Merkel cell polyomavirus infection and Merkel cell carcinoma - PubMed (original) (raw)
Review
Merkel cell polyomavirus infection and Merkel cell carcinoma
Wei Liu et al. Curr Opin Virol. 2016 Oct.
Abstract
Merkel cell polyomavirus is the only polyomavirus discovered to date that is associated with a human cancer. MCPyV infection is highly prevalent in the general population. Nearly all healthy adults asymptomatically shed MCPyV from their skin. However, in elderly and immunosuppressed individuals, the infection can lead to a lethal form of skin cancer, Merkel cell carcinoma. In the last few years, new findings have established links between MCPyV infection, host immune response, and Merkel cell carcinoma development. This review discusses these recent discoveries on how MCPyV interacts with host cells to achieve persistent infection and, in the immunocompromised population, contributes to MCC development.
Copyright © 2016 Elsevier B.V. All rights reserved.
Figures
Figure 1. An intact MCPyV sT antigen-coding sequence is found in nearly all of the viral genomes integrated into MCC tumors
Analysis of 30 sequences of MCPyV-positive MCC obtained from published studies [1**,16**,25,42,64,65] show that all of them encode a wild type sT gene. The break points represent the break sites of the integrated MCPyV genomes. The first stop mutations are the first stop codons found in the T antigen sequences of the integrated MCPyV genomes.
Figure 2. Molecular and cellular events contributing to MCPyV infection and MCC tumorigenesis
A. MCPyV oncoproteins drive cellular transformation through interaction with host proteins. Shown are the domain structures of MCPyV LT and sT as well as the cellular targets that they interact with to drive cancer development. CR1: conserved region 1; OBD: Origin Binding Domain; LSD: LT-stabilization domain. B. Molecular signaling contributing to MCPyV infection. Induction of MMP genes by the WNT/β-catenin signaling pathway and other growth factors, such as EGF and FGF, stimulates MCPyV infection. MMPs may contribute to MCPyV infection by disrupting the extracellular matrix of the host cells. In the physiological skin environment, skin damage induced by UV/ionizing radiation (IR) and wounding processes can activate both WNT signaling and MMP expression. Aging skin also shows dramatically increased MMP expression. Therefore, these major MCC risk factors may promote viral infection to drive MCC tumorigenesis.
Figure 3. The working models for MCPyV infection and MCC development
Human dermal fibroblasts are the major target cells of MCPyV infection in the human skin. Shown are two working models for understanding how MCPyV-infected cells may give rise to MCC tumors. MCPyV infection of dermal fibroblasts could induce their transformation (Model 1). Alternatively, benign Merkel cells or progenitor cells located in the immediate vicinity of the infected dermal fibroblasts could be infected as accidental bystanders. MCPyV infection of Merkel cells may lead to MCC because these cells represent a dead-end replication environment that promotes viral integration and transformation (Model 2).
References
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