Merkel cell polyomavirus oncoproteins induce microRNAs that suppress multiple autophagy genes
| Autor: | Catharina Larsson, Hong Xie, Weng-Onn Lui, Satendra Kumar, Viveca Björnhagen, Hao Shi, Linkiat Lee, C. Christofer Juhlin, Anders Höög, Jiwei Gao |
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| Rok vydání: | 2018 |
| Předmět: |
Cancer Research
Programmed cell death autophagy Skin Neoplasms Merkel cell polyomavirus medicine.disease_cause Autophagy-Related Protein 7 cell survival 03 medical and health sciences Molecular Cancer Biology 0302 clinical medicine Merkel cell carcinoma Cell Line Tumor Sequestosome-1 Protein medicine Humans Naphthyridines RNA Processing Post-Transcriptional Antigens Viral Tumor Polyomavirus Infections biology microRNA Autophagy BECN1 medicine.disease biology.organism_classification Carcinoma Merkel Cell MicroRNAs Tumor Virus Infections Oncology 030220 oncology & carcinogenesis Cancer cell Cancer research Ectopic expression Beclin-1 Macrolides Carcinogenesis |
| Zdroj: | International Journal of Cancer |
| ISSN: | 1097-0215 |
| Popis: | 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. What's new? About four‐fifths of Merkel cell carcinomas harbor the Merkel cell polyomavirus (MCPyV) genome, though mutations in viral T antigens generally render MCPyV replication‐deficient. Here, the authors describe a network by which MCPyV oncoproteins and viral‐regulated miRNAs hijack autophagy machinery in MCC. In cells, expression of MCPyV T‐antigens induced miR‐375, miR‐30a‐3p, and miR‐30a‐5p expression. Subsequent experiments validated these miRNAs as autophagy regulators that specifically target the genes ATG7, SQSTM1, and BECN1. Autophagy suppression protected MCC cell survival. This novel insight into the role of MCPyV and autophagy regulation in MCC may be relevant in the generation of future therapeutic strategies. |
| Databáze: | OpenAIRE |
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