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Int J Cancer. 2019 Jun 10. doi: 10.1002/ijc.32503. [Epub ahead of print]

Merkel cell polyomavirus oncoproteins induce microRNAs that suppress multiple autophagy genes.

Author information

1
Department of Oncology-Pathology, Karolinska Institutet; Cancer Center Karolinska, Karolinska University Hospital, Stockholm, Sweden.
2
Tianjin Life Science Research Center and Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
3
Department of Clinical Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
4
Department of Reconstructive Plastic Surgery, Karolinska University Hospital, Stockholm, Sweden.

Abstract

Viruses can inhibit host autophagy through multiple mechanisms, and evasion of autophagy plays an important role in immune suppression and viral oncogenesis. Merkel cell polyomavirus (MCPyV) T-antigens are expressed and involved in the pathogenesis of a large proportion of Merkel cell carcinoma (MCC). Yet, how MCPyV induces tumorigenesis is not fully understood. Herein, we show that MCPyV T-antigens induce miR-375, miR-30a-3p and miR-30a-5p expressions, which target multiple key genes involved in autophagy, including ATG7, SQSTM1 (p62) and BECN1. In MCC tumors, low expression of ATG7 and p62 are associated with MCPyV-positive tumors. Ectopic expression of MCPyV small T-antigen and truncated large T-antigen (LT), but not the wild-type LT, resulted in autophagy suppression, suggesting the importance of autophagy evasion in MCPyV-mediated tumorigenesis. Torin-1 treatment induced cell death, which was attenuated by autophagy inhibitor, but not pan-caspase inhibitor, suggesting a potential role of autophagy in promoting cell death in MCC. Conceptually, our study shows that MCPyV oncoproteins suppress autophagy to protect cancer cells from cell death, which contribute to a better understanding of MCPyV-mediated tumorigenesis and potential MCC treatment.

KEYWORDS:

Merkel cell carcinoma; Merkel cell polyomavirus; autophagy; cell survival; microRNA

PMID:
31180579
DOI:
10.1002/ijc.32503

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