Regulation of NM23 gene expression in the normal and malignant trophoblast by growth factors

Abstract

Summary nm23-H1 is a nucleoside diphosphate kinase with a functional role in the microtubular assembly and disassembly during cell proliferation and in G-protein dependent signal transduction. Gene expression for this kinase has been reported to be inversely correlated with metastatic ability of tumor cells. Normal trophoblast cells are highly invasive but non-metastatic. Numerous growth factors, e.g., TGF-α, EGF, TGF-β, and CSF-1, present at the fetomaternal interface, influence trophoblast functions such as proliferation, differentiation, and invasion. In this study, we investigated the influence of the above growth factors on nm23-H1 mRNA expression by first trimester normal trophoblast and two choriocarcinoma cell lines, JAr and JEG-3. The expression was found to be abundant in the normal trophoblast as well as choriocarcinomas, indicating that this expression was not suppressed in malignant trophoblast cells. We found that growth factors (e.g., TGFα, EGF, and CSF-1) which stirnulate normal trophoblast proliferation also stimulated nm23-H1 expression in the normal trophoblast indicating that the expression may be coupled with cell proliferation. A stimulatory effect noted with a neutralizing anti-TGF-β antibody can also be explained on the basis of stimulation of trophoblast proliferation due to removal of the anti-proliferative action of endogenous TGF-β. The expression of nm23H-1 in choriocarcinoma cells was unaltered by the growth factors except for some stimulation of JEG-3 cells noted with TGF-β. Since anti-TGF-β Ab also stimulated the expression in JEG-3 cells, we propose that TGF-β may have a dual influence in this case, one related to signal transduction, another to its anti-proliferation.