Stem cell related genes and malignant progression in gestational trophoblastic diseases

Abstract

Human germ cells and embryonic cells are similar to cancer cells from the view that both types of cell undergo deprogramming to a stem cell state and become potentially immortal and invasive. Cancer cells may thus express genes that are in common with those expressed in early embryonic cells, especially genes associated with deprogramming and resumption of the undifferentiated stem cell state. The development and malignant progression of gestational trophoblastic diseases, including hydatidiform moles and choriocarcinoma, may be associated with adoption of undifferentiated stem cell state by placental trophoblasts, with aberrant expression of the stem cell related genes. Oct4, Sox2, FoxD3, Stat3 and Nanog are important transcription factors of stem cells and c-mos is important in meiosis. The mRNA expression patterns of Oct-4, Sox2, FoxD3, Stat3 and Nanog were investigated using quantitative TaqMan real-time RT-PCR method on fresh frozen tissue of 15 hydatidiform moles and 15 first trimester normal placenta and two choriocarcinoma cell lines, JAR and JEG. The diagnosis in most of these cases has been confirmed by fluorescent microsatellite genotyping after microdissection and also with chromosome in situ hybridization to analyze the ploidy. TaqMan probes and primers were designed specific to these five genes. The real-time RT-PCR was performed on the ABI PRISM 7700 Sequence Detection System. The expression of the genes was normalized with respect to that of GADPH, a housekeeping gene. Immunohistochemical distribution of c-mos and Oct-4 using formalin-fixed, paraffin-embedded tissues was also performed in 45 hydatidiform moles, 17 choriocarcinomas, and five placental site trophoblastic tumors. A reduced RNA expression of Oct-4 (p=0.0002), Sox2 (p=0.27), FoxD3 (p=0.03), Stat3 (p=0.04) and Nanog (p=0.001) were found in hydatidiform moles when compared with normal placenta. Statistical significant difference was reached in four genes. The RNA expression of Stat3 in hydatidiform moles that regressed was higher than those that developed persistent gestational trophoblastic neoplasia requiring chemotherapy (p=0.033). C-mos expression was found predominantly in the syncytiotrophoblasts and villous intermediate trophoblasts but not in cytotrophoblasts. On the other hand, Oct-4 expression was found predominantly in cytotrophoblasts and villous intermediate trophoblasts while the expression was weak or absent in the syncytiotrophoblasts. These stem cell related genes may play a role in the pathogenesis of the gestational trophoblastic diseases and may even be a marker for predicting of clinical progression of hydatidiform moles.