The Merkel Cell Polyomavirus T-Antigens and IL-33/ST2-IL1RAcP Axis: Possible Role in Merkel Cell Carcinoma
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 th...
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| Format: | Article |
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MDPI AG
2022-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/7/3702 |
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| author | Kashif Rasheed Ugo Moens Benedetta Policastro John Inge Johnsen Virve Koljonen Harri Sihto Weng-Onn Lui Baldur Sveinbjørnsson |
| author_facet | Kashif Rasheed Ugo Moens Benedetta Policastro John Inge Johnsen Virve Koljonen Harri Sihto Weng-Onn Lui Baldur Sveinbjørnsson |
| author_sort | Kashif Rasheed |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T11:46:56Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T11:46:56Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-dd2f043603034a0b89f26e3437d27af42023-11-30T23:20:49ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-03-01237370210.3390/ijms23073702The Merkel Cell Polyomavirus T-Antigens and IL-33/ST2-IL1RAcP Axis: Possible Role in Merkel Cell CarcinomaKashif Rasheed0Ugo Moens1Benedetta Policastro2John Inge Johnsen3Virve Koljonen4Harri Sihto5Weng-Onn Lui6Baldur Sveinbjørnsson7Molecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsø, NorwayMolecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsø, NorwayMolecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsø, NorwayChildhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institute, 17177 Stockholm, SwedenDepartment of Plastic Surgery, University of Helsinki and Helsinki University Hospital, 00280 Helsinki, FinlandDepartment of Pathology, University of Helsinki, 00100 Helsinki, FinlandDepartment of Oncology-Pathology, Karolinska Institute, BioClinicum, Karolinska University Hospital, 17164 Solna, SwedenMolecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsø, NorwayMerkel 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.https://www.mdpi.com/1422-0067/23/7/3702cytokinesIL-33Merkel cell carcinomainflammationST2/IL1RL1IL1RAcP |
| spellingShingle | Kashif Rasheed Ugo Moens Benedetta Policastro John Inge Johnsen Virve Koljonen Harri Sihto Weng-Onn Lui Baldur Sveinbjørnsson The Merkel Cell Polyomavirus T-Antigens and IL-33/ST2-IL1RAcP Axis: Possible Role in Merkel Cell Carcinoma International Journal of Molecular Sciences cytokines IL-33 Merkel cell carcinoma inflammation ST2/IL1RL1 IL1RAcP |
| title | The Merkel Cell Polyomavirus T-Antigens and IL-33/ST2-IL1RAcP Axis: Possible Role in Merkel Cell Carcinoma |
| title_full | The Merkel Cell Polyomavirus T-Antigens and IL-33/ST2-IL1RAcP Axis: Possible Role in Merkel Cell Carcinoma |
| title_fullStr | The Merkel Cell Polyomavirus T-Antigens and IL-33/ST2-IL1RAcP Axis: Possible Role in Merkel Cell Carcinoma |
| title_full_unstemmed | The Merkel Cell Polyomavirus T-Antigens and IL-33/ST2-IL1RAcP Axis: Possible Role in Merkel Cell Carcinoma |
| title_short | The Merkel Cell Polyomavirus T-Antigens and IL-33/ST2-IL1RAcP Axis: Possible Role in Merkel Cell Carcinoma |
| title_sort | merkel cell polyomavirus t antigens and il 33 st2 il1racp axis possible role in merkel cell carcinoma |
| topic | cytokines IL-33 Merkel cell carcinoma inflammation ST2/IL1RL1 IL1RAcP |
| url | https://www.mdpi.com/1422-0067/23/7/3702 |
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