Analysis of gene expression changes in patient-derived gastric cancer cells after anticancer drug treatment or ALDH1A3 knockdown
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PROVIDER: PRJNA579327 | ENA |
REPOSITORIES: ENA
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Project description:Tumors consist of heterogeneous cell population, containing cancer cell subpopulations with anticancer drug-resistant property, called “persister” cells. To reveal the character of the persister cells, we analyzed gene expression profile of patient-derived gastric cells and residual cancer cells after treatment with 5-FU or SN38, an active metabolite of irinotecan. In our study, we identified ALDH1A3 as a marker and a cell proliferation factor of persister cells. To examine molecular pathways regulated by ALDH1A3, we analyzed gene expression profile of patient-derived gastric JSC15-3 in which ALDH1A3 was knocked down by using shRNAs.
2020-04-14 | GSE139331 | GEO
Project description:Drug-tolerant persister (DTP) cells arise in the early phase of chemotherapy and contribute to tumor relapse. In gastric cancer, we previously identified aldehyde dehydrogenase 1 family member A3 (ALDH1A3) as a DTP signature gene that contributes to survival after chemotherapy, while it remains elusive how the ALDH1A3-overexpressing DTP cells are enriched after chemotherapy and contribute to tumor promotion. Here, we demonstrated that ALDH1A3 was frequently overexpressed in clinical gastric cancer specimen after neoadjuvant chemotherapy and ALDH1A3 overexpression in gastric cancer patient-derived cells (PDCs) promoted tumor growth in vivo. Live imaging revealed that the ALDH1A3-overexpressing DTP cells were induced rather than selected after 5-fluorouracil (5-FU) treatment. We identified global elevation of histone H3 lysine 27 acetylation (H3K27ac) in the promoter regions of DTP cells including ALDH1A3 gene locus. Chemical screening further revealed bromodomain and extra-terminal motif (BET) protein inhibitors as efficient perturbators of the DTP phenotype. The BET inhibitors suppressed 5-FU-induced ADLH1A3 expression and selectively prevented the DTP cell proliferation. Importantly, ALDH1A3 downregulation and growth inhibition by BET inhibitors was rescued by exogenous ALDH1A3 expression. Among BET proteins, BRD4 was preferentially recruited to the ALDH1A3 promoter and promoted its expression in DTP cells. The BET inhibitor, Birabresib/OTX015, significantly suppressed ALDH1A3 expression and potentiated antitumor effect of 5-FU in gastric PDC xenograft model. These data indicate that the global H3K27ac induction and the BRD4-dependent ALDH1A3 induction is essential for gastric cancer drug tolerance.
2023-10-24 | GSE245888 | GEO
Project description:Drug-tolerant persister (DTP) cells arise in the early phase of chemotherapy and contribute to tumor relapse. In gastric cancer, we previously identified aldehyde dehydrogenase 1 family member A3 (ALDH1A3) as a DTP signature gene that contributes to survival after chemotherapy, while it remains elusive how the ALDH1A3-overexpressing DTP cells are enriched after chemotherapy and contribute to tumor promotion. Here, we demonstrated that ALDH1A3 was frequently overexpressed in clinical gastric cancer specimen after neoadjuvant chemotherapy and ALDH1A3 overexpression in gastric cancer patient-derived cells (PDCs) promoted tumor growth in vivo. Live imaging revealed that the ALDH1A3-overexpressing DTP cells were induced rather than selected after 5-fluorouracil (5-FU) treatment. We identified global elevation of histone H3 lysine 27 acetylation (H3K27ac) in the promoter regions of DTP cells including ALDH1A3 gene locus. Chemical screening further revealed bromodomain and extra-terminal motif (BET) protein inhibitors as efficient perturbators of the DTP phenotype. The BET inhibitors suppressed 5-FU-induced ADLH1A3 expression and selectively prevented the DTP cell proliferation. Importantly, ALDH1A3 downregulation and growth inhibition by BET inhibitors was rescued by exogenous ALDH1A3 expression. Among BET proteins, BRD4 was preferentially recruited to the ALDH1A3 promoter and promoted its expression in DTP cells. The BET inhibitor, Birabresib/OTX015, significantly suppressed ALDH1A3 expression and potentiated antitumor effect of 5-FU in gastric PDC xenograft model. These data indicate that the global H3K27ac induction and the BRD4-dependent ALDH1A3 induction is essential for gastric cancer drug tolerance.
2023-10-24 | GSE245887 | GEO
Project description:Background: Antimalarials have anticancer potential. Results: We have systematically tested five distinct antimalaria drugs in a panel of cancer cell lines. Conclusion: Three antimalarial classes display potent antiproliferative activity, and their potency is correlated with cancer cell gene expression patterns. Significance: We confirm and extend anticancer potential of these antimalarials and we discuss their therapeutic potential based on clinical data. Key words: Malaria, Anticancer drug, Drug Discovery, Genomics, Gene Expression, Bioinformatics, Cancer AffymetrixM-BM-. HG-U133 Plus 2.0 mRNA expression arrays were used to determine the expression. CEL result files were pre-processed using the RMA (Irizarry et al, 2003) algorithm. This microarray analysis was performed for 91 cell lines.
2013-10-26 | E-GEOD-51739 | biostudies-arrayexpress
Project description:Background: Antimalarials have anticancer potential. Results: We have systematically tested five distinct antimalaria drugs in a panel of cancer cell lines. Conclusion: Three antimalarial classes display potent antiproliferative activity, and their potency is correlated with cancer cell gene expression patterns. Significance: We confirm and extend anticancer potential of these antimalarials and we discuss their therapeutic potential based on clinical data. Key words: Malaria, Anticancer drug, Drug Discovery, Genomics, Gene Expression, Bioinformatics, Cancer
2013-10-26 | GSE51739 | GEO
Project description:Genome-wide mRNA expression profiles of 70 primary gastric tumors from the Australian patient cohort. Like many cancers, gastric adenocarcinomas (gastric cancers) show considerable heterogeneity between patients. Thus, there is intense interest in using gene expression profiles to discover subtypes of gastric cancers with particular biological properties or therapeutic vulnerabilities. Identification of such subtypes could generate insights into the mechanisms of cancer progression or lay the foundation for personalized treatments. Here we report a robust gene-xpression-based clustering of a large collection of gastric adenocarcinomas from Singaporean patients [GSE34942 and GSE15459]. We developed and validated a classifier for the three subtypes in Australian patient cohort. Profiling of 70 primary gastric tumors on Affymetrix GeneChip Human Genome U133 Plus 2.0 Array. All tumors were collected with approvals from Peter MacCallum Cancer Center, Australia; the Research Ethics Review Committee; and signed patient informed consent.
2012-07-04 | E-GEOD-35809 | biostudies-arrayexpress
Project description:Genome-wide mRNA expression profiles of 70 primary gastric tumors from the Australian patient cohort. Like many cancers, gastric adenocarcinomas (gastric cancers) show considerable heterogeneity between patients. Thus, there is intense interest in using gene expression profiles to discover subtypes of gastric cancers with particular biological properties or therapeutic vulnerabilities. Identification of such subtypes could generate insights into the mechanisms of cancer progression or lay the foundation for personalized treatments. Here we report a robust gene-xpression-based clustering of a large collection of gastric adenocarcinomas from Singaporean patients [GSE34942 and GSE15459]. We developed and validated a classifier for the three subtypes in Australian patient cohort.
2012-07-05 | GSE35809 | GEO
Project description:Genome-wide mRNA expression profiles of 56 primary gastric tumors from the Singapore patient cohort, batch B. Like many cancers, gastric adenocarcinomas (gastric cancers) show considerable heterogeneity between patients. Thus, there is intense interest in using gene expression profiles to discover subtypes of gastric cancers with particular biological properties or therapeutic vulnerabilities. Identification of such subtypes could generate insights into the mechanisms of cancer progression or lay the foundation for personalized treatments. Here we report a robust gene-expression-based clustering of a large collection of gastric adenocarcinomas (with GSE15459) from Singaporean patients. Profiling of 56 primary gastric tumors on Affymetrix GeneChip Human Genome U133 Plus 2.0 Array. All tumors were collected with approvals from the National Cancer Centre, Singapore; the Research Ethics Review Committee; and signed patient informed consent.
2014-09-05 | E-GEOD-34942 | biostudies-arrayexpress
Project description:Genome-wide mRNA expression profiles of 200 primary gastric tumors from the Singapore patient cohort. Gastric cancer (GC) is the second leading cause of global cancer mortality, with individual gastric tumors displaying significant heterogeneity in their deregulation of various oncogenic pathways. We aim to identify major oncogenic pathways in GC that robustly impact patient survival and treatment response. We used an in silico strategy based on gene expression signatures and connectivity analytics to map patterns of oncogenic pathway activation in 25 unique GC cell lines, and in 301 primary gastric cancers from three independent patient cohorts. Of 11 oncogenic pathways previously implicated in GC, we identified three predominant pathways (proliferation/stem cell, NF-kB, and Wnt/b-catenin) deregulated in the majority (>70%) of gastric tumors. Using a variety of proliferative, Wnt, and NF-kB-related assays, we experimentally validated the pathway predictions in multiple GC cell lines showing similar pathway activation patterns in vitro. Patients stratified at the level of individual pathways did not exhibit consistent differences in clinical outcome. However, patients grouped by oncogenic pathway combinations demonstrated robust and significant survival differences (e.g., high proliferation/high NF-kB vs. low proliferation/low NF-kB), suggesting that tumor behavior in GC is likely influenced by the combined effects of multiple oncogenic pathways. Our results demonstrate that GCs can be successfully taxonomized by oncogenic pathway activity into biologically and clinically relevant subgroups. Experiment Overall Design: Profiling of 200 primary gastric tumors on Affymetrix GeneChip Human Genome U133 Plus 2.0 Array. All tumors were collected with approvals from the National Cancer Centre, Singapore; the Research Ethics Review Committee; and signed patient informed consent.
2009-04-10 | E-GEOD-15459 | biostudies-arrayexpress
Project description:Gastric cancer (GC) stem cells (GCSCs) are characterized as high level of ALDH activity, however, the mechanisms of maintenance of high ALDH activity and stemness in GCSCs are largely unknown. Here, we report that KDM4C, a H3K9me2/3-demethylase, epigenetically regulates ALDH1A3 by histone demethylation and forms a feed-forward loop with ALDH1A3 to supports GS stemness. Ectopic expression of both KDM4C and ALDH1A3 promotes the properties of GCSCs, including spherogenecity, self-renewal, CD44 expression and ALDH activity; knockdown of anyone abolished the effect of each other. KDM4C directly binds to the promoter of ALDH1A3, leads to histone demethylation, thereby promoting ALDH1A3 transcription. Upregulated ALDH1A3 in turn transcriptionally upregulates KDM4C. Simultaneous inhibition of KDM4C and ALDH1A3 synergistically sensitizes GC sphere-derived cells to traditional chemotherapeutic drugs. The finding that upregulated ALDH1A3 promotes its own transcription via KDM4C-mediated epigenetic modification represents an important feed-forward mechanism for GCSCs to maintain stemness and promote tumourigenesis and our work thus suggests a novel therapeutic strategy for eradicating human GCSCs. To investigate the mechanisms underlying KDM4C promoting CG stemness, we identified the differentially expressed proteins (DEPs) between KDM4C-overexpressing and control AGS cells by iTRAQ-based quantitative proteomic analysis.
2022-02-16 | PXD023455 | Pride