Ascites exosomal lncRNA PLADE enhances platinum sensitivity by inducing R-loop in ovarian cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE247337 | GEO | 2023/11/15
REPOSITORIES: GEO
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Project description:Background: Despite an early response to platinum-based chemotherapy in advanced stage high-grade serous ovarian cancer (HGSOC), the majority of patients will relapse with drug-resistant disease. Aberrant epigenetic alterations like DNA methylation are common in HGSOC. Differences in DNA methylation are associated with chemoresponse in these patients. The objective of this study was to identify and validate novel epigenetic markers of chemoresponse using genome-wide analysis of DNA methylation in extreme chemoresponsive HGSOC patients. Methods: Genome-wide next-generation sequencing was performed on methylation-enriched tumor DNA of two HGSOC patient groups with residual disease, extreme responders (≥18 months progression-free survival (PFS), n = 8) and non-responders (≤6 months PFS, n = 10) to platinum-based chemotherapy. DNA methylation and expression data of the same patients were integrated to create a gene list. Genes were validated on an independent cohort of extreme responders (n = 21) and non-responders (n = 31) using pyrosequencing and qRT-PCR. In-silico validation was performed using publicly available DNA methylation (n = 91) and expression (n = 208) datasets of unselected advanced stage HGSOC patients. Functional validation of FZD10 on chemosensitivity was done in ovarian cancer cell lines using siRNA-mediated silencing. Results: Integrated genome-wide methylome and expression analysis identified 45 significantly differentially methylated and expressed genes between two chemoresponse groups. Four genes FZD10, FAM83A, MYO18B and MKX were successfully validated in an external set of extreme chemoresponsive HGSOC patients. High FZD10 and MKX methylation was related with extreme responders and high FAM83 and MYO18B methylation with extreme non-responders. In publicly available advanced stage HGSOC datasets, FZD10, MYO18B and MKX methylation levels were associated with PFS. High FZD10 methylation was strongly associated with improved PFS [HR=0.43, 95%CI=0.27-0.65, p=0.0002]. Consistently, low FZD10 expression was associated with improved PFS [HR=1.36, 95%CI=0.99-1.88, p=0.058]. FZD10 silencing caused significant sensitization towards cisplatin treatment in survival assays and apoptosis assays. Conclusions: By applying genome-wide integrated methylome analysis on extreme chemoresponsive HGSOC patients, we identified novel clinically relevant, epigenetically-regulated markers of platinum-sensitivity in HGSOC patients. The clinical potential of these markers in predictive and therapeutic approaches has to be further validated in prospective studies.
2017-08-17 | GSE97128 | GEO
Project description:Peritoneal carcinomatosis with malignant ascites is associated with dismal prognosis in gastric cancer. Malignant ascites is the most relevant body fluid in which to seek diagnostic biomarkers for peritoneal carcinomatosis. We aimed to identify and validate ascites-derived circulating microRNAs (miRNAs) that are differentially expressed between liver cirrhosis-associated benign ascites (LC-ascites) and gastric cancer-associated malignant ascites (GC-ascites). MiRNA expression levels were investigated in three independent cohorts. Overall, 165 ascites samples (73 LC-ascites and 92 GC-ascites) were obtained from the National Biobank of Korea. Initially, microarrays were used to screen the expression levels of 2,006 miRNAs in the discovery cohort (n = 22). Subsequently, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analyses were used to validate the expression levels of selected miRNAs in the training (n = 70) and validation (n= 73) cohorts. In addition, the levels of carcinoembryonic antigen (CEA), a commonly used tumor marker, were determined in the ascites samples. Expression levels of miR-574-3p, miR-181b-5p, miR-4481, and miR-181d were significantly lower in the GC-ascites samples than in the LC-ascites samples, and miR-181b-5p showed the best diagnostic performance for GC-ascites (area under the curve [AUC] = 0.798 and 0.846 for the training and validation cohorts, respectively). The diagnostic performance of CEA for GC-ascites was improved if CEA and miR-181b-5p were analyzed together (AUC = 0.981 and 0.946 for the training and validation cohorts, respectively). Overall, we identified ascites-derived circulating miRNAs capable of differentiating non-malignant ascites and GC-ascites, and demonstrated that the combined use of miR-181b-5p and CEA produces the optimal diagnostic yield.
2019-02-12 | GSE126399 | GEO
Project description:Introduction: Although High Grade Serous Ovarian Cancer (HGSOC) is considered a chemo-responsive disease, a proportion of patients do not respond to platinum-based chemotherapy at presentation or have progression-free survival of <6 months. Validated biomarkers of lack of response would enable alternative treatment stratification for these patients and identify novel mechanisms of resistance. Methods: Differential DNA methylation was investigated in independent tumour sets using Illumina 27K HumanMethylation arrays and validated by bisulphite pyrosequencing. Gene expression was by Affymetrix arrays and qRT-PCR. The role of Msh homeobox 1 (MSX1) in drug sensitivity was investigated by gene reintroduction into ovarian cancer cell lines. Results: CpG sites at contiguous genomic locations within the MSX1 gene have significantly lower levels of methylation in HGSOC which recur by 6 months compared to after 12 months and/or with RECIST response (p<0.05, q<0.05). A decrease in methylation at these intragenic CpG sites was significantly correlated with decreased MSX1 gene expression. Low expression of MSX1 was associated with poor progression-free survival independent of known clinical prognostic features (p=0.014). Three mutant or wild-type TP53 expressing ovarian cancer cell lines, resistant to cisplatin, have reduced MSX1 expression compared to matched parental, platinum sensitive, lines. Re-expression of MSX1 in resistant lines led to cisplatin sensitisation, increased apoptosis, increased p21 and BAX expression. However, in two TP53-null cell lines, MSX1 failed to change cisplatin sensitivity. Conclusion: Hypomethylation of MSX1 is a biomarker of resistant HGSOC disease at presentation and identifies a novel mechanism of platinum drug resistance. Bisulphite converted DNA from the 86 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2
2015-11-26 | E-GEOD-75414 | biostudies-arrayexpress
Project description:RNA-seq of FFPE-macrodissected HGSOC tissues and solid and ascites-derived HGSOC 2D cultures
| PRJEB40519 | ENA
Project description:Differ from the aggressive nature of HGSOC (high grade serous ovarian cancer), LGSOC (low grade serous ovarian cancer) is characterized by an early age of disease onset, slow growth pattern, and poor response to chemotherapy. To understand more specifically the underlying gene profiling discrepancy that contributes to their behavior distinction, we performed parallel gene expression profiling in 9 magnetic sorted tumor cells samples from matched primary tumors, ascites and metastases of 3 LGSOC patients as in HGSOC. By comparing the expression data among primary tumor cells, ascitic tumor cells and metastasis tumor cells, we identified a set of differential expressed genes along LGSOC progression. Further study revealed that the gene phenotype perturbance along LGSOC progression was quite different from that of HGSOC patients. We used microarrays to profile the expression of 9 matched tumor cells samples in order to identify molecular alteration between primary tumor cells, ascitic tumor cells and metastatic tumor cells in low grade serous ovarian cancer.
2017-12-19 | GSE73091 | GEO
Project description:Gastric cancer is one of the most lethal malignancies with high mortality and gastric cancer-specific biomarker is need due to the lack of specific method for early screening, diagnosis, and prognosis of the patients with gastric cancer. Ascites is known for an important source for conducing biomarker discovery because it contains the secreted proteins from malignant cells, growth factors, and cytokines. In this study, we have conducted a comprehensive proteome study using ascites of patients with inflammatory diseases and gastric cancer. In the discovery stage, we have identified 2761 ascites-specific proteins, where 234 proteins were quantitated using the label free quantitation method, the normalized spectral abundance factor (NSAF); 152 and 82 proteins showed up and down-regulated pattern, respectively. Our ascites proteome can be used as baseline data for the discovery of novel biomarkers of the gastric cancer.
2018-04-16 | PXD002213 | Pride
Project description:Introduction: Although High Grade Serous Ovarian Cancer (HGSOC) is considered a chemo-responsive disease, a proportion of patients do not respond to platinum-based chemotherapy at presentation or have progression-free survival of <6 months. Validated biomarkers of lack of response would enable alternative treatment stratification for these patients and identify novel mechanisms of resistance. Methods: Differential DNA methylation was investigated in independent tumour sets using Illumina 27K HumanMethylation arrays and validated by bisulphite pyrosequencing. Gene expression was by Affymetrix arrays and qRT-PCR. The role of Msh homeobox 1 (MSX1) in drug sensitivity was investigated by gene reintroduction into ovarian cancer cell lines. Results: CpG sites at contiguous genomic locations within the MSX1 gene have significantly lower levels of methylation in HGSOC which recur by 6 months compared to after 12 months and/or with RECIST response (p<0.05, q<0.05). A decrease in methylation at these intragenic CpG sites was significantly correlated with decreased MSX1 gene expression. Low expression of MSX1 was associated with poor progression-free survival independent of known clinical prognostic features (p=0.014). Three mutant or wild-type TP53 expressing ovarian cancer cell lines, resistant to cisplatin, have reduced MSX1 expression compared to matched parental, platinum sensitive, lines. Re-expression of MSX1 in resistant lines led to cisplatin sensitisation, increased apoptosis, increased p21 and BAX expression. However, in two TP53-null cell lines, MSX1 failed to change cisplatin sensitivity. Conclusion: Hypomethylation of MSX1 is a biomarker of resistant HGSOC disease at presentation and identifies a novel mechanism of platinum drug resistance.
2015-11-26 | GSE75414 | GEO
Project description:Characterizations of ascites proteome from ovarian PC and gastric PC have demonstrated that ascites contains elevated pro-tumorigenic factors. Reasoning that the composition of ascitic fluid might offer insight into the memory of key biological events occurring intra-abdominally, we hypothesized that paracrine factors essential for survival and growth of peritoneal deposits are secreted into and circulate within ascitic fluid. Our data from cytokine array profile suggest that ascites contains biologically active ligands capable of supporting cellular functions of cancer cells. To decipher downstream signalling pathways activated in cancer cells when exposed to ascites, we performed gene expression analysis of Colo-205 and SNU-C1 cells upon exposure to PC ascites.
2022-02-22 | GSE189004 | GEO
Project description:Epithelial ovarian cancer (EOC) is the most lethal gynecological tumor in developed countries and is characterized by high biological and molecular heterogeneity. High-grade serous ovarian carcinoma (HGSOC) is the most frequent and intractable form of the disease, mainly due to its rapid dissemination into the abdominal cavity, a process that is tightly linked to peritoneal ascites. Despite several studies provided insights into the genetic and epigenetic alterations relevant in EOC, the precise molecular alterations involved in tumor onset and progression remain largely unknown. Here we provide an experimental framework to perform a comprehensive investigation of molecular alterations relevant in HGSOC and ovarian cancer stem cells (OCSC) biology. We relied on a well characterized experimental set derived from human HGSOC-associated ascites and consisting of primary tumor cells, OCSC-enriched spheroids and serially propagated patient-derived xenografts, in order to define genetic and transcriptional signatures associated to specific HGSOC evolutionary trajectories. Such signatures exhibited prognostic value in a large cohort of HGSOC patients and allowed to define PI3K signaling as a novel vulnerability in OCSCs. Thus, our approach proved effective for the identification of druggable targets in HGSOC ascites, which is a major player in relapse and poor prognosis.
2022-02-18 | GSE154950 | GEO
Project description:Microarrays were used to examine gene expression changes in the surgical resections of high-grade serous ovarian cancer patients exhibiting clinically distinct levels of ascites volume. The present studies primary aim was to determine if there is a molecular gene expression difference between the patients presenting at time of surgery when high volumes ascites cases were compared to those with low volume ascites. The secondary aim was to determine what relevance this difference, if found, has to previously discovered molecular sub-types of high grade serous ovarian cancer. Total RNA obtained from snap-frozen stage III-IV high-grade serous ovarian cancer patients presenting with low volume (<=200 cc) or high volume (>=1000 cc) ascites volume.
2014-10-01 | E-GEOD-51831 | biostudies-arrayexpress