Overexpression of NANOG in Gestational Trophoblastic Diseases

Abstract

Gestational trophoblastic disease includes choriocarcinoma, a frankly malignant tumor, and hydatidiform mole (HM), which often leads to the development of persistent gestational trophoblastic neoplasia and requires chemotherapy. NANOG is an important transcription factor that is crucial for maintaining embryonic stem cell self-renewal and pluripotency. We postulated that NANOG is involved in the pathogenesis of gestational trophoblastic disease. In this study, significantly higher NANOG mRNA and protein expression levels, by quantitative PCR and immunoblotting, respectively, were demonstrated in HMs, particularly those that developed persistent disease, when compared with normal placentas. In addition, significantly increased nuclear NANOG immunoreactivity was found by immunohistochemistry in HMs (P < 0.001) and choriocarcinoma (P ‫؍‬ 0.002). Higher NANOG expression levels were demonstrated in HMs that developed persistent disease, as compared with those that regressed (P ‫؍‬ 0.025). Nuclear localization of NANOG was confirmed by confocal microscopy and immunoblotting in choriocarcinoma cell lines. There was a significant inverse correlation between NANOG immunoreactivity and apoptotic index assessed by M30 CytoDeath antibody (P ‫؍‬ 0.012). After stable knockdown of NANOG in the choriocarcinoma cell line JEG-3 by an shRNA approach, increased apoptosis was observed in relation to with enhanced caspases and poly(ADP-ribose) polymerase activities. NANOG knockdown was also associated with decreased mobility and invasion of JEG-3 and downregulation of matrix metalloproteases 2 and 9. These findings suggest that NANOG is involved in the pathogenesis and clinical progress of gestational trophoblastic disease , likely through its effect on apoptosis , cell migration , and invasion.

HTR8/SVneo Cells Display Trophoblast Progenitor Cell-Like Characteristics Indicative of Self-Renewal, Repopulation Activity, and Expression of “Stemness-” Associated Transcription Factors

“…We were surprised to see that NANOG was not expressed in JEG3 cells as described in a recent publication, in which NANOG was especially detected in the nuclear fraction of JEG3 cells [40]. Currently, we cannot explain this discrepancy other than in methodology differences, and further analyses on the mRNA and protein level are under way.…”

Nanog and Oct4 overexpression increases motility and transmigration of melanoma cells

“…In addition, these cells were shown to have a more motile and aggressive phenotype and express higher level of Nanog and Oct4 (Cheli et al 2011;Ramgolam et al 2011), two transcription factors expressed in embryonic stem cells, pointing out a loss of differentiation and an increase in plasticity (Kashyap et al 2009). Nanog expression was associated with cancer of poor prognosis, and its inhibition by RNA interference was shown to lead to a reduced migration and invasiveness of choriocarcinomas cells (Siu et al 2008) or decreased tumorigenesis of the prostate, breast and colon cancer cells (Jeter et al 2009). Oct4 has been shown to be expressed in low-differentiated glioma cells (Du et al 2009), and its expression in bladder cancer cells is associated with a poor prognosis and enhanced migratory phenotype (Chang et al 2008).…”

Cancer Vaccination Drives Nanog-Dependent Evolution of Tumor Cells toward an Immune-Resistant and Stem-like Phenotype

“…This property of Nanog is not entirely surprising since Nanog is one of the core transcription factors crucial for the maintainance of self-renewal and pluripotency of embryonic stem cells (36) and for the prolonged survival of tumor cells (37). Nonetheless, little is known about the molecular mechanisms by which Nanog functions.…”

“…CTLs have unequivocal specificity and potency to destroy transformed cells throughout the body without inflicting significant damage to normal tissue (1, 2). Generation of immune memory after tumor eradication should also protect against long-term relapse (3, 4). These advantages of vaccination over conventional cancer treatments fueled much of the enthusiasm for vaccination in the early 21 st century (5, 6).…”