Table 2.

Carcinogenesis mechanisms of MCPyV in skin cancer.

First Author, Year, Country	Carcinogenesis Mechanism	Clinical Importance
Krump NA et al., 2021, Pennsylvania USA [34]	Primary human dermal fibroblasts (HDFs) can support MCPyV infection The onset of MCPyV replication and early Gene expression induces an inflammatory cytokine and interferon-stimulated gene (ISG) response.	Exploring how MCPyV interacts with innate immunity during its infectious cycle. Understanding the biology of MCPyV could lead to targeted therapies for MCPyV-associated MCC.
Guadagni S et al., 2020, Italy [35]	Identified the relationship between MCPyV and oncogenic alternative Δ exon 6–7 TrkAIII splicing in fresh, nonfixed, MCPyV-positive MCC metastasis	Identifies patients who may benefit from the following: Inhibitors of MCPyV T-antigen and/or TrkAIII expression or Clinically approved Trk kinase inhibitors: larotrectinib or entrectinib
Zhao J et al., 2020, Dallas, TX [36]	MCPyV sT-induced ncNF-κB signaling is an essential tumorigenic pathway in MCC	The first identification of the ncNF-κB signaling pathway activation by any polyomavirus and its critical role in MCC tumorigenesis.
Nwogu N et al., 2020, Pennsylvania USA [37]	MCPyV sT-mediated MMP-9 activation is driven through the large T stabilization domain (LSD)”, a known E3 ligase-targeting domain, in MCC.	Metastatic MCC may be treated in the future with a novel approach, in which MMP-9 may serve as the biochemical culprit for treatment targeting and development.
Gupta P et al., 2020, Lyon, France [38]	Twenty-eight genes were revealed to be specifically deregulated by MCPyV, using a comparison of gene expression profiles. The MCPyV early gene downregulated the expression of the N-myc downstream-regulated gene 1 (NDRG1) (a tumor supressor) in MCPyV gene-expressing NIKs and hTERT-MCPyV gene-expressing human keratinocytes (HK) compared to their expression in the controls.	New paradigms of molecular targeted therapies can provide hope for patients affected by this highly aggressive cancer.
Longino NV et al., 2019, Seattle Washington [39]	The identification of CD4+ T-cell responses against six MCPyV epitopes One epitope was of particular interest, because it included a conserved, essential viral oncogenic domain which binds to and/or disables the cellular retinoblastoma (Rb) tumor suppressor.	Therapeutic vaccines may use this key step for detoxification. More in-depth studies of MCPyV-specific CD4+ T cells may use these new tools to provide a broader insight into the cancer-specific CD4+ T-cell responses.
Wu JH et al., 2019, Houston, TX, USA [40]	MCPyV small T (sT) antigen induces the activation of the DNA damage response (DDR) pathway. The hyperphosphorylation of histone H2AX is a marker of DNA damage and was observed in MCPyV-positive MCC cells in humans.	A novel link between MCPyV sT and the DDR pathway in MCC. DDR could be quantified to evaluate radiotherapy or chemotherapy response. More attention should be given to studying the implication of the DDR pathway for the management of MCC.