Differential methylation of E2 binding sites in episomal and integrated HPV 16 genomes in preinvasive and invasive cervical lesions
Differential methylation of E2 binding sites in episomal and integrated HPV 16 genomes in preinvasive and invasive cervical lesions
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DOI：
10.1002/ijc.27906
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发表时间：
2013-05-01
影响因子：
6.4
通讯作者：
Doeberitz, Magnus von Knebel
中科院分区：
文献类型：
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作者：
Chaiwongkot, Arkom;Vinokurova, Svetlana;Doeberitz, Magnus von Knebel
HPV16E6-E7癌基因表达增强可能触发宫颈鳞状上皮细胞的肿瘤性转化。HPVE2蛋白是E6-E7基因的关键转录调控因子。它与病毒上游调节区(URR)中的四个E2结合位点(E2BS 14)结合。例如，通过E2BS的甲基化来修饰E2功能被认为是为了触发病毒E6-E7癌基因的增强表达。在大多数HPV转化的癌前病变和大约一半的宫颈癌中，HPV基因组保持在染色体外、异体状态，而在其余病变中，它们整合到宿主细胞的染色体中。在这里，我们比较了18例HPV16阳性癌前病变和33例浸润性宫颈癌中HPV16URR的E2BS 14的甲基化情况。与显示单一整合拷贝的病变相比，仅有上体HPV16基因组的所有病变中E2BSs1、3和4中的Cpg甲基化程度更高。具有多个HPV16整合拷贝的样本显示所有CPGS的甲基化水平都很高，这表明大多数多拷贝是由于广泛的甲基化而沉默的。这些数据支持这样的假设，即只要病毒基因组保持在上体状态，E2BSs1、3和4的差异甲基化与宫颈病变中病毒癌基因表达的激活有关。一旦病毒整合到宿主细胞染色体中，由于整合的HPV基因组的复杂表观遗传变化，这些甲基化模式可能会发生实质性变化。
Enhanced expression of the HPV 16 E6-E7 oncogenes may trigger neoplastic transformation of the squamous epithelial cells at the uterine cervix. The HPV E2 protein is a key transcriptional regulator of the E6-E7 genes. It binds to four E2 binding sites (E2BSs 14) in the viral upstream regulatory region (URR). Modification of E2 functions, for example, by methylation of E2BSs is hypothesized to trigger enhanced expression of the viral E6-E7 oncogenes. In the majority of HPV-transformed premalignant lesions and about half of cervical carcinomas HPV genomes persist in an extra-chromosomal, episomal state, whereas they are integrated into host cells chromosomes in the remaining lesions. Here we compared the methylation profile of E2BSs 14 of the HPV 16 URR in a series of 18 HPV16-positive premalignant lesions and 33 invasive cervical cancers. CpGs within the E2BSs 1, 3, and 4 were higher methylated in all lesions with only episomal HPV16 genomes compared with lesions displaying single integrated copies. Samples with multiple HPV16 integrated copies displayed high methylation levels for all CpGs suggesting that the majority of multiple copies were silenced by extensive methylation. These data support the hypothesis that differential methylation of the E2BSs 1, 3 and 4 is related to the activation of viral oncogene expression in cervical lesions as long as the viral genome remains in the episomal state. Once the virus becomes integrated into host cell chromosomes these methylation patterns may be substantially altered due to complex epigenetic changes of integrated HPV genomes.