Loss of gene function as a consequence of human papillomavirus DNA integration
Loss of gene function as a consequence of human papillomavirus DNA integration
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DOI：
10.1002/ijc.27433
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发表时间：
2012-09-01
影响因子：
6.4
通讯作者：
Duerst, Matthias
中科院分区：
文献类型：
--
作者：
Schmitz, Martina;Driesch, Corina;Duerst, Matthias
人乳头瘤病毒（HPV）基因组整合到宿主染色质中是宫颈癌发生过程中的一个标志性步骤。整合确保了驱动癌变的病毒癌基因E6和E7的组成性表达。然而，整合对宿主DNA也有影响。越来越多的证据表明，整合不仅发生在脆性位点和易位断点，也发生在转录活跃区域。事实上，大量的整合位点实际上会破坏宿主基因，从而可能影响基因表达。毫无疑问，即使基因表达的微小变化也可能影响细胞表型，但在活检材料中，小幅度的变化很难可靠地量化。因此，我们探讨了这样一个问题：基因功能的完全丧失，即插入突变与第二个等位基因的缺失或表观遗传修饰相结合，是否也是与宫颈癌相关的现象。在分析的10例预先选定的鳞状细胞癌中，所有病毒整合位点都位于已知基因的内含子序列内，产生了正义方向的病毒 - 细胞融合转录本。此外，对于两例肿瘤，我们提供了受HPV整合影响的基因完全功能丧失的证据。特别值得注意的是，其中一个涉及的基因是最近描述的新型肿瘤抑制基因蓖麻锌指蛋白1。尽管我们的研究没有提供功能证据表明受HPV整合影响的任何基因在转化过程中存在因果关系，但对插入突变在宫颈癌中的作用进行全面系统的研究似乎是有必要的。
Integration of the human papillomavirus (HPV) genome into the host chromatin is a characteristic step in cervical carcinogenesis. Integration ensures constitutive expression of the viral oncogenes E6 and E7 which drive carcinogenesis. However, integration has also an impact on host DNA. There is increasing evidence that integration not only occurs in fragile sites and translocation breakpoints but also in transcriptionally active regions. Indeed, a substantial number of integration sites actually disrupt host genes and may thereby affect gene expression. No doubt, even subtle changes in gene expression may influence the cell phenotype but small fold changes are difficult to quantify reliably in biopsy material. We have, therefore, addressed the question whether a complete loss of gene function that is insertional mutagenesis in combination with deletion or epigenetic modification of the second allele is also a phenomenon pertinent to cervical cancer. Out of the ten preselected squamous cell carcinomas analyzed, all viral integration sites were located within the intron sequences of known genes, giving rise to viralcellular fusion transcripts of sense orientation. Moreover, for two tumors, we provide evidence for complete functional loss of the gene affected by HPV integration. Of particular note is that one of the genes involved is the recently described novel tumor suppressor gene castor zinc finger 1. Although our study provides no functional proof that any of the genes affected by HPV integration are causally involved in the transformation process, an exhaustive systematic look at the role of insertional mutagenesis in cervical cancer appears to be warranted.