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Angiogenesis, Metastasis, and the Cellular Microenvironment

Defective 3A Trophoblast-Endometrial Cell Adhesion and Altered 3A Growth and Survival by Human Papillomavirus Type 16 Oncogenes¹

Departments of ¹ Obstetrics and Gynecology and ² Emergency Medicine, University of Arkansas for Medical Sciences, Little Rock, AR

Requests for reprints: Paul L. Hermonat, Department of Obstetrics and Gynecology, Slot 518, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205. Phone: (501) 686-5046; Fax: (501) 686-5784. E-mail: Hermonatpaull{at}uams.edu

Human papillomaviruses (HPVs) are found in trophoblasts of spontaneous abortions and replicate in these cells in culture. We used recombinant adeno-associated viruses (rAAV) to introduce the HPV-16 E6 and E7 oncogenes into 3A trophoblasts. AAV/E7/Neo-infected 3A trophoblasts died rapidly, but AAV/E6/Neo- and AAV/E6-E7/Neo-infected cells grew more rapidly than AAV/Neo-infected 3A cells and parental 3A. After G418 selection, the resulting E6-E7/3A and E6/3A cell lines were found to be highly defective for binding RL95 and HEC endometrial cells compared to Neo/3A and parental 3A. Serum requirements and soft agar colony formation analysis showed that E6-E7/3A had the most malignant phenotype, followed by E6/3A, with parental 3A cells having the lowest. E6/3A and E6-E7/3A were also immortal. Thus, HPV-16 oncogene expression may lead to outright trophoblast death, defective endometrial cell recognition, or a malignant phenotype. Any of these changes might lead to disruption/dysfunction of the trophoblast layer/gestational loss.

Key Words: trophoblast • human papillomavirus • E7 • E6 • endometrial cell • adeno-associated virus