Abstract

Merkel cell carcinoma (MCC) is an aggressive skin cancer frequently caused by the Merkel cell polyomavirus (MCPyV). It is still under discussion, in which cells viral integration and MCC development occurs. Recently, we demonstrated that a virus-positive MCC derived from a trichoblastoma, an epithelial neoplasia bearing Merkel cell (MC) differentiation potential. Accordingly, we hypothesized that MC progenitors may represent an origin of MCPyV-positive MCC. To sustain this hypothesis, phenotypic comparison of trichoblastomas and physiologic human MC progenitors was conducted revealing GLI family zinc finger 1 (GLI1), Keratin 17 (KRT 17), and SRY-box transcription factor 9 (SOX9) expressions in both subsets. Furthermore, GLI1 expression in keratinocytes induced transcription of the MC marker SOX2 supporting a role of GLI1 in human MC differentiation. To assess a possible contribution of the MCPyV T antigens (TA) to the development of an MC-like phenotype, human keratinocytes were transduced with TA. While this led only to induction of KRT8, an early MC marker, combined GLI1 and TA expression gave rise to a more advanced MC phenotype with SOX2, KRT8, and KRT20 expression. Finally, we demonstrated MCPyV-large T antigens’ capacity to inhibit the degradation of the MC master regulator Atonal bHLH transcription factor 1 (ATOH1). In conclusion, our report suggests that MCPyV TA contribute to the acquisition of an MC-like phenotype in epithelial cells.

Highlights

  • Merkel cell carcinoma (MCC) is an aggressive cutaneous neoplasm with a five-year overall survival rate of 40% [1]

  • We recently demonstrated that Merkel cell polyomavirus (MCPyV) integration in a TB gave rise to an MCPyV-positive MCC [31]

  • In accordance with this hypothesis, ectopic T antigens (TA) expression in normal human epidermal keratinocytes (NHEK) led to induction of early MC markers while concomitant induction of SOX2, KRT8, and KRT20 were only achieved upon co-expression of TA and GLI family zinc finger 1 (GLI1)

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Summary

Introduction

Merkel cell carcinoma (MCC) is an aggressive cutaneous neoplasm with a five-year overall survival rate of 40% [1]. MCC tumor cells display small cell carcinoma features and express both neuroendocrine and epithelial markers. In 2008, Feng et al detected the sequence of a hitherto unknown polyomavirus integrated in the genomes of MCC tumor cells [2]. Subsequent studies revealed that approximately 80% of MCC cases are Merkel cell polyomavirus (MCPyV)-positive, and expression of the two viral T antigens (TA) (small T (sT) and large T antigens (LT)) are considered as the main drivers for carcinogenesis and growth of such tumors [2]. MCs can be found either in the appendages of the skin or in the basal layer of the epidermis. They function as mechanoreceptors capable of transmitting tactile stimuli onto

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