Merkel Cell Polyomavirus Small Tumor Antigen Activates Matrix Metallopeptidase-9 Gene Expression for Cell Migration and Invasion

Merkel cell polyomavirus (MCV) small T antigen (sT) is the main oncoprotein for the development of Merkel cell carcinoma (MCC). MCC is a rare, clinically aggressive neuroendocrine tumor of the skin with a high propensity for local, regional, and distant spread. The dysregulation of matrix metallopro...

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Bibliographic Details
Published inbioRxiv
Main Authors Nwogu, Nnenna, Ortiz, Luz E, Whitehouse, Adrian, Hyun Jin Kwun
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 13.05.2020
Subjects
ADAM protein
Antigens
Cell activation
Cell adhesion & migration
Cell migration
Gelatinase B
Gene expression
Invasiveness
Matrix metalloproteinase
Mesenchyme
Metastases
Neuroendocrine tumors
Phenotypes
Transcription activation
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Summary:Merkel cell polyomavirus (MCV) small T antigen (sT) is the main oncoprotein for the development of Merkel cell carcinoma (MCC). MCC is a rare, clinically aggressive neuroendocrine tumor of the skin with a high propensity for local, regional, and distant spread. The dysregulation of matrix metalloproteinase-9 (MMP-9) has been implicated in multiple essential roles in the development of various malignant tumor cell invasion and metastasis. Previously, MCV sT was shown to induce the migratory and invasive phenotype of MCC cells through the transcriptional activation of the Sheddase molecule, ADAM 10 (A disintegrin and metalloprotease domain-containing protein 10). In this study, we show that MCV sT protein stimulates differential expression of epithelial-mesenchymal transition (EMT) associated genes, including MMP-9 and Snail. This effect is dependent on the presence of the large T stabilization domain (LSD), which is known to be responsible for cell transformation through targeting of promiscuous E3 ligases, including FBW7, a known MMP-9 and Snail regulator. Chemical treatments of MMP-9 markedly inhibited sT-induced cell migration and invasion. These results suggest that MCV sT contributes to the activation of MMP-9 as a result of FBW7 targeting, and increases the invasive potential of cells, which can be used for targeted therapeutic intervention. Competing Interest Statement The authors have declared no competing interest. Footnotes * Introduction and Discussion sections updated; Figure 2 and 5 revised; author affiliations updated; Supplemental files updated.
DOI:10.1101/2020.03.02.974303