Abstract 3562: Merkel cell polyomavirus t-antigen regulates aggresome formation and autophagy in merkel cell carcinoma

Abstract

Abstract Merkel cell carcinoma (MCC) is an aggressive and deadly skin cancer. About 80% of MCCs harbor integrated Merkel cell polyomavirus (MCV) genome with a mutation in the large T (LT) gene, leading to expression of truncated LT and intact small T (sT). The molecular mechanism how the virus contributes to MCC development is still not fully understood. Paranuclear dot-like staining of cytokeratin 20 is a typical characteristic of MCC. However, it is unexplored whether these dot-like structures are functionally important in MCC. In this study, we aimed to characterize the identity of these dot-like structures and to determine whether MCV T-antigens play a role in the formation of these structures. Using immunostaining, we showed that these structures were co-localized with aggresome markers (including intermediate filaments, BAG3 and HSP70) and were localized at the microtubule organization center, as demonstrated by the presence of γ-tubulin. These structures became dispersed to the periphery upon microtubule depolymerization using colcemid. Similarly, silencing of BAG3 in MCV-positive MCC cells resulted in aggresome clearance. Interestingly, we observed that these structures were associated with MCV-positive MCCs and silencing of MCV T-antigens led to dispersion of the aggresome. Additionally, ectopically expressed truncated, but not wild-type, LT could facilitate aggresome formation in MCV-negative cells. We also showed that silencing of MCV T-antigens induced autophagy in MCV-positive MCC cells, while ectopically expressed MCV T-antigens suppressed autophagy in MCV-negative MCC cells. In conclusion, we uncover a novel role of MCV T-antigen in hijacking cellular degradation pathways, suggesting that the autophagy-aggresome pathway plays important roles in MCV infection and MCC tumorigenesis. Citation Format: Hao Shi. Merkel cell polyomavirus t-antigen regulates aggresome formation and autophagy in merkel cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3562.