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Differentiation-Dependent Expression of the BCL-2 Proto-Oncogene in the Human Trophoblast Lineage

Departments of Obstetrics and Gynecology and Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Hiroya Matsuo, MD, PhD

Departments of Obstetrics and Gynecology and Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

George Coukos, MD, PhD

Departments of Obstetrics and Gynecology and Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Emma E. Furth, MD

Departments of Obstetrics and Gynecology and Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Mary P. Bronner, MD

Departments of Obstetrics and Gynecology and Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Cindy M. VanArsdale, MD

Departments of Obstetrics and Gynecology and Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Stanislaw Krajewsky, MD, PhD

Departments of Obstetrics and Gynecology and Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

John C. Reed, MD, PhD

Departments of Obstetrics and Gynecology and Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Jerome F. Strauss, MD, PhD

Departments of Obstetrics and Gynecology and Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania,

OBJECTIVE : We explored the role of the BCL-2 proto-oncogene in the life cycle of trophoblast cells by examining: 1) the patterns of BCL-2 expression in normal placenta at various gestational ages and in specimens of hydatidiform moles and choriocarcinomas, and 2) the effects of cyclic adenosine monophosphate (cAMP) treatment of JEG-3 choriocarcinoma cells, which induces differentiated functions, on BCL-2.

METHODS: BCL-2 protein was localized by indirect immunofluorescence and immunoperox idase staining of tissue sections and cells using monoclonal and polyclonal antibodies. Western and Northern blotting were used to assess BCL-2 and p53 protein and mRNA levels, respectively. JEG-3 cells were transfected with a BCL-2 expression plasmid to establish that BCL-2 protein could be expressed at high levels in this cell type.

RESULTS: BCL-2 immunostaining was most prominent in the syncytiotrophoblast of normal placenta. It was found in syncytiotrophoblast of complete and partial hydatidiform moles, whereas cytotrophoblast staining was weak. BCL-2 immunostaining was also barely detectable in chorio carcinoma cells (JEG-3 cells) and a primary choriocarcinoma. However, BCL-2 protein could be transiently overexpressed in JEG-3 cells by transfection with an expression plasmid. Western blot analysis revealed low levels of BCL-2 in JEG-3 cells and a rise in BCL-2 protein in placental extracts from 10 weeks' gestation to term. In contrast, p53 protein was abundant in JEG-3 cells and normal placenta at 10 weeks'gestation, but low at term. BCL-2 transcripts were substantially more abundant in term placenta than in JEG-3 cells. Treatment of JEG-3 cells with 8-Br-cAMP, which induces genes characteristic of the syncytiotrophoblast, raised BCL-2 protein approximately twofold, whereas p53 mRNA declined.

CONCLUSIONS: We conclude that: 1) There is a differentiation-dependent pattern of BCL-2 expression in the placenta, with the protein being most abundant in terminally differentiated trophoblast cells; 2) there appears to be an inverse relation between BCL-2 and p53 expression in trophoblast; and 3) cAMP regulates BCL-2 protein in trophoblast cells. We speculate that the expression of BCL-2 in terminally differentiated trophoblast cells, and hence resistance to apoptotic cell death, may be one mechanism by which trophoblast mass is preserved during pregnancy. Conversely, the relatively low expression of BCL-2 in choriocarcinoma cells may render them more susceptible to apoptosis. (J Soc Gynecol Invest 1994;1:164-72)

Key Words: Proto-oncogene • BCL-2 • apoptosis • trophoblast • choriocarcinoma.

Journal of the Society for Gynecologic Investigation, Vol. 1, No. 2, 164-172 (1994)
DOI: 10.1177/107155769400100212


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