Inhibition of RUNX2 transcriptional activity blocks the proliferation, migration and invasion of epithelial ovarian carcinoma cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE46477 | GEO | 2013/09/23
SECONDARY ACCESSION(S): PRJNA200588
REPOSITORIES: GEO
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Project description:Previously, we have identified the RUNX2 gene as hypomethylated and overexpressed in post-chemotherapy (CT) primary cultures derived from epithelial ovarian cancer (EOC) patients, when compared to primary cultures derived from matched primary (prior to CT) tumors. However, we found no differences in the RUNX2 methylation in primary EOC tumors and EOC omental metastases, suggesting that DNA methylation-based epigenetic mechanisms have no impact on RUNX2 expression in advanced (metastatic) stage of the disease. Moreover, RUNX2 displayed significantly higher expression not only in metastatic tissue, but also in high-grade primary tumors and even in low malignant potential tumors. Knockdown of the RUNX2 expression in EOC cells led to sharp decrease of cell proliferation and significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as various genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon RUNX2 suppression, while a number of pro-apoptotic genes and some EOC tumor suppressor genes were induced. Taken together, our data are indicative for a strong oncogenic potential of the RUNX2 gene in EOC progression and suggest that RUNX2 might be a novel EOC therapeutic target. Further studies are needed to more completely elucidate the functional implications of RUNX2 and other members of the RUNX gene family in ovarian tumorigenesis. To better understand the molecular mechanisms of RUNX2 gene action in ovarian cancer cells, we employed the Agilent Whole Human Genome microarrays, containing ~ 44,000 genes to identify global gene expression changes upon RUNX2 suppression in SKOV3 cells. We compared the gene expression of the previously selected clone shRNA- RUNX2-knockdown clone 3 (cl3) against the corresponding control clone. The microarray experiments were performed in duplicates, as two hybridizations were carried out for the RUNX2-suppressing cell clone against the corresponding control, using a fluorescent dye reversal (dye-swap) technique.
2013-09-23 | E-GEOD-46477 | biostudies-arrayexpress
Project description:Chemotherapy (CT) resistance in ovarian cancer is broad and encompasses diverse, unrelated drugs, suggesting more than one mechanism of resistance. We aimed to analyze the gene expression patterns in primary serous epithelial ovarian cancer (EOC) samples displaying different responses to first-line CT in an attempt to identify specific molecular signatures associated with response to CT. Initially, the expression profiles of 15 chemoresistant serous EOC tumors [time to recurrence (TTR) ≤6 months] and 10 chemosensitive serous EOC tumors (TTR ≥30 months) were independently analyzed which allowed the identification of specific sets of differentially expressed genes that might be functionally implicated in the evolution of the chemoresistant or the chemosensitive phenotype. Our data suggest that the intrinsic chemoresistance in serous EOC cells may be attributed to the combined action of different molecular mechanisms and factors linked with drug influx and efflux and cell proliferation, as possible implications of other molecular events including altered metabolism, apoptosis and inflammation cannot be excluded. Next, gene expression comparison using hierarchical clustering clearly distinguished chemosensitive and chemo- resistant tumors from the 25 serous EOC samples (training set), and consecutive class prediction analysis was used to develop a 43-gene classifier that was further validated in an independent cohort of 15 serous EOC patients and 2 patients with other ovarian cancer histotypes (test set). The 43-gene predictor set properly classified serous EOC patients at high risk for early (≤22 months) versus late (>22 months) relapse after initial CT. Thus, gene expression array technology can effectively classify serous EOC tumors according to CT response. The proposed 43-gene model needs further validation. 2 condition experiment: chemoresistant clinical samples versus chemosensitive samples
2011-07-23 | E-GEOD-28739 | biostudies-arrayexpress
Project description:Chemotherapy (CT) resistance in ovarian cancer is broad and encompasses diverse, unrelated drugs, suggesting more than one mechanism of resistance. We aimed to analyze the gene expression patterns in primary serous epithelial ovarian cancer (EOC) samples displaying different responses to first-line CT in an attempt to identify specific molecular signatures associated with response to CT. Initially, the expression profiles of 15 chemoresistant serous EOC tumors [time to recurrence (TTR) ≤6 months] and 10 chemosensitive serous EOC tumors (TTR ≥30 months) were independently analyzed which allowed the identification of specific sets of differentially expressed genes that might be functionally implicated in the evolution of the chemoresistant or the chemosensitive phenotype. Our data suggest that the intrinsic chemoresistance in serous EOC cells may be attributed to the combined action of different molecular mechanisms and factors linked with drug influx and efflux and cell proliferation, as possible implications of other molecular events including altered metabolism, apoptosis and inflammation cannot be excluded. Next, gene expression comparison using hierarchical clustering clearly distinguished chemosensitive and chemo- resistant tumors from the 25 serous EOC samples (training set), and consecutive class prediction analysis was used to develop a 43-gene classifier that was further validated in an independent cohort of 15 serous EOC patients and 2 patients with other ovarian cancer histotypes (test set). The 43-gene predictor set properly classified serous EOC patients at high risk for early (≤22 months) versus late (>22 months) relapse after initial CT. Thus, gene expression array technology can effectively classify serous EOC tumors according to CT response. The proposed 43-gene model needs further validation.
2011-07-24 | GSE28739 | GEO
Project description:Previously, we have identified cytosolic form of the grainyhead transcription factor 2 gene (GRHL2) as notably hypomethylated in low-malignant potential (LMP) and high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. Here we show that GRHL2 is strongly overexpressed in both LMP and HG serous EOC tumors, thus suggesting that epigenetic mechanisms might be implicated in GRHL2 overexpression in serous epithelial ovarian cancer (EOC). Knockdown of the GRHL2 expression in EOC cells led to sharp decrease of cell proliferation and induced G1-phase cell cycle arrest. Additionally, GRHL2 suppression significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon BCAT1 suppression, while some tumor suppressor genes were induced. Taken together, our data are indicative for a strong oncogenic potential of the GRHL2 gene in advanced EOC and identify this transaminase as a novel EOC biomarker and putative EOC therapeutic target.
2017-04-21 | GSE90132 | GEO
Project description:Previously, we have identified cytosolic form of the branched chain amino-acid transaminase 1 (BCAT1) as notably hypomethylated in low-malignant potential (LMP) and high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. Here we show that BCAT1 is strongly overexpressed in both LMP and HG serous EOC tumors, thus suggesting that epigenetic mechanisms might be implicated in BCAT1 overexpression in serous epithelial ovarian cancer (EOC). Knockdown of the BCAT1 expression in EOC cells led to sharp decrease of cell proliferation and induced S-phase cell cycle arrest. Additionally, BCAT1 suppression significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon BCAT1 suppression, while some tumor suppressor genes were induced. Taken together, our data are indicative for a strong oncogenic potential of the BCAT1 gene in advanced EOC and identify this transaminase as a novel EOC biomarker and putative EOC therapeutic target.
2015-10-01 | GSE64424 | GEO
Project description:Epithelial ovarian cancer (EOC) accounts for 4% of all cancers in women and is the leading cause of death from gynecologic malignancies. It is well established that cancer invasion and metastasis still represent the major causes of the failure of cancer treatment. Previously, we identified the mannose receptor LY75 (DEC205/CD205) gene as notably hypomethylated in high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. LY75 has been identified as a putative antigen-uptake receptor, which is expressed abundantly on dendritic cells, which are specialist antigen presenting cells to T lymphocytes for the initiation of an immune response. The implication of LY75 in EOC tumorigenesis is currently unknown. Here we show that LY75 is strongly overexpressed in HG serous EOC tumors as compared to normal ovarian tissue. Importantly, shRNA-mediated LY75 knockout in the mesenchymal EOC cells (SKOV3) led to mesenchymal to epithelial transition (MET), associated with overexpression of epithelial markers E-cadherin and EPCAM and loss of expression of mesenchymal markers Fibronectin, N-cadherin Snail1 and Twist1. In addition, LY75 suppression significantly inhibited EOC cell migration and invasion in vitro. However, LY75 knockdown led to enhanced tumor cell dissemination and significantly increased lethality in vivo, in xenograft model of advanced peritoneal EOC. Thus, our findings indicate that LY75 could play an essential role in the mesenchymal-to-epithelial transition (MET) of EOC cells and support the hypothesis that, while epithelial-to-mesenchymal transition (EMT) enables the invasiveness of tumor cells, a MET-associated epithelial phenotype could be essential for their metastatic colonization. To better understand the molecular mechanisms of LY75 gene action in epithelial ovarian cancer (EOC), we employed the Agilent Whole Human Genome microarrays, containing ~ 44,000 genes to identify global gene expression changes upon LY75 suppression in SKOV3 EOC cells. We compared the gene expression of the previously selected shRNA-mediated LY75-knockdown clones sh-S3 and sh-S6 against the corresponding control (ctrl) clone. The microarray experiments were performed in duplicates, as two hybridizations were carried out for each of the LY75-suppressing cell clone against the corresponding control, using a fluorescent dye reversal (dye-swap) technique.
2016-04-01 | E-GEOD-74711 | biostudies-arrayexpress
Project description:Epithelial ovarian cancer (EOC) accounts for 4% of all cancers in women and is the leading cause of death from gynecologic malignancies. It is well established that cancer invasion and metastasis still represent the major causes of the failure of cancer treatment. Previously, we identified the mannose receptor LY75 (DEC205/CD205) gene as notably hypomethylated in high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. LY75 has been identified as a putative antigen-uptake receptor, which is expressed abundantly on dendritic cells, which are specialist antigen presenting cells to T lymphocytes for the initiation of an immune response. The implication of LY75 in EOC tumorigenesis is currently unknown. Here we show that LY75 is strongly overexpressed in HG serous EOC tumors as compared to normal ovarian tissue. Importantly, shRNA-mediated LY75 knockout in the mesenchymal EOC cells (SKOV3) led to mesenchymal to epithelial transition (MET), associated with overexpression of epithelial markers E-cadherin and EPCAM and loss of expression of mesenchymal markers Fibronectin, N-cadherin Snail1 and Twist1. In addition, LY75 suppression significantly inhibited EOC cell migration and invasion in vitro. However, LY75 knockdown led to enhanced tumor cell dissemination and significantly increased lethality in vivo, in xenograft model of advanced peritoneal EOC. Thus, our findings indicate that LY75 could play an essential role in the mesenchymal-to-epithelial transition (MET) of EOC cells and support the hypothesis that, while epithelial-to-mesenchymal transition (EMT) enables the invasiveness of tumor cells, a MET-associated epithelial phenotype could be essential for their metastatic colonization.
2016-04-01 | GSE74711 | GEO
Project description:Epithelial ovarian cancer (EOC) is a high-risk cancer presenting with heterogeneous tumors. The high incidence of EOC metastasis from primary tumors to nearby tissues and organs is a major driver of EOC lethality. We used cellular models of spheroid formation and re-adherence to investigate cellular signaling dynamics in each step toward EOC metastasis. In our system, adherent cells model primary tumors, spheroids formation represents the initiation of metastatic spread, while re-adherent spheroid cells represent secondary tumors. Proteomic and phosphoproteomic analyses show that spheroid cells are hypoxic and show markers for cell cycle arrest. Aurora kinase B (AURKB) abundance and downstream substrate phosphorylation are significantly reduced in spheroids and re-adherent cells, explaining their cell cycle arrest phenotype. The proteome of re-adherent cells is most similar to spheroids, yet greater changes in the phosphoproteome show that spheroid cells stimulate Rho-associated kinase 1 (ROCK1) mediated signaling, which controls cytoskeletal organization. In spheroids, we found significant phosphorylation of ROCK1 substrates that were reduced in both adherent and re-adherent cells. Application of the ROCK1-specific inhibitor Y-27632 to spheroids increased the rate of re-adherence and spheroid density. The data suggest ROCK1 inhibition increases EOC metastatic potential. We identified novel pathways controlled by AURKB and ROCK1 as major drivers of metastatic behavior in EOC cells. Our data show that phosphoproteomic reprogramming precedes proteomic changes that characterize spheroid re-adherence in EOC metastasis.
2024-01-26 | PXD043220 | Pride
Project description:Previously, we have identified the polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) gene as notably hypomethylated in low-malignant potential (LMP) and high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. Here we show that GALNT3 is strongly overexpressed in both LMP and HG serous EOC tumors, thus suggesting that epigenetic mechanisms might be implicated in GALNT3 overexpression in serous epithelial ovarian cancer (EOC). Moreover, GALNT3 expression significantly correlated with shorter progression-free survival (PFS) periods in serous EOC patients with advanced disease. Knockdown of the GALNT3 expression in EOC cells led to sharp decrease of cell proliferation and induced S-phase cell cycle arrest. Additionally, GALNT3 suppression significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon GALNT3 suppression, while some tumor suppressor genes were induced. Moreover, GALNT3 downregulation was associated with reduced MUC1 protein expression in EOC cells, probably related to destabilization of the MUC1 protein due to lack of GALNT3 glycosylation activity.Taken together, our data are indicative for a strong oncogenic potential of the GALNT3 gene in advanced EOC and identify this transferase as a novel EOC biomarker and putative EOC therapeutic target. Our findings also suggest that GALNT3 overexpression might contribute to ovarian etiology through aberrant mucin O-glycosylation. To better understand the molecular mechanisms of GALNT3 gene action in ovarian cancer cells, we employed the Agilent Whole Human Genome microarrays, containing ~ 44,000 genes to identify global gene expression changes upon GALNT3 suppression in A2780s cells. We compared the gene expression of the previously selected clone shRNA- GALNT3-knockdown clones 1 & 2 (sh-cl1 & sh-cl2) against the corresponding control (ctrl) clone. The microarray experiments were performed in duplicates, as four hybridizations were carried out for the GALNT3-suppressing cell clones against the corresponding control, using a fluorescent dye reversal (dye-swap) technique.
2014-05-22 | E-GEOD-52602 | biostudies-arrayexpress
Project description:Previously, we have identified the polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) gene as notably hypomethylated in low-malignant potential (LMP) and high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. Here we show that GALNT3 is strongly overexpressed in both LMP and HG serous EOC tumors, thus suggesting that epigenetic mechanisms might be implicated in GALNT3 overexpression in serous epithelial ovarian cancer (EOC). Moreover, GALNT3 expression significantly correlated with shorter progression-free survival (PFS) periods in serous EOC patients with advanced disease. Knockdown of the GALNT3 expression in EOC cells led to sharp decrease of cell proliferation and induced S-phase cell cycle arrest. Additionally, GALNT3 suppression significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon GALNT3 suppression, while some tumor suppressor genes were induced. Moreover, GALNT3 downregulation was associated with reduced MUC1 protein expression in EOC cells, probably related to destabilization of the MUC1 protein due to lack of GALNT3 glycosylation activity.Taken together, our data are indicative for a strong oncogenic potential of the GALNT3 gene in advanced EOC and identify this transferase as a novel EOC biomarker and putative EOC therapeutic target. Our findings also suggest that GALNT3 overexpression might contribute to ovarian etiology through aberrant mucin O-glycosylation.
2014-05-22 | GSE52602 | GEO