TY - JOUR
T1 - Oncogenes and tumor angiogenesis
T2 - The HPV-16 E6 oncoprotein activates the vascular endothelial growth factor (VEGF) gene promoter in a p53 independent manner
AU - López-Ocejo, Omar
AU - Viloria-Petit, Alicia
AU - Bequet-Romero, Mónica
AU - Mukhopadhyay, Debabrata
AU - Rak, Janusz
AU - Kerbel, Robert S.
N1 - Funding Information:
We are grateful to Dr Lawrence Banks for providing J4O16E6 and PJ4O plasmids. We gratefully thank Dr Larry Donehower and Dr Yaacov Ben-David for help in providing MEF p53+/+ and p537/7 cells. Dr Federico DeMarco's help in providing HPK1A cells is also highly appreciated. Ms Lynda Woodcock and Mrs Cassandra Cheng provided excellent secretarial assistance. This work was supported by grants from the Medical Research Council of Canada (MT-5815) and National Institutes of Health, USA (CA-41233) to RS Kerbel.
PY - 2000/9/21
Y1 - 2000/9/21
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Cervical cancer
KW - Oncogenes
KW - Tumor
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U2 - 10.1038/sj.onc.1203817
DO - 10.1038/sj.onc.1203817
M3 - Article
C2 - 11030150
AN - SCOPUS:0034699338
SN - 0950-9232
VL - 19
SP - 4611
EP - 4620
JO - Oncogene
JF - Oncogene
IS - 40
ER -