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Elucidating Mechanisms of Transformation and Tumorigenesis by Merkel Cell Polyomavirus Tumor Antigens

出版	University of Washington Libraries, 2020
URL	http://books.google.com.hk/books?id=40bjzQEACAAJ&hl=&source=gbs_api

註釋In 2008, Merkel cell polyomavirus (MCPyV) was found to be the etiologic agent of 80% of Merkel cell carcinomas (MCC) through expression of two viral oncoproteins: the Small Tumor antigen (ST) and a truncated form of the Large Tumor antigen (LT-t). In order to elucidate mechanisms of transformation by these tumor antigens, we sought to define which of the tumor antigen(s) is responsible for transformation and tumorigenesis, the domains of the tumor antigen(s) responsible for this phenotype, and the cellular binding partners and pathways perturbed through interaction with the MCPyV tumor antigen(s). Various transformation assays using primary human foreskin fibroblasts (HFF), the potential host cell for natural MCPyV infection, transduced with MCPyV tumor antigens identified MCPyV ST as the dominant transforming protein, with LT-t showing no evidence of transforming potential in the assay. MCPyV ST expressing HFFs were also found to be tumorigenic when injected into NOD scid gamma mice, consistent with in vitro transformation assay experiments. As MCPyV is the only human polyomavirus (HPyV) routinely found in a human cancer, we next sought to determine whether MCPyV ST is unique in its transforming ability. The ST antigens of two other skin tropic human polyomaviruses, Human Polyomavirus 7 (HPyV7) and Trichodysplasia spinulosa polyomavirus (TSPyV), were found to be non-transforming in HFFs, consistent with no association with these viruses and cancer. Mutational analysis of known MCPyV ST domains identified amino acids 116-120 and 91-95 as individually necessary for transformation. In order to identify the cellular binding partners and pathways necessary for transformation by MCPyV ST, TurboID Mass Spectrometry and Next-Generation RNA Sequencing (NGS) comparing the transforming MCPyV ST and non-transforming HPyV7 ST, TSPyV ST, MCPyV ST 116-120A and MCPyV ST 91-95A was performed. A total of 8 novel MCPyV ST interactors, with known oncogenic or tumor suppressive functions, were found to interact with ST, including Yes-associated protein 1 (YAP1), a transcriptional co-activator of the Hippo pathway. Interestingly, NGS found YAP target genes to be deregulated in ST compared to untransduced (UT) HFFs. Future experiments aim to further define the interaction between MCPyV ST and YAP, the role of this interaction in transformation and tumorigenesis by MCPyV ST, and YAP as a potential therapeutic target for the treatment of MCC.