Oncogenes and tumor angiogenesis:: the HPV-16 E6 oncoprotein activates the vascular endothelial growth factor (VEGF) gene promoter in a p53 independent manner
Oncogenes and tumor angiogenesis:: the HPV-16 E6 oncoprotein activates the vascular endothelial growth factor (VEGF) gene promoter in a p53 independent manner
复制标题
DOI：
10.1038/sj.onc.1203817
复制
发表时间：
2000-09-21
期刊：
影响因子：
8
通讯作者：
Kerbel, RS
中科院分区：
文献类型：
--
作者：
López-Ocejo, O;Viloria-Petit, A;Kerbel, RS
与其他类型的癌前病变和癌一样，血管生成与高度宫颈发育不良和宫颈的浸润性鳞状细胞癌相关。已知血管内皮细胞生长因子（VEGF）是血管生成的最重要诱导物之一，并且在宫颈癌中上调。人乳头瘤病毒16（HPV-16）在病因学上与人宫颈癌相关，HVP-16 E6和E7蛋白参与了靶细胞的永生化过程。由于突变型ras、EGF受体、ErbB 2/Her 2、c-myc和v-src等癌基因上调VEGF表达，我们想知道HVP-16 E6蛋白是否也能以类似的方式发挥作用。我们发现HPV-16 E6阳性细胞通常表达高水平的VEGF信息。此外，VEGF启动子-Luc（荧光素酶）报告基因与E6在人角质形成细胞和小鼠成纤维细胞中的共表达表明，E6癌蛋白上调VEGF启动子活性，并且以不依赖于p53的方式进行。在VEGF启动子的-194 ~-50 bp之间存在一个E6反应区，它包含4个Sp-1位点，也是组成性VEGF转录所必需的。综上所述，我们的结果提示HPV癌蛋白E6可能通过直接刺激VEGF基因而促进肿瘤血管生成。
Like other types of pre-malignant lesions and carcinoma, angiogenesis is associated with high-grade cervical dysplasia and with invasive squamous carcinoma of the cervix, Vascular endothelial cell growth factor (VEGF) is known to be one of the most important inducers of angiogenesis and is upregulated in carcinoma of the cervix, Human Papilloma Virus 16 (HPV-16) has been etiologically linked to human cervical cancer, and the major oncogenic proteins encoded by the viral genome, E6 and E7, are involved in the immortalization of target cells, Because several oncogenes including mutant ras, EGF receptor, ErbB2/Her2, c-myc and v-src upregulate VEGF expression, we asked whether HVP-16 E6 oncoprotein could act in a similar fashion. We found that HPV-16 E6-positive cells generally express high levels of VEGF message. Furthermore, co-expression of the VEGF promoter-Luc (luciferase) reporter gene with E6 in both human keratinocytes and mouse fibroblast showed that E6 oncoprotein upregulates VEGF promoter activity, and does so in a p53 independent manner. An E6 responsive region which comprises four Sp-1 sites, between -194 and -50 bp of the VEGF promoter, is also necessary for constitutive VEGF transcription, Taken together, our results suggest the possibility that the HPV oncoprotein E6 may contribute to tumor angiogenesis by direct stimulation of the VEGF gene.