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Key Genes And Pathways Controlled By E2F1 In Human Castration-Resistant Prostate Cancer Cells.

ABSTRACT: Background:Treatment of castration-resistant prostate cancer (CRPC) is an enormous challenge. As E2F transcription factor 1 (E2F1) is an essential factor in CRPC, this study investigated the genes and pathways controlled by E2F1 and their effects on cellular behavior in CRPC. Methods:In vitro assays were used to evaluate cellular proliferation, apoptosis, and behavior. Cellular expression was quantified by RNA sequencing (RNA-seq). Gene co-expression was assessed using the GeneMANIA database, and correlations were analyzed with the GEPIA server. Altered pathways of differentially expressed genes (DEGs) were revealed by functional annotation. Module analysis was performed using the STRING database and hub genes were filtered with the Cytoscape software. Some DEGs were validated by real-time quantitative PCR (RT-qPCR). Results:Knockdown of E2F1 significantly inhibited proliferation and accelerated apoptosis in PC3 cells but not in DU145 cells. Invasion and migration were reduced for both cell lines. A total of 1811 DEGs were identified in PC3 cells and 27 DEGs in DU145 cells exhibiting E2F1 knockdown. Ten overlapping DEGs, including TMOD2 and AIF1L, were identified in both knockdown cell lines and were significantly enriched for association with actin filament organization pathways. TMOD2 and KREMEN2 were genes co-expressed with E2F1; six overlapping DEGs were positively correlated with transcription factor E2F1. DEGs of the PC3 and DU145 groups were associated with multiple pathways. Five DEGs that overlapped between the two cell lines and three hub DEGs from PC3 cells were validated by RT-qPCR. Conclusion:The results of this study suggest that E2F1 has a critical role in regulating actin filaments, as indicated by the change in expression level of several genes, including TMOD2 and AIF1L, in CRPC. This extends our understanding of the cellular responses affected by E2F1 in CRPC.

SUBMITTER: Zhou Q

PROVIDER: S-EPMC6827506 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Key Genes And Pathways Controlled By E2F1 In Human Castration-Resistant Prostate Cancer Cells.

Zhou Qingniao Q Wang Chengbang C Zhu Yuanyuan Y Wu Qunying Q Jiang Yonghua Y Huang Yuanjie Y Hu Yanling Y

OncoTargets and therapy 20191031

<h4>Background</h4>Treatment of castration-resistant prostate cancer (CRPC) is an enormous challenge. As E2F transcription factor 1 (E2F1) is an essential factor in CRPC, this study investigated the genes and pathways controlled by E2F1 and their effects on cellular behavior in CRPC.<h4>Methods</h4>In vitro assays were used to evaluate cellular proliferation, apoptosis, and behavior. Cellular expression was quantified by RNA sequencing (RNA-seq). Gene co-expression was assessed using the GeneMAN ...[more]

PMID: 31802906

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Project description:BackgroundEndothelial progenitor cells (CEPs) and circulating endothelial cells (CECs) are potential biomarkers of response to anti-angiogenic treatment regimens. In the current study, we investigated the effect of docetaxel and sunitinib on CEP/CEC kinetics and clinical response in castration resistant prostate cancer (CRPC) patients.Patients and methodsChemonaive patients with CRPC were enrolled in this study to receive either sunitinib (37.5 mg/d), in combination with docetaxel (75 mg/m2) or docetaxel alone. CEP and CEC kinetics were analyzed for every cycle. The primary objective was to compare CEP/CEC pharmacodynamics between both treatment arms. We also investigated if CEC/CEP spikes, induced by MTD docetaxel, are suppressed by sunitinib in patients treated with docetaxel/sunitinib relative to docetaxel monotherapy.ResultsA total of 27 patients were enrolled. We observed a significant increase of CEP/CEC (total/viable) counts over time within each cycle (coefficients 0.29233, 0.22092 and 0.26089, respectively; p<0.001). However, no differences between the treatment groups, in terms of CEP and CEC kinetics, were detected. In the docetaxel monotherapy arm 4 (30%) patients responded to therapy with a 50% PSA decline, while 9 (64%) patients showed a PSA decline in the combination group (n.s.). The median PFS in the docetaxel monotherapy group was 3.1 months (2.6-3.6 months, 95% CI) and 6.2 months (4.9-7.4 months, 95% CI; p = 0.062) in the combination arm. Sunitinib/docetaxel was reasonably well tolerated and toxicity manageable.ConclusionIn summary, no significant differences in CEC and CEP kinetics between the treatment arms were observed, although a highly significant increase of CEPs/CECs within each cycle over time was detected. These results mirror the challenge we have to face when employing anti-angiogenic strategies in CRPC. Additional preclinical research is needed to elucidate the underlying molecular mechanisms. However, docetaxel/sunitinib therapy resulted in a better response in terms of PSA decline and a trend towards improved PFS.Trial registeryclinicaltrialsregister.eu EudraCT 2007-003705-27.

Dataset Information

Key Genes And Pathways Controlled By E2F1 In Human Castration-Resistant Prostate Cancer Cells.

Publications

Key Genes And Pathways Controlled By E2F1 In Human Castration-Resistant Prostate Cancer Cells.

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