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Article

The Merkel Cell Polyomavirus T-Antigens and IL-33/ST2-IL1RAcP Axis: Possible Role in Merkel Cell Carcinoma

1
Molecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsø, Norway
2
Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institute, 17177 Stockholm, Sweden
3
Department of Plastic Surgery, University of Helsinki and Helsinki University Hospital, 00280 Helsinki, Finland
4
Department of Pathology, University of Helsinki, 00100 Helsinki, Finland
5
Department of Oncology-Pathology, Karolinska Institute, BioClinicum, Karolinska University Hospital, 17164 Solna, Sweden
*
Author to whom correspondence should be addressed.
Present address: Institute for Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
Academic Editor: Rocco Cappellesso
Int. J. Mol. Sci. 2022, 23(7), 3702; https://doi.org/10.3390/ijms23073702
Received: 4 February 2022 / Revised: 18 March 2022 / Accepted: 21 March 2022 / Published: 28 March 2022
(This article belongs to the Special Issue Role of Signaling Pathways in the Viral Life Cycle 2.0)
Merkel cell polyomavirus (MCPyV) is a causal factor in Merkel cell carcinoma (MCC). The oncogenic potential is mediated through its viral oncoproteins large T-antigen (LT) and small T-antigen (sT). Cytokines produced by tumor cells play an important role in cancer pathogenesis, and viruses affect their expression. Therefore, we compared human cytokine and receptor transcript levels in virus positive (V+) and virus negative (V−) MCC cell lines. Increased expression of IL-33, a potent modulator of tumor microenvironment, was observed in V+ MCC cell lines when compared to V− MCC-13 cells. Transient transfection studies with luciferase reporter plasmids demonstrated that LT and sT stimulated IL-33, ST2/IL1RL1 and IL1RAcP promoter activity. The induction of IL-33 expression was confirmed by transfecting MCC-13 cells with MCPyV LT. Furthermore, recombinant human cytokine domain IL-33 induced activation of MAP kinase and NF-κB pathways, which could be blocked by a ST2 receptor antibody. Immunohistochemical analysis demonstrated a significantly stronger IL-33, ST2, and IL1RAcP expression in MCC tissues compared to normal skin. Of interest, significantly higher IL-33 and IL1RAcP protein levels were observed in MCC patient plasma compared to plasma from healthy controls. Previous studies have demonstrated the implication of the IL-33/STL2 pathway in cancer. Because our results revealed a T-antigens-dependent induction of the IL-33/ST2 axis, IL-33/ST2 may play a role in the tumorigenesis of MCPyV-positive MCC. Therefore, neutralizing the IL-33/ST2 axis may present a novel therapeutic approach for MCC patients. View Full-Text
Keywords: cytokines; IL-33; Merkel cell carcinoma; inflammation; ST2/IL1RL1; IL1RAcP; tumor microenvironment cytokines; IL-33; Merkel cell carcinoma; inflammation; ST2/IL1RL1; IL1RAcP; tumor microenvironment
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MDPI and ACS Style

Rasheed, K.; Moens, U.; Policastro, B.; Johnsen, J.I.; Koljonen, V.; Sihto, H.; Lui, W.-O.; Sveinbjørnsson, B. The Merkel Cell Polyomavirus T-Antigens and IL-33/ST2-IL1RAcP Axis: Possible Role in Merkel Cell Carcinoma. Int. J. Mol. Sci. 2022, 23, 3702. https://doi.org/10.3390/ijms23073702

AMA Style

Rasheed K, Moens U, Policastro B, Johnsen JI, Koljonen V, Sihto H, Lui W-O, Sveinbjørnsson B. The Merkel Cell Polyomavirus T-Antigens and IL-33/ST2-IL1RAcP Axis: Possible Role in Merkel Cell Carcinoma. International Journal of Molecular Sciences. 2022; 23(7):3702. https://doi.org/10.3390/ijms23073702

Chicago/Turabian Style

Rasheed, Kashif, Ugo Moens, Benedetta Policastro, John Inge Johnsen, Virve Koljonen, Harri Sihto, Weng-Onn Lui, and Baldur Sveinbjørnsson. 2022. "The Merkel Cell Polyomavirus T-Antigens and IL-33/ST2-IL1RAcP Axis: Possible Role in Merkel Cell Carcinoma" International Journal of Molecular Sciences 23, no. 7: 3702. https://doi.org/10.3390/ijms23073702

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