Molecular Inflammation Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, 9037 Tromsø, Norway.
Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institute, 17177 Stockholm, Sweden.
Int J Mol Sci. 2022 Mar 28;23(7):3702. doi: 10.3390/ijms23073702.
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.
默克尔细胞多瘤病毒（MCPyV）是默克尔细胞癌（MCC）的致病因素。其致癌潜能是通过其病毒癌蛋白大 T 抗原（LT）和小 T 抗原（sT）介导的。肿瘤细胞产生的细胞因子在癌症发病机制中起着重要作用，而病毒会影响它们的表达。因此，我们比较了病毒阳性（V+）和病毒阴性（V-）MCC 细胞系中人类细胞因子和受体转录本的水平。与 V-MCC-13 细胞相比，在 V+MCC 细胞系中观察到 IL-33 的表达增加，IL-33 是肿瘤微环境的有力调节剂。用荧光素酶报告质粒的瞬时转染研究表明，LT 和 sT 刺激 IL-33、ST2/IL1RL1 和 IL1RAcP 启动子活性。用 MCPyV LT 转染 MCC-13 细胞证实了 IL-33 表达的诱导。此外，重组人细胞因子域 IL-33 诱导 MAP 激酶和 NF-κB 途径的激活，这可以被 ST2 受体抗体阻断。免疫组织化学分析表明，与正常皮肤相比，MCC 组织中 IL-33、ST2 和 IL1RAcP 的表达明显更强。有趣的是，与健康对照组相比，MCC 患者血浆中 IL-33 和 IL1RAcP 蛋白水平明显更高。先前的研究已经证明了 IL-33/STL2 途径在癌症中的作用。因为我们的结果揭示了 T 抗原依赖性诱导的 IL-33/ST2 轴，IL-33/ST2 可能在 MCPyV 阳性 MCC 的肿瘤发生中起作用。因此，中和 IL-33/ST2 轴可能为 MCC 患者提供一种新的治疗方法。
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