Crucial cross-talk of interleukin-1β and progesterone in human choriocarcinoma

Abstract

Abstract. Choriocarcinoma is a highly malignant epithelial tumour that is most often associated with hydatidiform mole and presents the most common emergency medical problem in the management of trophoblast disease. We hypothesise that the hormones/cytokines present within the tumour microenvironment play key roles in the development of choriocarcinoma. In this study we assessed the effects of interleukin-1β (IL-1β) on cell death in the presence or absence of the sex hormone progesterone using two choriocarcinoma cell lines (BeWo and JEG-3) as in vitro experimental models. Although IL-1β induced cell death in both cell lines, the effect was more pronounced in JEG-3 cells, where cell death reached 40% compared to 15% in BeWo cells. Cell death of JEG-3 cells in response to IL-1β was significantly decreased by co-treatment with 100 nM and 1000 nM progesterone and completely abolished at a progesterone concentration of 1000 nM. Progesterone was also able to induce phosphorylation of ERK 1/2 in these cells. Pretreatment of JEG-3 cells with a specific MAPK inhibitor (UO126) inhibited progesterone's inhibitory effect on cell death. Collectively, these data provide evidence of cross-talk between progesterone and IL-1β in this aggressive and poorly understood tumour that involves activation of a MAPK pathway and involvement of numerous progesterone receptors. IntroductionGestational trophoblastic tumors are a group of diseases in which cancer (malignant) cells grow in the tissues that are formed following conception. They span from a benign hydatidiform mole, through an invasive mole to a highly malignant form of choriocarcinoma. Choriocarcinoma is malignant (both histologically and clinically) and is one of the most frequent emergency medical issues in the management disease of trophoblastic origin. The clinical symptoms vary, ranging from bleeding when the disease is localized in the uterus to a diverse repertoire of symptoms from metastases with the central nervous system, lungs, and liver the most frequent sites of secondary tumour formation. Therefore, choriocarcinomas present certain diagnostic challenges (1).Gestational choriocarcinoma is a highly malignant epithelial tumour that is most often associated with hydatidiform mole. On the occasions that pathology is available the characteristic findings exhibit the structure of the villous trophoblast but with sheets of syncytiotrophoblast or cytotrophoblast cells, haemorrhage, necrosis and intravascular growth are also common. A number of studies have shown involvement of certain tumourassociated genes in choriocarcinoma (1). For example, p53 oncoprotein immunoreactivity was significantly stronger in choriocarcinoma than in normal placenta (2). Studies from the same group revealed that c-myc, c-erbB-2, c-fms and bcl-2 oncoproteins may be important in the pathogenesis of complete mole and choriocarcinoma since they appear to be overexpressed in this aggressive tumour (3). The cellular mdm2 gene, which has a potential transforming activity that can be activated by over...

The Attenuation of Trophoblast Invasion Caused by the Downregulation of EZH2 Is Involved in the Pathogenesis of Human Recurrent Miscarriage

“…Our work indicated that progesterone could activate the ERK1/2 pathway and, thus, significantly increase the expression of EZH2 accompanied with the decreased level of CDX1, but not the PI3K/AKT signaling pathway. This is in accordance with the results that report that progesterone is able to induce phosphorylation of ERK1/2 in two choriocarcinoma cell lines (BeWo and JEG-3) 49 and is consistent with the reports demonstrating that the phosphorylation of EZH2 at serine 21 suppresses its methyltransferase activity responsible for H3-K27 trimethylation 50, 51. The decreased expression of EZH2 in women with RM provides new insights into the epigenetic mechanisms underlying the pathogenesis of RM and paves new avenues for the development of novel therapeutics.…”

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