DNA methylation characteristics associated with chemotherapy resistance in epithelial ovarian cancer
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PROVIDER: S-EPMC10926131 | biostudies-literature | 2024 Feb
REPOSITORIES: biostudies-literature
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Project description:ObjectiveLAMA3 is a widely studied methylated gene in multiple tumors, but the relationship between chemotherapy resistance in ovarian cancer is unclear. In this study, LAMA3 methylation was predicted by bioinformatics, and the ability of LAMA3 methylation to predict the chemotherapy resistance and prognosis of ovarian cancer was confirmed in experiments.MethodsMultiple databases have performed the bioinformatics analysis of methylation and transcription factor binding site (TFBS) on the promoter region of LAMA3 gene. Pyrosequencing detected the methylation of LAMA3. QRT-PCR and immunohistochemistry detected the expression of LAMA3. Real Time Cell Analyzer (RTCA) detects changes in cell proliferation, migration and invasion ability. Flow cytometry was used to detect apoptosis.ResultsCPG islands of 176 bp, 134 bp, 125 bp and 531 bp were predicted in the promoter region of LAMA3 gene. The 4 prediction results are basically overlapped. 7 transcription factor binding sites were predicted, and the one with the highest score was on the predicted CpG island located in the proximal promoter region. LAMA3 hypermethylation and low expression are both associated with chemotherapy resistance and poor prognosis in ovarian cancer. LAMA3 methylation was negatively correlated with expression. After upregulation of LAMA3, the proliferation ability of chemoresistant ovarian cancer cell decreased, while the ability of apoptosis, invasion and migration increased.ConclusionLAMA3 hypermethylation is associated with chemotherapy resistance and poor prognosis. As a typical CpG island gene, LAMA3(cg20937934) and LAMA3(cg13270625) hypermethylation is negatively correlated with low expression. LAMA3 promotes the invasion, migration and apoptosis of SKOV3DDP. In the future, the mechanism of LAMA3 methylation in ovarian cancer will need to be further studied.
| S-EPMC8126133 | biostudies-literature
Project description:To identify potential aberrantly differentially methylated genes (DMGs) correlated with chemotherapy response (CR) and establish a polygenic methylation prediction model of CR in epithelial ovarian cancer (EOC), we accessed 177 (47 chemo-sensitive and 130 chemo-resistant) samples corresponding to three DNA-methylation microarray datasets from the Gene Expression Omnibus and 306 (290 chemo-sensitive and 16 chemo-resistant) samples from The Cancer Genome Atlas (TCGA) database. DMGs associated with chemotherapy sensitivity and chemotherapy resistance were identified by several packages of R software. Pathway enrichment and protein-protein interaction (PPI) network analyses were constructed by Metascape software. The key genes containing mRNA expressions associated with methylation levels were validated from the expression dataset by the GEO2R platform. The determination of the prognostic significance of key genes was performed by the Kaplan-Meier plotter database. The key genes-based polygenic methylation prediction model was established by binary logistic regression. Among accessed 483 samples, 457 (182 hypermethylated and 275 hypomethylated) DMGs correlated with chemo resistance. Twenty-nine hub genes were identified and further validated. Three genes, anterior gradient 2 (AGR2), heat shock-related 70-kDa protein 2 (HSPA2), and acetyltransferase 2 (ACAT2), showed a significantly negative correlation between their methylation levels and mRNA expressions, which also corresponded to prognostic significance. A polygenic methylation prediction model (0.5253 cutoff value) was established and validated with 0.659 sensitivity and 0.911 specificity.
| S-EPMC7943968 | biostudies-literature
Project description:High-grade serous ovarian cancer is the most common ovarian cancer type. Although the combination of surgery and platinum-taxane chemotherapy provide an effective treatment, drug resistance frequently occurs leading to poor outcome. In order to clarify the molecular mechanisms of drug resistance, the DNA methylation and transcriptomic changes, associated with the development of drug resistance in high-grade serous ovarian cancer, were examined from patient derived malignant ascites cells. In parallel with large-scale transcriptome changes, cisplatin resistance was associated with loss of hypermethylation at several CpG sites primarily localized in the intergenic regions of the genome. The transcriptome and CpG methylome changes in response to cisplatin treatment of both sensitive and resistant cells were minimal, indicating the importance of post-translational mechanisms in regulating death or survival of the cells. The response of resistant cells to high concentrations of cisplatin revealed transcriptomic changes in potential key drivers of drug resistance, such as KLF4. Among the strongest changes was also induction of IL6 in resistant cells and the expression was further increased in response to cisplatin. Also, several other components of IL6 signaling were affected, further supporting previous observations on its importance in malignant transformation and development of drug resistance in ovarian cancer.
| S-EPMC5431431 | biostudies-literature
Project description:JARID1B, a histone demethylase, has been reported to be highly expressed in various human cancers. In the present study, we investigated the association of JARID1B level with epithelial ovarian cancer (EOC) and prognosis of patients with EOC. We analyzed JARID1B expression in 20 normal ovaries, 20 benign ovarian tumor (BOT) samples, and 45 epithelial ovarian carcinoma specimens by quantitative PCR (qRT-PCR) and western blotting analyses. JARID1B was further examined in 120 EOC specimens from patients with different histological stages via immunohistochemistry. Possible correlations between JARID1B levels and prognosis as well as chemotherapy resistance of EOC patients were determined by univariate and multivariate analyses. JARID1B level was significantly increased in EOC, as compared to normal ovaries and BOT. Among 120 EOC cases examined, the 5-year progression-free survival (PFS) rates were 17 and 85% in patients with high and low JARID1B expression, respectively (hazard ratio = 17.85, 95% confidence interval (CI) 6.31-50.51, P < 0.001). Similarly, the 5-year overall survival (OS) rates for patients with high and low JARID1B expression were 28 and 92% respectively (hazard ratio = 21.8, 95% CI 5.92-71.81, P < 0.001). Positive correlation between JARID1B level and chemotherapy resistance was observed in patients with EOC (odds ratio (OR) 36.81, 95% CI 4.84-280.11, P < 0.001). JARID1B could serve as an important biomarker for prognosis and chemotherapy resistance of EOC patients.
| S-EPMC4428534 | biostudies-literature
Project description:Background: Platinum resistance poses a significant problem for oncology clinicians. As a result, the role of epigenetics and DNA methylation in platinum-based chemoresistance has gained increasing attention from researchers in recent years. A systematic investigation of aberrant methylation patterns related to platinum resistance across various cancer types is urgently needed. Methods: We analyzed the platinum chemotherapy response-related methylation patterns from different perspectives of 618 patients across 13 cancer types and integrated transcriptional and clinical data. Spearman's test was used to evaluate the correlation between methylation and gene expression. Cox analysis, the Kaplan-Meier method, and log-rank tests were performed to identify potential risk biomarkers based on differentially methylated positions (DMPs) and compare survival based on DMP values. Support vector machines and receiver operating characteristic curves were used to identify the platinum-response predictive DMPs. Results: A total of 3,703 DMPs (p value < 0.001 and absolute delta beta >0.10) were identified, and the DMP numbers of each cancer type varied. A total of 39.83% of DMPs were hypermethylated and 60.17% were hypomethylated in platinum-resistant patients. Among them, 405 DMPs (Benjamini and Hochberg adjusted p value < 0.05) were found to be associated with prognosis in tumor patients treated with platinum-based regimens, and 664 DMPs displayed the potential to predict platinum chemotherapy response. In addition, we defined six DNA DMPs consisting of four gene members (mesothelin, protein kinase cAMP-dependent type II regulatory subunit beta, msh homeobox 1, and par-6 family cell polarity regulator alpha) that may have favorable prognostic and predictive values for platinum chemotherapy. Conclusion: The methylation-transcription axis exists and participates in the complex biological mechanism of platinum resistance in various cancers. Six DMPs and four associated genes may have the potential to serve as promising epigenetic biomarkers for platinum-based chemotherapy and guide clinical selection of optimal treatment.
| S-EPMC8117351 | biostudies-literature
Project description:BackgroundLow expression of NCALD(neurocalcin delta) in peripheral blood of ovarian cancer patients predicts poor prognosis. However, the molecular mechanism of NCALD in ovarian cancer and its relationship with chemotherapy outcomes is unclear. The aim of this study was to investigate the potential signaling pathways of NCALD and to evaluate its ability to predict chemotherapy outcomes and prognosis.MethodsHigh-throughput RNA sequencing data were downloaded from TCGA. GSEA explored the potential signaling pathways of NCALD. The expression of NCALD in chemotherapy sensitive and chemotherapy resistant ovarian cancer patients was detected by TCGA data and clinical samples. ROC analysis confirmed the ability of NCALD to predict chemotherapy outcomes. The association between NCALD expression and prognosis in ovarian cancer patients was assessed using Kaplan-Meier plotter.ResultsIn patients with NCALD overexpression, genes expression related to ERK1 / 2 signaling pathway, NF-kappaB signaling pathway, TGF-β signaling pathway and immune response pathway was increased, especially ERK1 / 2 signaling pathway. The expression of NCALD in chemoresistant patients was significantly lower than chemosensitive patients. In TCGA data and immunohistochemical samples, the AUC of NCALD expression predicting chemotherapy outcome was 0.59 and 0.64, respectively. In clinical samples, low expression of NCALD was associated with poor OS and PFS.ConclusionsNCALD may activate the ERK1 / 2 signaling pathway in ovarian cancer. As a new biomarker of chemotherapy sensitivity, NCALD was significantly down-regulated in chemotherapy resistance ovarian cancer patients. Low expression of NCALD in ovarian cancer is associated with poor OS and PFS. In the future, further research will be needed on the potential mechanism and clinical application value of NCALD in ovarian cancer.
| S-EPMC7106630 | biostudies-literature
Project description:BackgroundEsophageal squamous cell carcinoma (ESCC) is one of the most severe cancers and is characterized by chemotherapy resistance and poor prognosis associated with epithelial-mesenchymal transition (EMT). In a previous study, a low mitochondrial DNA (mtDNA) copy number was associated with poorer prognosis and induced EMT in ESCC. However, the detailed mechanism related to mtDNA copy number and EMT is unclear. The aim of this study was to clarify the mechanism by which a change in mtDNA copy number contributes to EMT and to examine treatment of chemotherapy resistance in ESCC.MethodsThe association between low mtDNA copy number and chemotherapy resistance was investigated using specimens from 88 patients who underwent surgery after neoadjuvant chemotherapy. Then, the mtDNA content of human ESCC cell lines, TE8 and TE11, was depleted by knockdown of mitochondrial transcription factor A expression. The present study focused on modulation of mitochondrial membrane potential (MMP) and DNA methylation as the mechanisms by which mtDNA copy number affects EMT. mRNA and protein expression, chemotherapy sensitivity, proliferation, MMP and DNA methylation were evaluated, and in vitro and in vivo assays were conducted to clarify these mechanisms.ResultsESCC patients with decreased mtDNA copy number who underwent R0 resection after neoadjuvant chemotherapy had significantly worse pathological response and recurrence-free survival. Additionally, low mtDNA copy number was associated with resistance to chemotherapy in vitro and in vivo. mtDNA controlled MMP, and MMP depolarization induced EMT. Depletion of mtDNA and low MMP induced DNA methylation via a DNA methylation transcription factor (DNMT), and a DNMT inhibitor suppressed EMT and improved chemotherapy sensitivity in mtDNA-depleted ESCC cells, as shown by in vitro and in vivo assays.ConclusionThis study showed that decreased mtDNA copy number induced EMT via modulation of MMP and DNA methylation in ESCC. Therapeutic strategies increasing mtDNA copy number and DNMT inhibitors may be effective in preventing EMT and chemosensitivity resistance.
| S-EPMC9422107 | biostudies-literature
Project description:The vacuolar ATPase H+ transporting V1 subunit B1 (ATP6V1B1) belongs to the family of ATP6Vs, which functions to transport hydrogen ions. The expression of ATP6V1B1 and associated clinicopathological features have been linked to various cancers; however, its role in epithelial ovarian cancer (EOC) has remained to be explored. The present study aimed to unveil the function, molecular mechanisms and clinical significance of ATP6V1B1 in EOC. The mRNA levels of ATP6V1 subunits A, B1 and B2 in EOC tissues were determined using data from the Gene Expression Profiling Interactive Analysis database and RNA sequencing. Protein levels of ATP6V1B1 were evaluated through immunohistochemistry staining of EOC, borderline, benign and normal epithelial tissues. The association between ATP6V1B1 expression and clinicopathological features and prognosis of patients with EOC was analyzed. Furthermore, the biological role of ATP6V1B1 in ovarian cancer cell lines was also assessed. RNA sequencing and public dataset analyses revealed elevated ATP6V1B1 mRNA levels in EOCs. High ATP6V1B1 protein levels were also observed in EOC compared with those of borderline and benign tumors and nonadjacent normal epithelial tissues. High ATP6V1B1 expression was associated with the serous cell type, advanced International Federation of Gynecology and Obstetrics stage, high/advanced tumor grade, elevated serum cancer antigen 125 levels and platinum resistance (P<0.001, P<0.001, P=0.035, P=0.029 and P=0.011, respectively). High expression levels of ATP6V1B1 were also associated with poor overall and disease‑free survival (P<0.001). Knockdown of ATP6V1B1 decreased cancer cell proliferation and colony‑forming abilities (P<0.001) in vitro by inducing cell cycle arrest in G0/G1 phase. Significant upregulation of ATP6V1B1 was observed in EOC and the prognostic significance and association with chemotherapy resistance of ATP6V1B1 in EOC was demonstrated, rendering it an EOC‑related biomarker for prognostic evaluation and chemotherapy resistance, as well as a potential therapeutic target for patients with EOC.
| S-EPMC10091082 | biostudies-literature
Project description:BackgroundEpithelial ovarian cancer (EOC) is a spectrum of different diseases, which makes their treatment a challenge. Forkhead box M1 (FOXM1) is an oncogene aberrantly expressed in many solid cancers including serous EOC, but its role in non-serous EOCs remains undefined. We examined FOXM1 expression and its correlation to prognosis across the three major EOC subtypes, and its role in tumorigenesis and chemo-resistance in vitro.MethodsGene signatures were generated by microarray for 14 clear-cell and 26 endometrioid EOCs, and 15 normal endometrium snap-frozen biopsies. Validation of FOXM1 expression was performed by RT-qPCR and immunohistochemistry in the same samples and additionally in 50 high-grade serous EOCs and in their most adequate normal controls (10 luminal fallopian tube and 20 ovarian surface epithelial brushings). Correlations of FOXM1 expression to clinic-pathological parameters and patients' prognosis were evaluated by Kaplan-Meier and Cox proportional-hazards analyses. OVCAR-3 and two novel deeply characterized EOC cell lines (EOC-CC1 and OSPC2, with clear-cell and serous subtype, respectively) were employed for in vitro studies. Effects of FOXM1 inhibition by transient siRNA transfection were evaluated on cell-proliferation, cell-cycle, colony formation, invasion, and response to conventional first- and second-line anticancer agents, and to the PARP-inhibitor olaparib. Gene signatures of FOXM1-silenced cell lines were generated by microarray and confirmed by RT-qPCR.ResultsA significant FOXM1 mRNA up-regulation was found in EOCs compared to normal controls. FOXM1 protein overexpression significantly correlated to serous histology (p = 0.001) and advanced FIGO stage (p = 0.004). Multivariate analyses confirmed FOXM1 protein overexpression as an independent indicator of worse disease specific survival in non-serous EOCs, and of shorter time to progression in platinum-resistant cases. FOXM1 downregulation in EOC cell lines inhibited cell growth and clonogenicity, and promoted the cytotoxic effects of platinum compounds, doxorubicin hydrochloride and olaparib. Upon FOXM1 knock-down in EOC-CC1 and OSPC2 cells, microarray and RT-qPCR analyses revealed the deregulation of several common and other unique subtype-specific FOXM1 putative targets involved in cell cycle, metastasis, DNA repair and drug response.ConclusionsFOXM1 is up-regulated in all three major EOCs subtypes, and is a prognostic biomarker and a potential combinatorial therapeutic target in platinum resistant disease, irrespective of tumor histology.
| S-EPMC5422964 | biostudies-literature
Project description:Ovarian cancer is the most-deadly gynecologic malignancy, with greater than 14,000 women expected to succumb to the disease this year in the United States alone. In the front-line setting, patients are treated with a platinum and taxane doublet. Although 40-60% of patients achieve complete clinical response to first-line chemotherapy, 25% are inherently platinum-resistant or refractory with a median overall survival of about one year. More than 80% of women afflicted with ovarian cancer will recur. Many attempts have been made to understand the mechanism of platinum and taxane based chemotherapy resistance. However, despite decades of research, few predictive markers of chemotherapy resistance have been identified. Here, we review the current understanding of one of the most common genetic alterations in epithelial ovarian cancer, CCNE1 (cyclin E1) amplification, and its role as a potential predictive marker of cytotoxic chemotherapy resistance. CCNE1 amplification has been identified as a primary oncogenic driver in a subset of high grade serous ovarian cancer that have an unmet clinical need. Understanding the interplay between cyclin E1 amplification and other common ovarian cancer genetic alterations provides the basis for chemotherapeutic resistance in CCNE1 amplified disease. Exploration of the effect of cyclin E1 amplification on the cellular machinery that causes dysregulated proliferation in cancer cells has allowed investigators to explore promising targeted therapies that provide the basis for emerging clinical trials.
| S-EPMC7277958 | biostudies-literature