Oncogenes and tumor angiogenesis: the HPV-16 E6 oncoprotein activates the vascular endothelial growth factor (VEGF) gene promoter in a p53 independent manner.
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.
López-Ocejo
O
O
Vaccine Division, Centre for Genetic Engineering and Biotechnology, Havana, Cuba.
Viloria-Petit
A
A
Bequet-Romero
M
M
Mukhopadhyay
D
D
Rak
J
J
Kerbel
R S
RS
D019898:Autocrine Communication; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000821:virology; D016228:Endothelial Growth Factors / Q000235:genetics* / Q000378:metabolism; D066246:ErbB Receptors / Q000502:physiology; D005260:Female; D016158:Genes, p53; D006367:HeLa Cells / Q000378:metabolism / Q000821:virology; D006801:Humans; D015603:Keratinocytes / Q000821:virology; D008222:Lymphokines / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000503:physiopathology; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000502:physiology*; D027383:Papillomaviridae / Q000235:genetics* / Q000502:physiology; D030361:Papillomavirus Infections / Q000473:pathology / Q000821:virology; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012097:Repressor Proteins; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016211:Transforming Growth Factor alpha / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000821:virology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D014412:Tumor Virus Infections / Q000473:pathology / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014846:Vulvar Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology
C068651:E6 protein, Human papillomavirus type 16; D016228:Endothelial Growth Factors; D008222:Lymphokines; D009363:Neoplasm Proteins; D009856:Oncogene Proteins, Viral; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D016211:Transforming Growth Factor alpha; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D066246:ErbB Receptors