The Merkel Cell Polyomavirus T Antigens Function as Tumor Promoters in Murine Skin

SIMPLE SUMMARY: Merkel cell polyomavirus, a recently discovered human virus, is linked to the development of a rare form of skin cancer called Merkel cell carcinoma. The virus does not replicate in cancer cells, yet there is continued expression of viral proteins known as T antigens. The T antigens are believed to contribute to Merkel cell carcinoma development, yet how they do so remains an active area of research. In this study, we used transgenic mice expressing the viral T antigens in their skin to determine at which stage of skin cancer development these viral proteins function. We discovered that the Merkel cell polyomavirus T antigens function as tumor promoters, rather than tumor initiators, in the skin. These findings suggest that other tumor-initiating events may cooperate with the tumor-promoting activities of the viral T antigens, thus providing important insight into how Merkel cell polyomavirus can cause cancer in human skin. ABSTRACT: Merkel cell polyomavirus (MCPyV) causes the majority of human Merkel cell carcinomas (MCC), a rare but highly aggressive form of skin cancer. We recently reported that constitutive expression of MCC tumor-derived MCPyV tumor (T) antigens in the skin of transgenic mice leads to hyperplasia, increased proliferation, and spontaneous epithelial tumor development. We sought to evaluate how the MCPyV T antigens contribute to tumor formation in vivo using a classical, multi-stage model for squamous cell carcinoma development. In this model, two chemical carcinogens, DMBA and TPA, contribute to two distinct phases of carcinogenesis—initiation and promotion, respectively—that are required for tumors to develop. By treating the MCPyV transgenic mice with each chemical carcinogen, we determined how the viral oncogenes contributed to carcinogenesis. We observed that the MCPyV T antigens synergized with the tumor initiator DMBA, but not with the tumor promoter TPA, cause tumors. Therefore, the MCPyV tumor antigens function primarily as tumor promoters, similar to that seen with human papillomavirus (HPV) oncoproteins. These studies provide insight into the role of MCPyV T antigen expression in tumor formation in vivo and contribute to our understanding of how MCPyV may function as a human DNA tumor virus.