Cellular sheddases are induced by Merkel cell polyomavirus small tumour antigen to mediate cell dissociation and invasiveness.
Cellular sheddases are induced by Merkel cell polyomavirus small tumour antigen to mediate cell dissociation and invasiveness.
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DOI：
10.1371/journal.ppat.1007276
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发表时间：
2018-09
期刊：
影响因子：
6.7
通讯作者：
Whitehouse A
中科院分区：
文献类型：
--
作者：
Nwogu N;Boyne JR;Dobson SJ;Poterlowicz K;Blair GE;Macdonald A;Mankouri J;Whitehouse A
默克尔细胞癌（MCC）是一种侵袭性皮肤癌，具有高复发和转移倾向。默克尔细胞多瘤病毒（MCPyV）被认为是大多数MCC病例的致病因素。MCPyV小肿瘤抗原（ST）被认为是主要的病毒转化因子，然而，将ST表达与MCC的高转移性联系起来的潜在机制尚未完全阐明。转移是一个复杂的过程，形成继发性肿瘤部位需要几个离散的步骤。支撑癌细胞转移能力的一个基本特征是它们如何与相邻的肿瘤细胞和周围的细胞外基质相互作用。在这里，我们证明了MCPyV ST表达破坏了细胞-细胞连接的完整性，从而增强了细胞解离，并在此过程中涉及细胞脱落酶，A解整合素和金属蛋白酶（ADAM）10和17蛋白。ADAM 10和17活性的抑制降低了MCPyV ST诱导的细胞解离和运动性，将其功能归因于MCPyV诱导的转移过程的关键。与这些数据一致，我们证实ADAM 10和17在MCPyV阳性原发性MCC肿瘤中上调。这些新的发现暗示细胞脱落酶作为关键的宿主细胞因子，有助于病毒介导的细胞转化和转移。值得注意的是，ADAM蛋白表达可能是MCC预后的新生物标志物，并且鉴于目前对用于癌症治疗的细胞脱落酶抑制剂的兴趣，它突出了ADAM 10和17活性作为针对播散性MCC的靶向干预的新机会。大多数癌症相关死亡是由于转移性疾病。因此，了解转移过程的分子和细胞机制对于开发新的治疗干预措施以提高癌症患者的生存率至关重要。默克尔细胞癌（MCC）是一种侵袭性和高转移性癌症。默克尔细胞多瘤病毒（MCPyV）已被认为是大多数MCC病例的病原体。MCPyV小肿瘤抗原（ST）被认为是主要的癌蛋白。然而，关于MCPyV ST可能涉及导致MCC肿瘤中观察到的高转移扩散率的机制知之甚少。在这里，我们表明，特定的细胞脱落酶，即解整合素和金属蛋白酶（ADAM）10和17蛋白水平增加后，MCPyV ST表达。此外，我们表明，MCPyV ST诱导的ADAM 10和17需要破坏细胞-细胞连接，导致细胞解离，迁移和侵袭增加。因此，ADAM蛋白表达可能提供MCC预后的新生物标志物。此外，将细胞脱落酶与MCPyV阳性MCC转移相关联可提供新的治疗干预。
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. The majority of cancer-related deaths occur due to metastatic disease. Therefore, understanding the molecular and cellular mechanisms underlying the process of metastasis is essential to developing new therapeutic interventions to improve cancer patient survival. Merkel cell carcinoma (MCC) is an aggressive and highly metastatic cancer. Merkel cell polyomavirus (MCPyV) has been implicated as the causative agent in the majority of MCC cases. The MCPyV small tumour antigen (ST) is believed to function as the major oncoprotein. However, little is known about the mechanisms through which MCPyV ST may be implicated in causing the high rates of metastatic spread observed in MCC tumours. Here we show that specific cellular sheddases, namely A disintegrin and metalloproteinase (ADAM) 10 and 17 protein levels are increased upon MCPyV ST expression. Moreover, we show that MCPyV ST-induced ADAM 10 and 17 are required to breakdown cell-cell junctions resulting in increased cell dissociation, migration and invasion. As such, ADAM protein expression may provide a novel biomarker of MCC prognosis. In addition, linking cellular sheddases to MCPyV-positive MCC metastasis may provide novel therapeutic interventions.
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影响因子：
6.7
作者：
Berrios C;Padi M;Keibler MA;Park DE;Molla V;Cheng J;Lee SM;Stephanopoulos G;Quackenbush J;DeCaprio JA
通讯作者：
DeCaprio JA
影响因子：
3.8
作者：
Duffy MJ;Mullooly M;O'Donovan N;Sukor S;Crown J;Pierce A;McGowan PM
通讯作者：
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影响因子：
11.2
作者：
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通讯作者：
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影响因子：
10.6
作者：
Edwards DR;Handsley MM;Pennington CJ
通讯作者：
Pennington CJ
影响因子：
4.2
作者：
Giebeler N;Zigrino P
通讯作者：
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