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MCPyV Large T Antigen-Induced Atonal Homolog 1 Is a Lineage-Dependency Oncogene in Merkel Cell Carcinoma.
Journal of Investigative Dermatology ( IF 5.7 ) Pub Date : 2019-07-05 , DOI: 10.1016/j.jid.2019.06.135
Kaiji Fan 1 , Jan Gravemeyer 2 , Cathrin Ritter 2 , Kashif Rasheed 3 , Thilo Gambichler 4 , Ugo Moens 3 , Masahiro Shuda 5 , David Schrama 6 , Jürgen C Becker 7
Affiliation  

Despite the fact that the transcription factor ATOH1 is a master regulator of Merkel cell development, its role in Merkel cell carcinoma (MCC) carcinogenesis remains controversial. Here, we provide several lines of evidence that ATOH1 is a lineage-dependent oncogene in MCC. Luciferase assays revealed binding of ATOH1 and subsequent activation to the promoter of miR-375, which is one of the most abundant microRNAs in MCCs. Overexpression of ATOH1 in variant MCC cell lines and fibroblasts induced miR-375 expression, whereas ATOH1 knockdown in classical MCC cell lines reduced miR-375 expression. Moreover, ATOH1 overexpression in these cells changed their growth characteristics from adherent to suspension and/orspheroidal growth, that is, resembling the neuroendocrine growth pattern of classical MCC cell lines. Notably, ectopic expression of different Merkel cell polyomavirus (MCPyV)-derived truncated large T antigens induced ATOH1 expression in fibroblasts, which was paralleled by miR-375 expression and similar morphologic changes. In summary, MCPyV-associated carcinogenesis is likely to induce the characteristic neuroendocrine features of MCC via induction of ATOH1; thus, ATOH1 can be regarded as a lineage-dependent oncogene in MCC.

中文翻译:

MCPyV大T抗原诱导的非同源性同源物1是默克尔细胞癌中的谱系依赖性致癌基因。

尽管转录因子ATOH1是默克尔细胞发育的主要调节因子,但其在默克尔细胞癌(MCC)癌变中的作用仍然存在争议。在这里,我们提供了一些证据,表明ATOH1是MCC中依赖于谱系的致癌基因。萤光素酶测定揭示了ATOH1的结合并随后激活了miR-375的启动子,miR-375是MCC中最丰富的microRNA之一。在变体MCC细胞系和成纤维细胞中ATOH1的过表达诱导miR-375表达,而经典MCC细胞系中ATOH1的敲低降低了miR-375的表达。此外,这些细胞中ATOH1的过度表达将其生长特性从粘附性变为悬浮和/或类球体生长,即类似于经典MCC细胞系的神经内分泌生长模式。尤其,异源于默克尔细胞多瘤病毒(MCPyV)的截短大T抗原的异位表达诱导了成纤维细胞中ATOH1的表达,这与miR-375的表达和相似的形态学变化平行。总之,与MCPyV相关的癌变可能通过诱导ATOH1诱导MCC的特征性神经内分泌特征。因此,ATOH1可被视为MCC中的谱系依赖性致癌基因。
更新日期:2019-12-19
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