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

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.

• Authors: Satendra Kumar, Hong Xie, Hao Shi, Jiwei Gao, Carl Christofer Juhlin, Viveca Björnhagen, Anders Höög, Linkiat Lee, Catharina Larsson, Weng-Onn Lui
• Journal: International journal of cancer (Int J Cancer) Vol. 146 Issue 6 Pg. 1652-1666 (03 15 2020) ISSN: 1097-0215 [Electronic] United States
• PMID: 31180579 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

Chemical References

• 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one
• Antigens, Viral, Tumor
• BECN1 protein, human
• Beclin-1
• Macrolides
• MicroRNAs
• Naphthyridines
• SQSTM1 protein, human
• Sequestosome-1 Protein
• bafilomycin A
• ATG7 protein, human
• Autophagy-Related Protein 7

Topics

• Antigens, Viral, Tumor (metabolism)
• Autophagy (drug effects, genetics)
• Autophagy-Related Protein 7 (biosynthesis, genetics)
• Beclin-1 (biosynthesis, genetics)
• Carcinoma, Merkel Cell (drug therapy, genetics, pathology, virology)
• Cell Line, Tumor
• Humans
• Macrolides (pharmacology)
• Merkel cell polyomavirus (metabolism)
• MicroRNAs (biosynthesis, genetics, metabolism)
• Naphthyridines (pharmacology)
• Polyomavirus Infections (genetics, metabolism, pathology, virology)
• RNA Processing, Post-Transcriptional
• Sequestosome-1 Protein (biosynthesis, genetics)
• Skin Neoplasms (drug therapy, genetics, pathology, virology)
• Tumor Virus Infections (genetics, metabolism, pathology, virology)