Decreased Expression of Beclin 1 Correlates Closely with Bcl-xL Expression and Poor Prognosis of Ovarian Carcinoma

Lin, Huan Xin; Qiu, Hui; Zeng, Fei; Rao, Hui Lan; Yang, Guowei; Kung, Hsiang Fu; Zhu, Xiao Feng; Zeng, Yi Xin; Cai, Mu Yan; Xie, Dan

doi:10.1371/journal.pone.0060516

Cited by 45 publications

(54 citation statements)

References 40 publications

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“…Therefore, an increased frequency of follow-up in patients with loss of BECN1, to detect recurrence earlier, may allow patients to quickly receive further beneficial cytoreductive surgery or second-line chemotherapy. Multiple previous studies have demonstrated comparable data in line with the present study, in that the loss of BECN1 was reported to be associated with an unfavorable prognosis of several solid cancers, including ovarian carcinoma (15,(25)(26)(27). In contrast, other studies demonstrated that the loss of BECN1 was significantly correlated with improved survival in patients with endometrial cancer, renal cell cancer, and colorectal cancer (28)(29)(30).…”

Section: Discussionsupporting

confidence: 90%

Loss of beclin 1 expression in ovarian cancer: A potential biomarker for predicting unfavorable outcomes

et al. 2017

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Abstract. The clinicopathological significance and prognostic value of the expression of proteins associated with autophagy, beclin 1 (BECN1), 1A/1B-light chain 3 (LC3) and high mobility group box-1 protein (HMGB-1), were investigated in patients with ovarian carcinoma, receiving combination chemotherapy with a platinum agent and a taxane. Immunohistochemical staining was performed for autophagy-associated proteins in tumor tissues from 141 patients with ovarian carcinoma. Clinical data were collected retrospectively by reviewing medical charts, and the association between protein expression, clinicopathological features and survival was investigated. Amongst 141 ovarian carcinoma samples, the loss of BECN1, LC3, and HMGB-1 expression was identified in 59 (41.8%), 35 (24.8%), and 66 (46.8%) samples, respectively. Clinicopathological factors were not significantly associated with the loss of BECN1 expression. However, significant associations were demonstrated between the expression of BECN1, LC3, and HMGB-1. In addition, loss of BECN1 expression demonstrated a significant association with poor progression-free and poor overall survival. Multivariate analysis demonstrated that loss of BECN1 expression and postoperative residual tumor were significant independent predictors of poor progression-free survival and poor overall survival. These results indicated that loss of BECN1 expression in ovarian carcinoma is a negative prognosticator in patients receiving platinum-based chemotherapy. Assessment of BECN1 expression may be useful for predicting an unfavorable response to platinum-based chemotherapy in ovarian carcinoma.

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Section: Discussionsupporting

confidence: 90%

Loss of beclin 1 expression in ovarian cancer: A potential biomarker for predicting unfavorable outcomes

et al. 2017

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“…However, it has been reported by Lin et al that decreased BECN1 expression is correlated with shortened survival in ovarian cancer patients, 30 which is in contrast with our data. The reason is unclear, but the proportion of patients with Grade 3 (23.7%, 40/169 cases) was lower in Lin's report than those in our series (63.1%, 99/157 cases).…”

Section: (C) (Line Mock) Plasmid; (E and F)contrasting

confidence: 99%

TXNDC17 promotes paclitaxel resistance via inducing autophagy in ovarian cancer

Zhang¹,

et al. 2015

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These authors contributed equally to this work.Keywords: autophagy, BECN1, ovarian cancer, paclitaxel resistance, TXNDC17Abbreviations: 95% CI, 95% confidence interval; ALDOC, aldolase C, fructose-bisphosphate; ATG5, autophagy-related 5; BafA1, bafilomycin A 1 ; BECN1, Beclin 1, autophagy-related; CNN3, calponin 3, acidic; DAPI, 4', 6-diamidino-2-phenylindole; FLNA, filamin A, a; GenMAPP, gene microarray pathway profiler; GO, gene ontology; HBSS, Hank's balanced salt solution; HR, hazard ratio; KEGG, Kyoto encyclopedia of genes and genome; LC-MS/MS, liquid chromatography-mass spectrometry/ mass spectrometry; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 b; OS, overall survival; PFS, progression-free survival; PGAM1, phosphoglycerate mutase 1 (brain); siRNA, short interfering RNA; SQSTM1, sequestosome 1; TNF, tumor necrosis factor; TXN, thioredoxin; TXNDC17, thioredoxin domain containing 17; UTP23, small subunit (SSU) processome component, homolog (yeast).Paclitaxel is recommended as a first-line chemotherapeutic agent against ovarian cancer, but drug resistance becomes a major limitation of its success clinically. The key molecule or mechanism associated with paclitaxel resistance in ovarian cancer still remains unclear. Here, we showed that TXNDC17 screened from 356 differentially expressed proteins by LC-MS/MS label-free quantitative proteomics was more highly expressed in paclitaxel-resistant ovarian cancer cells and tissues, and the high expression of TXNDC17 was associated with poorer prognostic factors and exhibited shortened survival in 157 ovarian cancer patients. Moreover, paclitaxel exposure induced upregulation of TXNDC17 and BECN1 expression, increase of autophagosome formation, and autophagic flux that conferred cytoprotection for ovarian cancer cells from paclitaxel. TXNDC17 inhibition by siRNA or enforced overexpression by a pcDNA3.1(C)-TXNDC17 plasmid correspondingly decreased or increased the autophagy response and paclitaxel resistance. Additionally, the downregulation of BECN1 by siRNA attenuated the activation of autophagy and cytoprotection from paclitaxel induced by TXNDC17 overexpression in ovarian cancer cells. Thus, our findings suggest that TXNDC17, through participation of BECN1, induces autophagy and consequently results in paclitaxel resistance in ovarian cancer. TXNDC17 may be a potential predictor or target in ovarian cancer therapeutics.

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“…Furthermore, ceramide has also been found to cause autophagy which results in either cell survival or death (14). Previous research has reported that ceramide caused COX-2-dependent apoptosis in ovarian cancer OVCAR-3 cells (15). In the present study, C2-ceramide did not only induce cell apoptosis, but also autophagy.…”

Section: Discussionsupporting

confidence: 62%

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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Decreased Expression of Beclin 1 Correlates Closely with Bcl-xL Expression and Poor Prognosis of Ovarian Carcinoma

Cited by 45 publications

References 40 publications

Loss of beclin 1 expression in ovarian cancer: A potential biomarker for predicting unfavorable outcomes

Loss of beclin 1 expression in ovarian cancer: A potential biomarker for predicting unfavorable outcomes

TXNDC17 promotes paclitaxel resistance via inducing autophagy in ovarian cancer

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

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