Department of Dermatology, McGovern Medical School at University of Texas Health Science Center, Houston, Texas, USA.
Baylor College of Medicine, Houston, Texas, USA.
Intervirology. 2019;62(2):96-100. doi: 10.1159/000501419. Epub 2019 Aug 9.
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cancer of the skin with high rates of metastasis and mortality. Besides well-established factors including genetic mutations and UV-induced DNA damage in Merkel cell carcinogenesis, the recent discovery of the Merkel cell polyomavirus (MCPyV) has shed light on the viral etiology of MCC. In the current study, we provide novel evidence that MCPyV small T (sT) antigen induces the DNA damage response (DDR) pathway. Our data show that in human MCC cells, the presence of MCPyV is associated with hyperphosphorylation of histone H2AX, a marker for DNA damage. We observed that overexpression of MCPyV sT antigen induced the phosphorylation of histone H2AX as well as the activation of ataxia telangiectasia mutant (ATM), an upstream kinase important for H2AX phosphorylation. Moreover, we observed that MCPyV sT expression also induced the hyperphosphorylation of other ATM downstream molecules (including 53BP1 and CHK2) as well as the hypermethylation of histone 3 and histone 4. These findings disclose a novel link between MCPyV sT and the DDR pathway in MCC. Given that measurement of DDR is clinically useful for evaluating treatment response to radio- and chemotherapy, our findings warrant further investigation to evaluate the potential implications of this pathway for MCC management.
默克尔细胞癌（Merkel cell carcinoma，MCC）是一种侵袭性的皮肤神经内分泌癌，具有很高的转移率和死亡率。除了在 Merkel 细胞癌发生中已确立的遗传突变和 UV 诱导的 DNA 损伤等因素外，Merkel 细胞多瘤病毒（Merkel cell polyomavirus，MCPyV）的最近发现揭示了 MCC 的病毒病因。在本研究中，我们提供了新的证据表明 MCPyV 小 T（small T，sT）抗原诱导 DNA 损伤反应（DNA damage response，DDR）途径。我们的数据表明，在人 Merkel 细胞癌细胞中，MCPyV 的存在与组蛋白 H2AX 的过度磷酸化有关，H2AX 是 DNA 损伤的标志物。我们观察到，MCPyV sT 抗原的过表达诱导了组蛋白 H2AX 的磷酸化以及共济失调毛细血管扩张突变（ataxia telangiectasia mutant，ATM）的激活，ATM 是 H2AX 磷酸化的重要上游激酶。此外，我们观察到 MCPyV sT 表达还诱导了 ATM 下游其他分子（包括 53BP1 和 CHK2）的过度磷酸化以及组蛋白 3 和组蛋白 4 的过度甲基化。这些发现揭示了 MCPyV sT 与 MCC 中 DDR 途径之间的新联系。鉴于 DDR 的测量对于评估放射和化学疗法的治疗反应具有临床意义，我们的发现值得进一步研究，以评估该途径对 MCC 管理的潜在意义。
