Choriocarcinoma is a highly aggressive tumor that develops from germ cells. Some choriocarcinomas originate in the testes or ovaries, while others may develop in the uterus after a normal pregnancy or after miscarriage. The tumor is characterized by early hematogenous spread to distal organs, such as the lung and brain. Transforming growth factor β1 (TGF-β1) is key in regulating tumor cell proliferation and invasion through a variety of Smad-dependent and -independent pathways, including the p38 mitogen-activated protein kinase (MAPK) pathway. There appears to be crosstalk between the TGF-β/Smad and p38 MAPK pathways; however, the molecular mechanisms underlying the crosstalk are not fully understood. The present study validated the role of TGF-β signaling in cancer progression and explored the interaction between Smad and p38 MAPK signaling on transduction mediators in choriocarcinoma using the JEG-3 cell line. MTT assay was used to detect the effect of TGF-β1 on JEG-3 cell proliferation. Cells were treated with p38 MAPK inhibitor and TGF-β receptor inhibitor, followed by TGF-β1, and reverse transcription quantitative real-time polymerase chain reaction was used to examine the transcriptional levels of Smad3 and TGF-β receptors. The data demonstrated that TGF-β can enhance the viability of JEG-3 cells. Blockade of the TGF-β and p38 MAPK pathways attenuated the expression of Smad3, TGF-β receptor type I (TβRI) and TβRII, and inhibited their expression in a dose-dependent manner. Analysis revealed that p38 MAPK is involved in and contributes to the TGF-β pathway, dependent on the regulation of TβRI, TβRII and Smad3. Further investigation of the interactions between the TGF-β and p38 MAPK pathways may offer potential venues for therapeutic intervention for choriocarcinoma.
Abstract. Choriocarcinoma is a highly malignant trophoblastic tumor related to pregnancy that often occurs with a complete hydatidiform mole. It grows quickly and can also widely metastasize to other organs or tissues through both the venous and lymphatic systems. The transforming growth factor-β1 (TGF-β1) belongs to a growth factor superfamily and has been suggested to play a critical role in regulating the genesis and development of choriocarcinoma through a variety of Smad-independent pathways, including the p38 MAPK pathway. Previous studies indicated that TGF-β can activate the p38 MAPK pathway. In this study, we investigated Smad and p38 MAPK signaling in JEG-3 choriocarcinoma cells using p38 MAPK inhibitor and TGF-β receptor inhibitor. Immunofluorescence and western blot assays were used to detect the proteins in Smad and p38 MAPK pathways. Our data demonstrated that TGF-β can activate Smad3 and induce Smad3 translocation into the nucleus in JEG-3 cells. Blockade of the TGF-β pathway significantly reduced the expression levels of p38 and phospho-p38. p38 MAPK inhibitors (SB 203580) can attenuate TGF-β1-induced Smad3 expression and suppress the activation of smad3. These findings indicate crosstalk between p38 and smad3 through TGF-β1 in choriocarcinoma cells.
Predictive value of β2-microglobulin (β2-MG) and transforming growth factor-β (TGF-β) for elderly hypertensive nephropathy was investigated. The clinical data of 56 patients with hypertensive nephropathy and admitted to Affiliated Hospital of Chengde Medical College from December 2015 to December 2017, were retrospectively analyzed and the clinical data were used as the study group, the clinical data of 50 patients with hypertension, but not nephropathy, were selected as the control group. The expression levels of β2-MG and TGF-β in the serum were detected by ELISA. The correlation between β2-MG and TGF-β was analyzed by Pearson's correlation. The sensitivity and specificity of β2-MG, TGF-β and combined application in the diagnosis of hypertensive nephropathy were analyzed by ROC curve. The expression levels of β2-MG and TGF-β in the serum of the patients in the study group were significantly higher than those in the control group (P<0.001). There was a positive correlation between the expression levels of β2-MG and TGF-β in the serum of the patients in the study group (r=0.619, P<0.001). The AUC of β2-MG in the diagnosis of hypertensive nephropathy was 0.786. The AUC of TGF-β in the diagnosis of hypertensive nephropathy was 0.793. The AUC of the combined application of β2-MG and TGF-β in the diagnosis of hypertensive nephropathy was 0.860. β2-MG and TGF-β were highly expressed in the patients with hypertensive nephropathy, and the expression levels of β2-MG and TGF-β were positively correlated (r=0.619, P<0.001). The combined application of β2-MG and TGF-β in the diagnosis of hypertensive nephropathy could reduce or even avoid the missed diagnosis caused by single detection. The two indicators complemented and confirmed each other, which had a great significance for improving the positive diagnosis rate of hypertensive nephropathy.
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