma sphere self-renewal and tumor growth of xenotransplanted cells, supporting an important role of Sox2 in tumor initiation and tumor maintenance 22 .…”