Oncogenes and tumor angiogenesis: The HPV-16 E6 oncoprotein activates the vascular endothelial growth factor (VEGF) gene promoter in a p53 independent manner

• Published in: Oncogene Vol. 19; no. 40; pp. 4611 - 4620
• Main Authors: LOPEZ-OCEJO, Omar, VILORIA-PETIT, Alicia, BEQUET-ROMERO, Monica, MUKHOPADHYAY, Debabrata, RAK, Janusz, KERBEL, Robert S
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 21.09.2000; Nature Publishing Group
• Subjects: Angiogenesis; Autocrine Communication; Biological and medical sciences; c-Myc protein; Cancer; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Carcinoma, Squamous Cell - virology; Cell cycle; Cell growth; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cervical cancer; Cervix; Dysplasia; E6 gene; Endothelial cells; Endothelial Growth Factors - genetics; Endothelial Growth Factors - secretion; ErbB-2 protein; Female; Fundamental and applied biological sciences. Psychology; Genes, p53; Genetic engineering; Genomes; Health sciences; HeLa Cells - metabolism; HeLa Cells - secretion; HeLa Cells - virology; Human papillomavirus; human papillomavirus 16; Humans; Immortalization; Invasiveness; Keratinocytes; Keratinocytes - virology; Kinases; Lymphokines - genetics; Lymphokines - secretion; Molecular and cellular biology; Myc protein; Neoplasm Proteins - physiology; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - physiopathology; Oncogene Proteins, Viral - genetics; Oncogene Proteins, Viral - physiology; Oncogenes; Oncoproteins; p53 Protein; Papillomaviridae - genetics; Papillomaviridae - physiology; Papillomavirus Infections - pathology; Papillomavirus Infections - virology; Promoter Regions, Genetic; Proteins; Receptor, Epidermal Growth Factor - physiology; Recombinant Fusion Proteins - biosynthesis; Reporter gene; Repressor Proteins; Transcription; Transcription, Genetic; Transcriptional Activation; Transforming Growth Factor alpha - physiology; Tumor Cells, Cultured - metabolism; Tumor Cells, Cultured - secretion; Tumor Cells, Cultured - virology; Tumor Suppressor Protein p53 - physiology; Tumor Virus Infections - pathology; Tumor Virus Infections - virology; Tumors; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology; Uterine Cervical Neoplasms - virology; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Vulvar Neoplasms - metabolism; Vulvar Neoplasms - pathology; Vulvar Neoplasms - virology; Toronto Ontario Canada; Canada; Cuba; Human; Transcription promoter; p53 Protein; V-Onc gene; Papovaviridae; Uterine cervix; Gene expression; Carcinogenesis; Female genital diseases; Papillomavirus; Virus; Angiogenesis; Human papillomavirus 16; Human papillomavirus; Regulation(control); Vascular endothelium growth factor; Cell line; Gene; Tumor; Uterine cervix diseases; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1203817

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.