Abstract
Polyomaviruses are non-enveloped, dsDNA viruses that are common in mammals, including humans. All polyomaviruses encode the large T-antigen and small t-antigen proteins that share conserved functional domains, comprising binding motifs for the tumor suppressors pRb and p53, and for protein phosphatase 2A, respectively. At present, 13 different human polyomaviruses are known, and for some of them their large T-antigen and small t-antigen have been shown to possess oncogenic properties in cell culture and animal models, while similar functions are assumed for the large T- and small t-antigen of other human polyomaviruses. However, so far the Merkel cell polyomavirus seems to be the only human polyomavirus associated with cancer. The large T- and small t-antigen exert their tumorigenic effects through classical hallmarks of cancer: inhibiting tumor suppressors, activating tumor promoters, preventing apoptosis, inducing angiogenesis and stimulating metastasis. This review elaborates on the putative roles of human polyomaviruses in some of the emerging hallmarks of cancer. The reciprocal interactions between human polyomaviruses and the immune system response are discussed, a plausible role of polyomavirus-encoded and polyomavirus-induced microRNA in cancer is described, and the effect of polyomaviruses on energy homeostasis and exosomes is explored. Therapeutic strategies against these emerging hallmarks of cancer are also suggested.
Highlights
Polyomaviruses are naked, circular double-stranded DNA viruses that infect birds and mammals, and recently the first fish-associated polyomavirus was described [1,2]
Expression of cell surface markers was performed to determine the functionality of the immune cells. These analyses revealed that the expression of MHC-I in Merkel cell PyV (MCPyV)-positive Merkel cell carcinoma (MCC) was significantly lower than in virus-negative MCC [96]
MCPyV interference with the NF-κB pathway is further sustained by the observations that IκB levels were 60% lower in the MCPyV-positive MCC cell line MKL-1 compared with MCPyV-negative MCC13 cells, and by a declined expression of NF-κB and NF-κB-associated genes in virus-positive MCC compared to virus-negative MCC [99,117]
Summary
Polyomaviruses are naked, circular double-stranded DNA viruses that infect birds and mammals, and recently the first fish-associated polyomavirus was described [1,2]. The genome of most polyomaviruses is approximately 5000 base-pairs and encodes regulatory proteins and structural proteins. Eddy led to the identification of the first polyomavirus They showed that a filtrate from a mouse leukaemia could cause multiple tumors in new-born mice and later it was demonstrated that these multiple tumors were virus-. This virus, Simian virus 40 (SV40), was shown to transform cells, including human cells, to induce tumors in animal models, and to be present in human cancers. One case of hamster polyomavirus-induced lymphoma in a hamster outside of the laboratory environment has been described [15], while two novel mammalian polyomaviruses have been isolated from benign tumors. Despite a similar genetic organization to that of mammalian polyomavirus, their LT-ag lacks homologies to the p53 binding sequences of mammalian polyomavirus and not all avian polyomavirus LT-ag possess the consensus sequence LXCXE required for pRb binding [18]
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