scholarly journals Transcriptional epigenetic regulation of Fkbp1/Pax9 genes is associated with impaired sensitivity to platinum treatment in ovarian cancer

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Javier Andrés Soto ◽  
Carlos Rodríguez-Antolín ◽  
Olga Vera ◽  
Olga Pernía ◽  
Isabel Esteban-Rodríguez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Candidate Genes ◽  
Cell Lines ◽  
Clinical Data ◽  
Epigenetic Regulation ◽  
Chemotherapy Response ◽  
Potential Candidate ◽  
Platinum Sensitivity ◽  
Translational Level

Abstract Background In an effort to contribute to overcoming the platinum resistance exhibited by most solid tumors, we performed an array of epigenetic approaches, integrating next-generation methodologies and public clinical data to identify new potential epi-biomarkers in ovarian cancer, which is considered the most devastating of gynecological malignancies. Methods We cross-analyzed data from methylome assessments and restoration of gene expression through microarray expression in a panel of four paired cisplatin-sensitive/cisplatin-resistant ovarian cancer cell lines, along with publicly available clinical data from selected individuals representing the state of chemoresistance. We validated the methylation state and expression levels of candidate genes in each cellular phenotype through Sanger sequencing and reverse transcription polymerase chain reaction, respectively. We tested the biological role of selected targets using an ectopic expression plasmid assay in the sensitive/resistant tumor cell lines, assessing the cell viability in the transfected groups. Epigenetic features were also assessed in 189 primary samples obtained from ovarian tumors and controls. Results We identified PAX9 and FKBP1B as potential candidate genes, which exhibited epigenetic patterns of expression regulation in the experimental approach. Re-establishment of FKBP1B expression in the resistant OVCAR3 phenotype in which this gene is hypermethylated and inhibited allowed it to achieve a degree of platinum sensitivity similar to the sensitive phenotype. The evaluation of these genes at a translational level revealed that PAX9 hypermethylation leads to a poorer prognosis in terms of overall survival. We also set a precedent for establishing a common epigenetic signature in which the validation of a single candidate, MEST, proved the accuracy of our computational pipelines. Conclusions Epigenetic regulation of PAX9 and FKBP1B genes shows that methylation in non-promoter areas has the potential to control gene expression and thus biological consequences, such as the loss of platinum sensitivity. At the translational level, PAX9 behaves as a predictor of chemotherapy response to platinum in patients with ovarian cancer. This study revealed the importance of the transcript-specific study of each gene under potential epigenetic regulation, which would favor the identification of new markers capable of predicting each patient’s progression and therapeutic response.

scholarly journals Large-scale integrated analysis of ovarian cancer tumors and cell lines identifies an individualized gene expression signature for predicting response to platinum-based chemotherapy

2019 ◽  
Vol 10 (9) ◽  
Author(s):  
Jie Sun ◽  
Siqi Bao ◽  
Dandan Xu ◽  
Yan Zhang ◽  
Jianzhong Su ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Cell Lines ◽  
Large Scale ◽  
Gene Expression Signature ◽  
Integrated Analysis ◽  
Chemotherapy Response ◽  
Expression Signature ◽  
Platinum Based Chemotherapy ◽  
Response To Chemotherapy

Abstract Heterogeneity in chemotherapeutic response is directly associated with prognosis and disease recurrence in patients with ovarian cancer (OvCa). Despite the significant clinical need, a credible gene signature for predicting response to platinum-based chemotherapy and for guiding the selection of personalized chemotherapy regimens has not yet been identified. The present study used an integrated approach involving both OvCa tumors and cell lines to identify an individualized gene expression signature, denoted as IndividCRS, consisting of 16 robust chemotherapy-responsive genes for predicting intrinsic or acquired chemotherapy response in the meta-discovery dataset. The robust performance of this signature was subsequently validated in 25 independent tumor datasets comprising 2215 patients and one independent cell line dataset, across different technical platforms. The IndividCRS was significantly correlated with the response to platinum therapy and predicted the improved outcome. Moreover, the IndividCRS correlated with homologous recombination deficiency (HRD) and was also capable of discriminating HR-deficient tumors with or without platinum-sensitivity for guiding HRD-targeted clinical trials. Our results reveal the universality and simplicity of the IndividCRS as a promising individualized genomic tool to rapidly monitor response to chemotherapy and predict the outcome of patients with OvCa.

scholarly journals SARS-CoV-2 Infection-Induced Promoter Hypomethylation as an Epigenetic Modulator of Heat Shock Protein A1L (HSPA1L) Gene

2021 ◽  
Vol 12 ◽  
Author(s):  
Jibran Sualeh Muhammad ◽  
Narjes Saheb Sharif-Askari ◽  
Zheng-Guo Cui ◽  
Mawieh Hamad ◽  
Rabih Halwani
Keyword(s):  
Epithelial Cells ◽  
Mrna Expression ◽  
Candidate Genes ◽  
Epigenetic Regulation ◽  
Dna Methyltransferases ◽  
Lung Epithelial Cells ◽  
Potential Candidate ◽  
Blood Samples ◽  
Lung Epithelial

Numerous researches have focused on the genetic variations affecting SARS-CoV-2 infection, whereas the epigenetic effects are inadequately described. In this report, for the first time, we have identified potential candidate genes that might be regulated via SARS-CoV-2 induced DNA methylation changes in COVID-19 infection. At first, in silico transcriptomic data of COVID-19 lung autopsies were used to identify the top differentially expressed genes containing CpG Islands in their promoter region. Similar gene regulations were also observed in an in vitro model of SARS-CoV-2 infected lung epithelial cells (NHBE and A549). SARS-CoV-2 infection significantly decreased the levels of DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) in lung epithelial cells. Out of 14 candidate genes identified, the expression of 12 genes was upregulated suggesting promoter hypomethylation, while only two genes were downregulated suggesting promoter hypermethylation in COVID-19. Among those 12 upregulated genes, only HSPA1L and ULBP2 were found to be upregulated in AZA-treated lung epithelial cells and immune cells, suggesting their epigenetic regulation. To confirm the hypomethylation of these two genes during SARS-CoV-2 infection, their promoter methylation and mRNA expression levels were determined in the genomic DNA/RNA obtained from whole blood samples of asymptomatic, severe COVID-19 patients and equally matched healthy controls. The methylation level of HSPA1L was significantly decreased and the mRNA expression was increased in both asymptomatic and severe COVID-19 blood samples suggesting its epigenetic regulation by SARS-CoV-2 infection. Functionally, HSPA1L is known to facilitate host viral replication and has been proposed as a potential target for antiviral prophylaxis and treatment.

scholarly journals Early clearance of serum HE4 and CA125 in predicting platinum sensitivity and prognosis in epithelial ovarian cancer

2020 ◽  
Author(s):  
Yan Rong ◽  
Li Li
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Clinical Data ◽  
First Line ◽  
Clinical Value ◽  
Platinum Sensitivity ◽  
Platinum Sensitive ◽  
Platinum Resistant ◽  
Line Chemotherapy ◽  
Sensitive Group

Abstract Objectives: To assess the clinical value of early clearance of HE4 and CA125 for platinum sensitivity and prognosis in patients with ovarian cancer.Method: HE4 and CA125 value including clinical data of 89 patients with ovarian cancer were collected. The clearance of HE4 and CA125 were assessed base on the platinum sensitivity, two-year PFS, PFS and OS.Results: 16 patients were classified as platinum resistant and 73 as platinum sensitive according to the response to platinum-base chemotherapy. When HE4 clearance after 3rd cycle chemotherapy or CA125 clearance after 1st cycle chemotherapy, it gave the highest AUC of 0.788, with 100% of sensitivity and 57.5% of specificity respectively between platinum resistant and platinum sensitive group. In addition, 59 patients were classified as two-year PFS group and 30 as not achieved two-year PFS group according to obtaining two-year PFS or not. It gave the highest AUC of 0.730, with 83.3% of sensitivity and 62.7% of specificity respectively when HE4 clearance after 3rd cycle chemotherapy or CA125 clearance after 1st cycle. The prolonged PFS and OS were significantly associated by the clearance of HE4 after 3rd cycle chemotherapy (p<0.0001, p<0.0001) as well as CA125 after 1st cycle chemotherapy (p<0.0001, p<0.0001).Conclusions: Our data suggested that the early clearance of HE4 and CA125 could predict platinum response and prognosis in patients with ovarian cancer. Monitoring the HE4 and CA125 during first-line chemotherapy might be helpful in predicting platinum sensitivity and risk to progress and relapse.

scholarly journals Coexisting Molecular Determinants of Acquired Oxaliplatin Resistance in Human Colorectal and Ovarian Cancer Cell Lines

2019 ◽  
Vol 20 (15) ◽  
pp. 3619 ◽  
Author(s):  
Paul Noordhuis ◽  
Adrianus C. Laan ◽  
Kasper van de Born ◽  
Richard J. Honeywell ◽  
Godefridus J. Peters
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Array Cgh ◽  
Ovarian Cancer Cell ◽  
Ovarian Cancer Cell Line ◽  
Continuous Exposure ◽  
Platinum Accumulation ◽  
Repair Genes

Oxaliplatin (OHP) treatment of colorectal cancer (CRC) frequently leads to resistance. OHP resistance was induced in CRC cell lines LoVo-92 and LoVo-Li and a platinum-sensitive ovarian cancer cell line, A2780, and related to cellular platinum accumulation, platinum-DNA adducts, transporter expression, DNA repair genes, gene expression arrays, and array-CGH profiling. Pulse (4 h, 4OHP) and continuous exposure (72 h, cOHP) resulted in 4.0 to 7.9-fold and 5.0 to 11.8-fold drug resistance, respectively. Cellular oxaliplatin accumulation and DNA-adduct formation were decreased and related to OCT1-3 and ATP7A expression. Gene expression profiling and pathway analysis showed significantly altered p53 signaling, xenobiotic metabolism, role of BRCA1 in DNA damage response, and aryl hydrocarbon receptor signaling pathways, were related to decreased ALDH1L2, Bax, and BBC3 (PUMA) and increased aldo-keto reductases C1 and C3. The array-CGH profiles showed focal aberrations. In conclusion, OHP resistance was correlated with total platinum accumulation and OCT1-3 expression, decreased proapoptotic, and increased anti-apoptosis and homologous repair genes.

Bipterostilbene, a Novel Compound From Rhubarb, Specifically Inhibits the Proliferation of Malignant B Cells Via Inactivation of AKT/mTOR Signaling Pathway

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1423-1423
Author(s):  
You Hua Yu ◽  
Na Guo ◽  
Yujing Gong ◽  
Baidong Liu ◽  
Hong Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Tumor Cell ◽  
B Cell ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Tumor Cell Proliferation ◽  
Mtor Signaling Pathway ◽  
B Cell Malignancies

Abstract Abstract 1423 Patients with B cell malignaces initially respond to current treatment modalities, however, such malignances remain incurable. Many new therapeutic options have become available during the past several years but nearly all patients develop resistance to currently available therapeutic options. Ideally, a new treatment should inhibit tumor growth, improve the efficacy of other anti-tumor agents, and improve both the overal survial and the quality of life for patients. Pterostilbene is predominantly found in Rhubarb. We synthesized bipterostilbene (5-(4-(4-(3,5-dihydroxylstyryl)phenoxy)styryl)-benzene-1,3-diol) (C28H22O5) of a molecular weight of 438.48 Kda. In this study, we first examined whether bipterostilbene affects tumor cells proliferation using breast cancer, ovarian cancer, lymphoma and multiple myeloma (MM) cell lines. The results of the MTS assay demonstrated that bipterostilbene significantly inhibited tumor cell proliferation of the lymphoma cell line (Raji) and the MM cell lines (RPMI1640 and MM1s) at 48 hours (IC50: 5μM for Raji, 4μM for RPMI8226, and 2 μM for MM1s). The induction of tumor cell apoptosis was most prominent at 72 hours. The extent of the inhibition of tumor cell proliferation and the induction of apoptosis was concentration-dependent. Bipterostilbene had minimal effects on breast and ovarian cancer cell lines. Noteworthy, bipterostilbene had no detectable cytotoxic effects on normal human peripheral blood mononuclear cells (PBMCs). The molecular mechanism by which bipterostilbene mediates its effects was examined. Both the AKT and the NF-κB signaling transduction pathways have been reported to play key roles in B cell metabolism, proliferation and survival. Using RT-PCR, bipterostilbene specifically inhibited AKT1 and mTOR gene expression when Raji or RPMI8226 tumor cells were treated with the IC50 concentration of bipterostilbene for 24 hours. Analysis of downstream gene products of the AKT pathway revealed that Cyclin D1 expression was slightly reduced and P21Cip and P27 kip expressions were not changed. Bipterostilbene did not alter AKT2 or AKT3 gene expression, demonstrating that this compound is specifically targeting AKT1. We further determined whether bipterostilbene interfered with IGF1-induced AKT/mTOR activation or IL-1β –mediated NF-κB phosphorylation by Western blot. The results showed that bipterostilbene markedly inhibited IGF1-induced phosphorylation of AKT but did not interfere with IL-1β-induced NF-κB activity and IκB phosphorylation. Overall, the results of our in vitro studies demonstrate that bipterostilbene inhibits tumor cell proliferation and enhances apoptosis of B-cell malignancies via inhibition of the AKT/mTOR signaling pathway with no detectable effect on the NF-κB signaling pathway. Importantly, bipterostilbene is not cytotoxic on normal hematopoietic cells at concentrations that were highly toxic to B-cell malignancies. We propose that bipterostilbene may be better tolerated than other anti- cancer drugs that are currently being used for the treatment of B-cell malignancies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Integrative analysis of key candidate genes and signaling pathways in ovarian cancer by bioinformatics

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Cuicui Dong ◽  
Xin Tian ◽  
Fucheng He ◽  
Jiayi Zhang ◽  
Xiaojian Cui ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Candidate Genes ◽  
Differentially Expressed Genes ◽  
Expression Profiling ◽  
Overlapping Genes ◽  
Hub Genes ◽  
Gynecological Tumors ◽  
Normal Tissues ◽  
Cancer Tissues

Abstract Background Ovarian cancer is one of the most common gynecological tumors, and among gynecological tumors, its incidence and mortality rates are fairly high. However, the pathogenesis of ovarian cancer is not clear. The present study aimed to investigate the differentially expressed genes and signaling pathways associated with ovarian cancer by bioinformatics analysis. Methods The data from three mRNA expression profiling microarrays (GSE14407, GSE29450, and GSE54388) were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes between ovarian cancer tissues and normal tissues were identified using R software. The overlapping genes from the three GEO datasets were identified, and profound analysis was performed. The overlapping genes were used for pathway and Gene Ontology (GO) functional enrichment analysis using the Metascape online tool. Protein–protein interactions were analyzed with the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). Subnetwork models were selected using the plugin molecular complex detection (MCODE) application in Cytoscape. Kaplan–Meier curves were used to analyze the univariate survival outcomes of the hub genes. The Human Protein Atlas (HPA) database and Gene Expression Profiling Interactive Analysis (GEPIA) were used to validate hub genes. Results In total, 708 overlapping genes were identified through analyses of the three microarray datasets (GSE14407, GSE29450, and GSE54388). These genes mainly participated in mitotic sister chromatid segregation, regulation of chromosome segregation and regulation of the cell cycle process. High CCNA2 expression was associated with poor overall survival (OS) and tumor stage. The expression of CDK1, CDC20, CCNB1, BUB1B, CCNA2, KIF11, CDCA8, KIF2C, NDC80 and TOP2A was increased in ovarian cancer tissues compared with normal tissues according to the Oncomine database. Higher expression levels of these seven candidate genes in ovarian cancer tissues compared with normal tissues were observed by GEPIA. The protein expression levels of CCNA2, CCNB1, CDC20, CDCA8, CDK1, KIF11 and TOP2A were high in ovarian cancer tissues, which was further confirmed via the HPA database. Conclusion Taken together, our study provided evidence concerning the altered expression of genes in ovarian cancer tissues compared with normal tissues. In vivo and in vitro experiments are required to verify the results of the present study.

scholarly journals Apoptosis-related gene expression can predict the response of ovarian cancer cell lines to treatment with recombinant human TRAIL alone or combined with cisplatin

Clinics ◽  
2020 ◽  
Vol 75 ◽  
Author(s):  
Letícia da Conceição Braga ◽  
Nikole Gontijo Gonçales ◽  
Rafaela de Souza Furtado ◽  
Warne Pedro de Andrade ◽  
Luciana Maria Silva ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Cancer Cell Lines ◽  
Related Gene ◽  
Ovarian Cancer Cell Lines ◽  
Apoptosis Related Gene

scholarly journals An Integrative Analysis of Transcriptome and GWAS Data to Identify Potential Candidate Genes Influencing Meat Quality Traits in Pigs

2021 ◽  
Vol 12 ◽  
Author(s):  
Xianxian Liu ◽  
Junjie Zhang ◽  
Xinwei Xiong ◽  
Congying Chen ◽  
Yuyun Xing ◽  
...  
Keyword(s):  
Gene Expression ◽  
Candidate Genes ◽  
Meat Quality ◽  
Integrative Analysis ◽  
Potential Candidate ◽  
Quality Traits ◽  
Eqtl Mapping ◽  
Meat Quality Traits ◽  
Genome Wide ◽  
A Genome

Understanding the genetic factors behind meat quality traits is of great significance to animal breeding and production. We previously conducted a genome-wide association study (GWAS) for meat quality traits in a White Duroc × Erhualian F2 pig population using Illumina porcine 60K SNP data. Here, we further investigate the functional candidate genes and their network modules associated with meat quality traits by integrating transcriptomics and GWAS information. Quantitative trait transcript (QTT) analysis, gene expression QTL (eQTL) mapping, and weighted gene co-expression network analysis (WGCNA) were performed using the digital gene expression (DGE) data from 493 F2 pig’s muscle and liver samples. Among the quantified 20,108 liver and 23,728 muscle transcripts, 535 liver and 1,014 muscle QTTs corresponding to 416 and 721 genes, respectively, were found to be significantly (p &lt; 5 × 10−4) correlated with 22 meat quality traits measured on longissiums dorsi muscle (LM) or semimembranosus muscle (SM). Transcripts associated with muscle glycolytic potential (GP) and pH values were enriched for genes involved in metabolic process. There were 42 QTTs (for 32 genes) shared by liver and muscle tissues, of which 10 QTTs represent GP- and/or pH-related genes, such as JUNB, ATF3, and PPP1R3B. Furthermore, a genome-wide eQTL mapping revealed a total of 3,054 eQTLs for all annotated transcripts in muscle (p &lt; 2.08 × 10−5), including 1,283 cis-eQTLs and 1771 trans-eQTLs. In addition, WGCNA identified five modules relevant to glycogen metabolism pathway and highlighted the connections between variations in meat quality traits and genes involved in energy process. Integrative analysis of GWAS loci, eQTL, and QTT demonstrated GALNT15/GALNTL2 and HTATIP2 as strong candidate genes for drip loss and pH drop from postmortem 45 min to 24 h, respectively. Our findings provide valuable insights into the genetic basis of meat quality traits and greatly expand the number of candidate genes that may be valuable for future functional analysis and genetic improvement of meat quality.

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