CXCR4 and RIF1 Overexpression Induces Resistance of Epithelial Ovarian Cancer to Cisplatin

2020 ◽  
Vol 106 (1_suppl) ◽  
pp. 31-31
Author(s):  
Lamiss Mohamed Abd El Aziz ◽  
Dareen Mohamed Abd El Aziz ◽  
Assama Elkady ◽  
Noha Elanwar
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Epithelial Ovarian Cancer ◽  
Progression Free Survival ◽  
Distant Metastases ◽  
Dna Breaks ◽  
University Hospitals ◽  
Double Strand Dna Breaks ◽  
Cisplatin Sensitivity ◽  
Novel Biomarkers

The chemoresistance of epithelial ovarian cancer (EOC) is a major problem Thus, the search for novel biomarkers associated with cisplatin sensitivity is overwhelming. Previous studies have shown that chemokine receptor (CXCR4) is associated with tumor growth, angiogenesis and distant metastases and replication regulatory timing factor (RIF1) is responsible for repair of double strand DNA breaks. This study, thus, aimed to identify the correlation between CXCR4 and RIF1 overexpression and cisplatin sensitivity in EOC. Patients and methods: Fifty five EOC patients were recruited to assess chemosensitivity of EOC to cisplatin based chemotherapy in Oncology Department, Tanta University Hospitals. Results: The results showed that patients with a higher CXCR4 and RIF1 expression exhibited a significantly lower chemosensitivity, worse overall survival and a poorer progression-free survival. The only prognostic associated with overall survival was CXCR4.

Nucleophosmin expression in ovarian cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15582-e15582
Author(s):  
Dineo Khabele ◽  
Andrew J Wilson ◽  
Annie Y Liu ◽  
Joseph Roland ◽  
Sarah Fletcher ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Dna Repair ◽  
Progression Free Survival ◽  
High Grade ◽  
Dna Breaks ◽  
Free Survival ◽  
Ovarian Cancers ◽  
Double Strand Dna Breaks ◽  
The Relationship

e15582 Background: The nucleolar protein, nucleophosmin (NPM1) is implicated multiple cellular processes, including proliferation, duplication of centrosomes, ARF-HDM2-p53 signaling. NPM1 is associated with sites of double strand DNA breaks, with persistence of its expression indicative of impaired DNA repair. Data from the TCGA data have emphasized that genomic instability through impaired DNA repair processes is a characteristic feature of many ovarian cancers. Our aim was to determine the expression of NPM1 in ovarian cancers and to determine the relationship between NPM1 expression and clinical outcomes including overall survival (OS), progression-free survival (PFS) and chemotherapy response. Methods: Tissue microarrays were created from 209 patients treated for ovarian cancer at a single institution from 1994-2004. Expression levels of NPM1 were examined by immunohistochemical staining. Slides were scored using the an automated image capture and analysis system. Positive nuclear staining was used to stratify tumors into high (>50%) and low (<50%) groups, and the results were related to overall survival (OS) and progression-free survival (PFS) via Kaplan-Meier analysis. The relationship between ki67, a proliferation marker and pH2AX, a mark of double strand DNA breaks was measured with Spearman rank correlation coefficient analyses. Results: The majority of tumors, 140/209 (69%) were of serous histology, advanced stage 146/209 (70%) and high grade 158/209 (76%). There was >50% NPM1 expression in 83/209 (40%) and <50% in 126/209 (60%) of the cases. Expression of NPM1 was higher in high grade tumors, and its expression alone was a significant predictor of PFS (p=0.022) but not OS (p=0.053). When adjusting for other predictors, NPM1 expression was predictive of PFS (p=0.047), but not OS (p=0.054). No relationship between NPM1 expression and response to platinum chemotherapy was observed. However, NPM1 expression correlated with Ki67 (r=0.43, p<0.0001) and pH2AX (r=0.22, p=0.0014). Conclusions: NPM1 expression is a mark of poor prognosis in ovarian cancer. Whether these observations reflect increased proliferation and/or genomic instability in ovarian cancer cells will be the focus of future investigation.

scholarly journals Correlation of PKM2 and CD44 Protein Expression with Poor Prognosis in Platinum-Treated Epithelial Ovarian Cancer: A Retrospective Study

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1013
Author(s):  
Chara Papadaki ◽  
Stavroula Manolakou ◽  
Eleni Lagoudaki ◽  
Spyros Pontikakis ◽  
Despo Ierodiakonou ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Prognostic Factor ◽  
Protein Expression ◽  
Epithelial Ovarian Cancer ◽  
Cancer Cells ◽  
Progression Free Survival ◽  
Free Survival ◽  
Protein Levels ◽  
Low Expression

CD44, a surface marker for cancer stem cells, interacts with PKM2, a key regulator of aerobic glycolysis, and enhances the glycolytic phenotype of cancer cells leading to antioxidant protection and macromolecules’ synthesis. To clarify the clinical importance of this “cross-talk” as a mechanism of drug resistance, we assessed the expression both of PKM2 and of CD44 in cancer cells of patients with epithelial ovarian cancer (EOC) treated with platinum-based treatment. One hundred and seventy-one patients with EOC were assessed for PKM2mRNA expression and PKM2 and CD44 proteins detection. Associations with progression-free survival (PFS) and overall survival (OS) were assessed with Kaplan–Meier and adjusted Cox regression models. PKM2mRNA and protein as well as CD44 protein were detectable in the majority of patients. Positive correlation between PKM2 and CD44 protein expression was observed (Spearman rho = 0.2, p = 0.015). When we used the median to group patients into high versus low expression, high PKM2mRNA and protein levels were significantly associated with lower progression-free survival (PFS; p = 0.003 and p = 0.002, respectively) and shorter overall survival (OS; p ≤ 0.001 and p = 0.001, respectively). However, high CD44 protein expression was significantly correlated only with shorter OS (p = 0.004). Moreover, patients with both high PKM2 and CD44 protein levels experienced shorter PFS and OS (p = 0.007 and p = 0.003, respectively) compared to patients with low expression of both proteins. Finally, higher PKM2mRNA and protein expression as well as CD44 protein expression (HR: 2.16; HR: 1.82; HR: 1.01, respectively) were independent prognostic factors for decreased median OS (mOS), whereas only PKM2 protein expression (HR: 1.95) was an independent prognostic factor for decreased median PFS (mPFS). In conclusion, PKM2 expression is a negative prognostic factor in EOC patients, but the interaction between CD44 and PKM2 that may be implicated in EOC platinum-resistance needs further investigation.

scholarly journals Identification and Analysis of Genes Associated with Epithelial Ovarian Cancer by Integrated Bioinformatics Methods

2020 ◽  
Author(s):  
Ting Gui ◽  
Chenhe Yao ◽  
Binghan Jia ◽  
Keng Shen
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Epithelial Ovarian Cancer ◽  
Protein Interactions ◽  
Therapeutic Targets ◽  
Progression Free Survival ◽  
The Cancer Genome Atlas ◽  
Ppi Network ◽  
Hub Genes ◽  
Free Survival

Abstract Background: Though considerable efforts have been made to improve the treatment of epithelial ovarian cancer (EOC), the prognosis of patients has remained poor. Identifying differentially expressed genes (DEGs) involved in EOC progression and exploiting them as novel biomarkers or therapeutic targets for EOC is highly valuable. Methods: Overlapping DEGs were screened out from three independent gene expression omnibus (GEO) datasets and subjected to Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses. The protein-protein interactions (PPI) network of DEGs was constructed in the STRING database. The top 20 hub genes were selected using cytoHubba. The expression of hub genes was detected in GEPIA, Oncomine, and human protein atlas (HPA) databases. The relationship of hub genes with the pathological stage and the overall survival and progression-free survival in EOC patients was investigated using the cancer genome atlas data. Results: A total of 306 DEGs were identified, including 265 up-regulated and 41 down-regulated. Through the PPI network analysis, the top 20 genes were screened out, among which 4 hub genes were selected after literature retrieval, including CDC45, CDCA5, KIF4A, ESPL1. The four genes were up-regulated in EOC tissues and the expression of these four genes decreased gradually with the continuous progression of EOC. Survival curves illustrated that patients with a lower level of CDCA5 and ESPL1 had better overall survival and progression-free survival. Conclusions: Two hub genes, CDCA5 and ESPL1, identified as playing tumor-promotive roles, could be utilized as potential novel therapeutic targets for EOC treatment.

scholarly journals Deregulation of Exo70 Facilitates Innate and Acquired Cisplatin Resistance in Epithelial Ovarian Cancer by Promoting Cisplatin Efflux

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3467
Author(s):  
Yujie Zhao ◽  
Xiaoting Hong ◽  
Xiong Chen ◽  
Chun Hu ◽  
Weihong Lu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Cisplatin Resistance ◽  
Progression Free Survival ◽  
Platinum Resistance ◽  
Lysosomal Degradation ◽  
Free Survival ◽  
Cisplatin Sensitivity

Whilst researches elucidating a diversity of intracellular mechanisms, platinum-resistant epithelial ovarian cancer (EOC) remains a major challenge in the treatment of ovarian cancer. Here we report that Exo70, a key subunit of the exocyst complex, contributes to both innate and acquired cisplatin resistance of EOC. Upregulation of Exo70 is observed in EOC tissues and is related to platinum resistance and progression-free survival of EOC patients. Exo70 suppressed the cisplatin sensitivity of EOC cells through promoting exocytosis-mediated efflux of cisplatin. Moreover, cisplatin-induced autophagy-lysosomal degradation of Exo70 protein by modulating phosphorylation of AMPK and mTOR, thereby reducing the cellular resistance. However, the function was hampered during prolonged cisplatin treatment, which in turn stabilized Exo70 to facilitate the acquired cisplatin resistance of EOC cells. Knockdown of Exo70, or inhibiting exocytosis by Exo70 inhibitor Endosidin2, reversed the cisplatin resistance of EOC cells both in vitro and in vivo. Our results suggest that Exo70 overexpression and excessive stability contribute to innate and acquired cisplatin resistance through the increase in cisplatin efflux, and targeting Exo70 might be an approach to overcome cisplatin resistance in EOC treatment.

scholarly journals Identification and analysis of genes associated with epithelial ovarian cancer by integrated bioinformatics methods

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0253136
Author(s):  
Ting Gui ◽  
Chenhe Yao ◽  
Binghan Jia ◽  
Keng Shen
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Epithelial Ovarian Cancer ◽  
Protein Interactions ◽  
Therapeutic Targets ◽  
Progression Free Survival ◽  
The Cancer Genome Atlas ◽  
Ppi Network ◽  
Hub Genes ◽  
Free Survival

Background Though considerable efforts have been made to improve the treatment of epithelial ovarian cancer (EOC), the prognosis of patients has remained poor. Identifying differentially expressed genes (DEGs) involved in EOC progression and exploiting them as novel biomarkers or therapeutic targets is of great value. Methods Overlapping DEGs were screened out from three independent gene expression omnibus (GEO) datasets and were subjected to Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses. The protein-protein interactions (PPI) network of DEGs was constructed based on the STRING database. The expression of hub genes was validated in GEPIA and GEO. The relationship of hub genes expression with tumor stage and overall survival and progression-free survival of EOC patients was investigated using the cancer genome atlas data. Results A total of 306 DEGs were identified, including 265 up-regulated and 41 down-regulated. Through PPI network analysis, the top 20 genes were screened out, among which 4 hub genes, which were not researched in depth so far, were selected after literature retrieval, including CDC45, CDCA5, KIF4A, ESPL1. The four genes were up-regulated in EOC tissues compared with normal tissues, but their expression decreased gradually with the continuous progression of EOC. Survival curves illustrated that patients with a lower level of CDCA5 and ESPL1 had better overall survival and progression-free survival statistically. Conclusion Two hub genes, CDCA5 and ESPL1, identified as probably playing tumor-promotive roles, have great potential to be utilized as novel therapeutic targets for EOC treatment.

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