Low expression of Foxo3a is Associated with Poor Prognosis in Ovarian Cancer Patients

Fei, Min; Zhao, Yueming; Wang, Yuchan; Lu, Mengji; Cheng, Chun; Huang, Xiaodong; Zhang, Dongmei; Lü, Jianxin; He, Song; Shen, Aiguo

doi:10.1080/07357900802146204

Cited by 73 publications

(62 citation statements)

References 37 publications

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“…FOXO3 acts as a suppressor of follicular activation at the earliest stages of follicular growth in mice (26). Low expression of FOXO3 has been significantly associated with poor prognosis in ovarian cancer patients (27). Detainment of FOXO3 could therefore be one option to treat ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of forkhead box O3 transcription is involved in C2-ceramide induced apoptosis and autophagy in ovarian cancer cells in vitro

Jin

Zheng

Xin

et al. 2014

Molecular Medicine Reports

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Abstract. Ceramide is a bioactive lipid which functions as a tumor suppressor, mediating processes such as apoptosis, growth arrest, senescence and differentiation. The effects of ceramide in ovarian cancers have not been well established. The objective of the present study was to investigate the effects of C2-ceramide treatment in A2780 ovarian cancer cells and its possible molecular mechanism. C2-ceramide-induced proliferation inhibition was analyzed using an MTT assay and Trypan blue test. Flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling were used to identify the induction of apoptosis. Transmission electron microscopy was used to confirm the formation of autophagosomes. Quantitative polymerase chain reaction was performed to analyze the messenger RNA expression of the autophagy and cell death associated genes and western blotting was used to analyze the protein expression of beclin 1, LC3, Akt, forkhead box O3 (FOXO3) and adenosine monophosphate-activated protein kinase in ovarian cancer cells. It was found that C2-ceramide inhibited A2780 cell proliferation in a time-and dose-dependent manner and C2-ceremide induced A2780 cell apoptosis and autophagy. However, C2-ceramide-induced autophagy did not result in cell death, but instead protected ovarian cancer cells from apoptosis. Akt inhibition and FOXO3 activation were implicated in C2-ceramide-treated ovarian cancer cells. Furthermore, FOXO3 target genes, which were associated with autophagy (MAP1LC3, GABARAP and GABARAPL1) and cell death (BNIP3, BNIP3L, BIM and PUMA), were upregulated. The present study has shown that C2-ceramide induced apoptosis and autophagy in ovarian cancer cells. FOXO3 transcription was upregulated, which may contribute to C2-ceramide-induced apoptosis and autophagy.

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Section: Discussionmentioning

confidence: 99%

Upregulation of forkhead box O3 transcription is involved in C2-ceramide induced apoptosis and autophagy in ovarian cancer cells in vitro

Jin

Zheng

Xin

et al. 2014

Molecular Medicine Reports

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“…It has been reported that low expression of FoxO3a in ovarian cancer is associated with poor prognosis of patients (Fei et al, 2009). Higher CCNG2 expression also correlates with recurrence-free survival in breast cancer patients (Adorno et al, 2009).…”

Section: Nodal Induces Cyclin G2 Transcription Via Foxo3a G Fu and C mentioning

confidence: 98%

Nodal enhances the activity of FoxO3a and its synergistic interaction with Smads to regulate cyclin G2 transcription in ovarian cancer cells

Peng

2011

Oncogene

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Nodal, a member of the transforming growth factor-b superfamily, has been recently shown to suppress cell proliferation and to stimulate the expression of cyclin G2 (CCNG2) in human epithelial ovarian cancer cells. However, the precise mechanisms underlying these events are not fully understood. In this study, we investigated the transcriptional regulation of CCNG2 by the Nodal signaling pathway. In ovarian cancer cells, overexpression of Nodal or its receptors, activin receptorlike kinase 7 (ALK7) or ALK4, resulted in an increase in the CCNG2 promoter activity. Several putative Forkhead box class O (FoxO)3a-binding sites are present in the human CCNG2 promoter and overexpression of FoxO3a enhanced the CCNG2 promoter activity. The functional FoxO3a-binding element (FBE) was mapped to a proximal region located between À398 and À380 bp (FBE1) through deletion and mutation analyses, as well as chromatin immunoprecipitation (IP) assay. Interestingly, mutation of the FBE1 not only abolished the effect of FoxO3a, but also blocked Nodal-induced CCNG2 transcription. Nodal stimulated FoxO3a mRNA and protein expression through the canonical Smad pathway and suppressed FoxO3a inactivation by inhibiting AKT activity. Silencing of FoxO3a using small interfering RNA significantly reduced the effect of Nodal on the CCNG2 promoter activity. On the other hand, overexpression of Smad2 and Smad3 enhanced the FoxO3a-induced CCNG2 promoter activity whereas knockdown of Smad4 blocked the activity of FoxO3a. Furthermore, IP assays revealed that FoxO3a formed complexes with Smad proteins and that Nodal enhanced the binding of FoxO3a to the CCNG2 promoter. Finally, silencing of FoxO3a reversed the inhibitory effect of Nodal on cell proliferation. Taken together, these findings demonstrated that Nodal signaling promotes CCNG2 transcription by upregulating FoxO3a expression, inhibiting FoxO3a phosphorylation and enhancing its synergistic interaction with Smads. These results also suggest that FoxO3a is an important mediator of Nodal signaling in ovarian cancer cells.

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“…In the future, it would be interesting to explore the potential relationship between genetic variation in FOXO3A and various cancers from the viewpoint that the former is a potential tumor suppressor (Fei et al 2009;Hu et al 2004;Mikse et al 2010;Yang et al 2008). So far, little is known about the link between germ line FOXO3A variation and a predisposition to cancer (Campa et al 2011).…”

Section: Discussionmentioning

confidence: 99%

“…It also plays an important role in growth arrest, DNA repair, and apoptosis in response to DNA damage and oxidative stress (Furukawa-Hibi et al 2002;Greer and Brunet 2005;Kops et al 2002;Tran et al 2002). Furthermore, FOXO3A has been implicated as a tumor suppressor (Fei et al 2009;Hu et al 2004;Mikse et al 2010;Yang et al 2008), and FOXO3A activity was consistently found to be downregulated in various cancers (Yang and Hung 2009;Greer and Brunet 2005). More recently, FOXO3A was also reported to stimulate a proapoptotic transcriptional program in response to a human lung carcinogen , and the FOXO3A gene region is a target of somatic deletion in lung adenocarcinoma (LAC) in both humans ) and mice (Herzog et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Adjustment for smoking does not alter the FOXO3A association with longevity

Däumer

Flachsbart

Caliebe

et al. 2013

AGE

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Human longevity is a multifactorial phenotype influenced by both genetic and environmental factors. Despite its heritability of 25-32 %, the genetic background of longevity is as yet largely unexplained. Apart from APOE status, variation in the FOXO3A gene is the only confirmed genetic contributor to survival into old age. On the other hand, FOXO3A activity is known to be downregulated in various cancers, and the gene was recently identified as a novel deletion hotspot in human lung adenocarcinoma. In view of the strong association between smoking and lung cancer, we set out to explore whether smoking modifies the known association between FOXO3A variation and longevity. To this end, we conducted a case-control study in two different populations, drawing upon extensive collections of old-aged individuals and younger controls available to us (1,613 German centenarians/nonagenarians and 1,104 controls; 1,088 Danish nonagenarians and 736 controls). In the German sample, 21 single nucleotide polymorphisms (SNPs) from the FOXO3A gene region were genotyped, whereas 15 FOXO3A SNPs were analyzed in the Danish sample. Eight SNPs were typed in both populations. Logistic regression analysis revealed that adjustment for smoking does not systematically alter the association between FOXO3A variation and longevity in neither population. Our analysis therefore suggests that the said association is not largely due to the confounding effects of lung cancer.

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Low expression of Foxo3a is Associated with Poor Prognosis in Ovarian Cancer Patients

Cited by 73 publications

References 37 publications

Upregulation of forkhead box O3 transcription is involved in C2-ceramide induced apoptosis and autophagy in ovarian cancer cells in vitro

Upregulation of forkhead box O3 transcription is involved in C2-ceramide induced apoptosis and autophagy in ovarian cancer cells in vitro

Nodal enhances the activity of FoxO3a and its synergistic interaction with Smads to regulate cyclin G2 transcription in ovarian cancer cells

Adjustment for smoking does not alter the FOXO3A association with longevity

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