Merkel Cell Polyomavirus Small T Antigen mRNA Level Is Increased following In Vivo UV-Radiation

Abstract

Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer involving Merkel cells. Recently, a new human polyomavirus was implicated in MCC, being present in 80% of the samples analyzed. In virus-positive MCC, the Merkel cell polyomavirus (MCPyV) is clonally integrated into the patients DNA, and carries mutations in its large T antigen, leading to a truncated protein. In non-symptomatic tissue MCPyV can reside at very low levels. MCC is also associated with older age, immunosuppression and sun exposure. However, the link with solar exposure remains unknown, as the precise mechanism and steps involved between time of infection by MCPyV and the development of MCC. We thus investigated the potential impact of solar simulated radiation (SSR) on MCPyV transcriptional activity. We screened skin samples of 20 healthy patients enrolled in a photodermatological protocol based on in vivo-administered 2 and 4 J/cm2 SSR. Two patients were infected with two new variants of MCPyV, present in their episomal form and RT-QPCR analyses on SSR-irradiated skin samples showed a specific and unique dose-dependent increase of MCPyV small t antigen transcript. A luciferase based in vitro assay confirmed that small t promoter is indeed UV-inducible. These findings demonstrate that solar radiation has an impact on MCPyV mRNA levels that may explain the association between MCC and solar exposure.

Human Merkel cell polyomavirus: virological background and clinical implications

“…MCPyV DNA has been detected at varying levels of frequency (0-100%) in skin samples, and in anal and penile swabs (1,9,20,21,26,(32)(33)(34)(35)(36)(37)(38). The MCPyV viral load on the skin surface varies from less than 1 copy per 1000 cells to 1000 copies per cell (9,26,30,(39)(40)(41).…”

“…The MCPyV viral load on the skin surface varies from less than 1 copy per 1000 cells to 1000 copies per cell (9,26,30,(39)(40)(41). The mean DNA copy per cell in normal skin has been reported to be 0.02-0.07 (42).…”

Merkel Cell Polyomavirus Infection, Large T Antigen, Retinoblastoma Protein and Outcome in Merkel Cell Carcinoma

“…The MCPyV T-antigen expression is necessary for the maintenance of MCPyV-positive MCC cell lines, but not a MCPyV-negative cell line (8). UV radiation exposure of the skin increases MCPyV small T-antigen mRNA expression, suggesting a link between MCC, age, MCPyV infection, and UV irradiation (9). Patients who have MCPyV DNA-positive MCC had more favorable survival than those diagnosed with MCPyV DNA-negative MCC, when MCPyV-positivity was defined as presence of any MCPyV DNA in the tumor tissue (10).…”

Involvement of Merkel Cell Polyomavirus in the Etiology and Pathogenesis of Merkel Cell Carcinoma: A Systematic Review

“…The mutant LT antigen found in MCC inhibits the repair that ultraviolet radiation (UVR) typically causes on DNA, probably mediated by decreasing expression of the XPC protein, which recognizes the DNA damage and initiate the repair process, and may be involved in carcinogenesis [66]. Furthermore, UVR can increase the expression levels of messenger RNA (mRNA) of MCV sT antigen [74]. The presence of high rates of pyrimidine dimers substitutions between mutations at the LT was observed, suggesting a of UVR role in transformation process [69].…”