Cellular sheddases are induced by Merkel cell polyomavirus small tumour antigen to mediate cell dissociation and invasiveness

Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high propensity for recurrence and metastasis. Merkel cell polyomavirus (MCPyV) is recognised as the causative factor in the majority of MCC cases. The MCPyV small tumour antigen (ST) is considered to be the main viral transforming factor, however potential mechanisms linking ST expression to the highly metastatic nature of MCC are yet to be fully elucidated. Metastasis is a complex process, with several discrete steps required for the formation of secondary tumour sites. One essential trait that underpins the ability of cancer cells to metastasise is how they interact with adjoining tumour cells and the surrounding extracellular matrix. Here we demonstrate that MCPyV ST expression disrupts the integrity of cell-cell junctions, thereby enhancing cell dissociation and implicate the cellular sheddases, A disintegrin and metalloproteinase (ADAM) 10 and 17 proteins in this process. Inhibition of ADAM 10 and 17 activity reduced MCPyV ST-induced cell dissociation and motility, attributing their function as critical to the MCPyV-induced metastatic processes. Consistent with these data, we confirm that ADAM 10 and 17 are upregulated in MCPyV-positive primary MCC tumours. These novel findings implicate cellular sheddases as key host cell factors contributing to virus-mediated cellular transformation and metastasis. Notably, ADAM protein expression may be a novel biomarker of MCC prognosis and given the current interest in cellular sheddase inhibitors for cancer therapeutics, it highlights ADAM 10 and 17 activity as a novel opportunity for targeted interventions for disseminated MCC.默克尔细胞癌（Merkel cell carcinoma, MCC）是一种侵袭性皮肤癌，具有极高的复发与转移倾向。默克尔细胞多瘤病毒（Merkel cell polyomavirus, MCPyV）被认为是绝大多数MCC病例的致病因素。MCPyV编码的小肿瘤抗原（small tumour antigen, ST）被视为主要的病毒转化因子，但将ST表达与MCC高转移特性联系起来的潜在机制仍有待全面阐明。转移是一个复杂的多阶段过程，需历经多个离散步骤方可形成继发肿瘤病灶。癌细胞具备转移能力的核心特征之一，在于其与邻近肿瘤细胞及周围细胞外基质的相互作用模式。本研究证实，MCPyV ST的表达会破坏细胞间连接的完整性，进而增强细胞解离能力，并明确细胞脱落酶——解整合素金属蛋白酶（A disintegrin and metalloproteinase, ADAM）10与17参与了这一过程。抑制ADAM10和ADAM17的活性可减轻MCPyV ST诱导的细胞解离与细胞运动能力，证实二者在MCPyV介导的转移过程中发挥关键作用。与上述实验结果一致，我们验证了MCPyV阳性的原发性MCC肿瘤中ADAM10与ADAM17的表达水平显著上调。这些全新发现表明，细胞脱落酶作为关键宿主细胞因子，参与了病毒介导的细胞转化与转移过程。值得注意的是，ADAM蛋白的表达或可作为MCC预后的新型生物标志物；鉴于当前针对细胞脱落酶抑制剂用于癌症治疗的研究热度，本研究也提示，靶向ADAM10与ADAM17的活性可为播散性MCC的干预治疗提供全新思路。