Abstract
BackgroundExpression of Nodal, a member of the TGF-β superfamily, is commonly absent in differentiated tissues, while its re-expression occurs in a variety of human malignancy. However, little is known about its involvement in ovarian tumorigenesis. Herein, we focused on the functional roles of Nodal in ovarian endometriosis-carcinoma lesions.MethodsRegulation and function of Nodal and its associated molecules, including Smad2, GSK-3β, and several cell kinetics-related molecules, were assessed using clinical samples consisting of 108 ovarian carcinomas and 33 endometriotic lesions, as well as ES-2 (ovarian clear cell carcinoma; OCCCa) and Ishikawa (endometrial carcinoma) cell lines.ResultsNodal expression was significantly higher in endometriosis and OCCCa lesions as compared to that of non-OCCCas, with positive correlations to phosphorylated forms of both Smad2 (pSmad2) and GSK-3β. When compared to endometriotic lesions, the expression of Nodal and pSmad2 was significantly decreased in OCCCa. Treatment of Ishikawa cells with TGF-β1 resulted in transcriptional upregulation of Nodal, along with increased pSmad2 expression, while inhibition of GSK-3β also induced an increase in Nodal expression at the posttranslational level. Both ES-2 and Ishikawa cells stably overexpressing Nodal had increased susceptibility to apoptosis in response to treatment with cisplatin and doxorubicin, respectively, together with higher cleaved caspase-3 expression and decreased Bcl2/Bax ratio. Moreover, the stable Nodal-overexpressing cells showed reduced cell proliferation, along with increased expression of p27kip1 and p21waf1. In clinical samples, a significantly higher number of apoptotic cells and lower Ki-67 labeling indices were observed in Nodal-positive as compared to Nodal-negative OCCCa.ConclusionsThese findings suggest that Nodal is a multifunctional cytokine involved in the modulation of cell kinetics in ovarian endometriosis-OCCCa lesions.
Highlights
Expression of Nodal, a member of the transforming growth factor β (TGF-β) superfamily, is commonly absent in differentiated tissues, while its re-expression occurs in a variety of human malignancy
Nodal expression in Ovarian epithelial carcinoma (OECa) and endometriosis Cytoplasmic Nodal immunoreactivity with or without nuclear staining was frequently observed in Ovarian clear cell carcinoma (OCCCa), while sporadic distribution or absence of Nodal-immunopositive cells was observed in non-OCCCa lesions including Ovarian endometrioid carcinoma (OEmCa), OMuCa, and OSeCa
We examined the association of Nodal expression with the TGF-β/Smad2 signal pathway in endometriosis and OCCCa/OEmCa. phosphorylated forms of both Smad2 (pSmad2) immunoreactivity was mainly located in cytoplasmic compartments with
Summary
Expression of Nodal, a member of the TGF-β superfamily, is commonly absent in differentiated tissues, while its re-expression occurs in a variety of human malignancy. Miura et al BMC Cancer (2019) 19:308 frequently detected in ovarian endometriotic cysts, and promotes development of the tumors through iron-induced persistent oxidative stress and DNA damage [9]. Such an inflammatory reaction alters the expression of transforming growth factor β (TGF-β), which can play multiple roles in human tumorigenesis by behaving as a tumor suppressor at early stages and a tumor promoter at late stages [10,11,12,13]. The role of Nodal may be dependent on the tumor cellular microenvironment and associated cell type
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