Browse
Submit Data
Databases
API
Help

Dataset Information

10 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

ARID3A and ARID3B induce stem promoting pathways in ovarian cancer cells.

ABSTRACT: ARID3A and ARID3B are paralogs from the AT-Rich interactive Domain (ARID) family. ARID3A and ARID3B associate to regulate genes in B-cells and cancer. We were the first to demonstrate that ARID3B regulates stem cell genes and promotes the cancer stem cell phenotype. Importantly, different knockout phenotypes in mice and distinct patterns of expression in adult animals suggests that ARID3A and ARID3B may have unique functions. In addition, high levels of ARID3B but not ARID3A induce cell death. Our goal was to express ARID3A, ARID3B, or both genes at a moderate level (as can be observed in cancer) and then identify ARID3 regulated genes. We transduced ovarian cancer cells with ARID3A-GFP, ARID3B-RFP, or both. RNA-sequencing was conducted. ARID3A and ARID3B regulated nearly identical sets of genes. Few genes (<5%) were uniquely regulated by ARID3A or ARID3B. ARID3A/B induced genes involved in cancer and stem cell processes including: Twist, MYCN, MMP2, GLI2, TIMP3, and WNT5B. We found that ARID3A and ARID3B also induced expression of each other, providing evidence of the cooperativity. While ARID3A and ARID3B likely have unique functions in distinct contexts, they are largely capable of regulating the same stem cell genes in cancer cells. This study provides a comprehensive list of genes and pathways regulated by ARID3A and ARID3B in ovarian cancer cells.

SUBMITTER: Dausinas P

PROVIDER: S-EPMC7384259 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

ARID3B Directly Regulates Ovarian Cancer Promoting Genes.

Project description:The DNA-binding protein AT-Rich Interactive Domain 3B (ARID3B) is elevated in ovarian cancer and increases tumor growth in a xenograft model of ovarian cancer. However, relatively little is known about ARID3B's function. In this study we perform the first genome wide screen for ARID3B direct target genes and ARID3B regulated pathways. We identified and confirmed numerous ARID3B target genes by chromatin immunoprecipitation (ChIP) followed by microarray and quantitative RT-PCR. Using motif-finding algorithms, we characterized a binding site for ARID3B, which is similar to the previously known site for the ARID3B paralogue ARID3A. Functionality of this predicted site was demonstrated by ChIP analysis. We next demonstrated that ARID3B induces expression of its targets in ovarian cancer cell lines. We validated that ARID3B binds to an epidermal growth factor receptor (EGFR) enhancer and increases mRNA expression. ARID3B also binds to the promoter of Wnt5A and its receptor FZD5. FZD5 is highly expressed in ovarian cancer cell lines, and is upregulated by exogenous ARID3B. Both ARID3B and FZD5 expression increase adhesion to extracellular matrix (ECM) components including collagen IV, fibronectin and vitronectin. ARID3B-increased adhesion to collagens II and IV require FZD5. This study directly demonstrates that ARID3B binds target genes in a sequence-specific manner, resulting in increased gene expression. Furthermore, our data indicate that ARID3B regulation of direct target genes in the Wnt pathway promotes adhesion of ovarian cancer cells.

| S-EPMC4486168 | biostudies-literature

ARID3B increases ovarian tumor burden and is associated with a cancer stem cell gene signature.

Project description:Ovarian cancer is the most deadly gynecological malignancy since most patients have metastatic disease at the time of diagnosis. Therefore, identification of critical pathways that contribute to ovarian cancer progression is necessary to yield novel therapeutic targets. Recently we reported that the DNA binding protein ARID3B is overexpressed in human ovarian tumors. To determine if ARID3B has oncogenic functions in vivo, ovarian cancer cell lines stably expressing ARID3B were injected intraperitoneally into nude mice. Overexpression of ARID3B increased tumor burden and decreased survival. To assess how ARID3B contributes to the increased tumor growth in vivo, we identified ARID3B induced genes in tumor ascites cells. ARID3B induced expression of genes associated with metastasis and cancer stem cells (CD44, LGR5, PROM1 (CD133), and Notch2). Moreover, ARID3B increased the number of CD133+ (a cancer stem cell marker) cells compared to control cells. The increase in CD133+ cells resulting from ARID3B expression was accompanied by enhanced paclitaxel resistance. Our data demonstrate that ARID3B boosts production CD133+ cells and increases ovarian cancer progression in vivo.

| S-EPMC4226688 | biostudies-literature

FOXP1 functions as an oncogene in promoting cancer stem cell-like characteristics in ovarian cancer cells.

Project description:Ovarian cancer has the highest mortality rate of all gynecological cancers with a high recurrence rate. It is important to understand the nature of recurring cancer cells to terminally eliminate ovarian cancer. The winged helix transcription factor Forkhead box P1 (FOXP1) has been reported to function as either oncogene or tumor-suppressor in various cancers. In the current study, we show that FOXP1 promotes cancer stem cell-like characteristics in ovarian cancer cells. Knockdown of FOXP1 expression in A2780 or SKOV3 ovarian cancer cells decreased spheroid formation, expression of stemness-related genes and epithelial to mesenchymal transition-related genes, cell migration, and resistance to Paclitaxel or Cisplatin treatment, whereas overexpression of FOXP1 in A2780 or SKOV3 ovarian cancer cells increased spheroid formation, expression of stemness-related genes and epithelial to mesenchymal transition-related genes, cell migration, and resistance to Paclitaxel or Cisplatin treatment. In addition, overexpression of FOXP1 increased promoter activity of ABCG2, OCT4, NANOG, and SOX2, among which the increases in ABCG2, OCT4, and SOX2 promoter activity were dependent on the presence of FOXP1-binding site. In xenotransplantation of A2780 ovarian cancer cells into nude mice, knockdown of FOXP1 expression significantly decreased tumor size. These results strongly suggest FOXP1 functions as an oncogene by promoting cancer stem cell-like characteristics in ovarian cancer cells. Targeting FOXP1 may provide a novel therapeutic opportunity for developing a relapse-free treatment for ovarian cancer patients.

| S-EPMC4823123 | biostudies-literature

Glucocorticoids induce differentiation and chemoresistance in ovarian cancer by promoting ROR1-mediated stemness.

Project description:Glucocorticoids are routinely used in the clinic as anti-inflammatory and immunosuppressive agents as well as adjuvants during cancer treatment to mitigate the undesirable side effects of chemotherapy. However, recent studies have indicated that glucocorticoids may negatively impact the efficacy of chemotherapy by promoting tumor cell survival, heterogeneity, and metastasis. Here, we show that dexamethasone induces upregulation of ROR1 expression in ovarian cancer (OC), including platinum-resistant OC. Increased ROR1 expression resulted in elevated RhoA, YAP/TAZ, and BMI-1 levels in a panel of OC cell lines as well as primary ovarian cancer patient-derived cells, underlining the translational relevance of our studies. Importantly, dexamethasone induced differentiation of OC patient-derived cells ex vivo according to their molecular subtype and the phenotypic expression of cell differentiation markers. High-throughput drug testing with 528 emerging and clinical oncology compounds of OC cell lines and patient-derived cells revealed that dexamethasone treatment increased the sensitivity to several AKT/PI3K targeted kinase inhibitors, while significantly decreasing the efficacy of chemotherapeutics such as taxanes, as well as anti-apoptotic compounds such as SMAC mimetics. On the other hand, targeting ROR1 expression increased the efficacy of taxane drugs and SMAC mimetics, suggesting new combinatorial targeted treatments for patients with OC.

| S-EPMC7522257 | biostudies-literature

ARID3B induces tumor necrosis factor alpha mediated apoptosis while a novel ARID3B splice form does not induce cell death.

Project description:Alternative splicing is a common occurrence in many cancers. Alternative splicing is linked with decreased apoptosis and chemoresistance in cancer cells. We previously demonstrated that ARID3B, a member of the AT-rich interactive domain (ARID) family of DNA binding proteins, is overexpressed in ovarian cancer. Therefore we wanted to assess the effect of ARID3B splice forms on cell viability. We identified a novel splice form of the ARID3B gene (designated as ARID3B Sh), which lacks the C-terminal exons 5-9 present in the full-length isoform (ARID3B Fl). ARID3B Fl is expressed in a variety of cancer cell lines. Expression of ARID3B Sh varied by cell type, but was highly expressed in most ovarian cancer lines. ARID3B is modestly transcriptionally activated by epidermal growth factor receptor (EGFR) signaling through the PEA3 transcription factor. We further found that ARID3B Fl is predominantly nuclear but is also present at the plasma membrane and in the cytosol. Endogenous ARID3B Sh is present in nuclear fractions, yet, when overexpressed ARID3B Sh accumulates in the cytosol and membrane fractions. The differential localization of these isoforms suggests they have different functions. Importantly, ARID3B Fl overexpression results in upregulation of pro-apoptotic BIM and induces Tumor Necrosis Factor alpha (TNF?) and TNF-related apoptosis inducing ligand (TRAIL) induced cell death. The ARID3B Fl-induced genes include TNF?, TRAIL, TRADD, TNF-R2, Caspase 10 and Caspase 7. Interestingly, ARID3B Sh does not induce apoptosis or expression of these genes. ARID3B Fl induces death receptor mediated apoptosis while the novel splice form ARID3B Sh does not induce cell death. Therefore alternative splice forms of ARID3B may play different roles in ovarian cancer progression.

| S-EPMC3409141 | biostudies-literature

Targeting the mitochondria activates two independent cell death pathways in ovarian cancer stem cells.

Project description:Cancer stem cells are responsible for tumor initiation and chemoresistance. In ovarian cancer, the CD44+/MyD88+ ovarian cancer stem cells are also able to repair the tumor and serve as tumor vascular progenitors. Targeting these cells is therefore necessary to improve treatment outcome and patient survival. The previous demonstration that the ovarian cancer stem cells are resistant to apoptotic cell death induced by conventional chemotherapy agents suggests that other forms of targeted therapy should be explored. We show in this study that targeting mitochondrial bioenergetics is a potent stimulus to induce caspase-independent cell death in a panel of ovarian cancer stem cells. Treatment of these cells with the novel isoflavone derivative, NV-128, significantly depressed mitochondrial function exhibited by decrease in ATP, Cox-I, and Cox-IV levels, and by increase in mitochondrial superoxide and hydrogen peroxide. This promotes a state of cellular starvation that activates two independent pathways: (i) AMPK?1 pathway leading to mTOR inhibition; and (ii) mitochondrial MAP/ERK kinase/extracellular signal-regulated kinase pathway leading to loss of mitochondrial membrane potential. The demonstration that a compound can specifically target the mitochondria to induce cell death in this otherwise chemoresistant cell population opens a new venue for treating ovarian cancer patients.

| S-EPMC3703662 | biostudies-literature

NF?B Promotes Ovarian Tumorigenesis via Classical Pathways That Support Proliferative Cancer Cells and Alternative Pathways That Support ALDH+ Cancer Stem-like Cells.

Project description:Understanding the mechanisms supporting tumor-initiating cells (TIC) is vital to combat advanced-stage recurrent cancers. Here, we show that in advanced ovarian cancers NF?B signaling via the RelB transcription factor supports TIC populations by directly regulating the cancer stem-like associated enzyme aldehyde dehydrogenase (ALDH). Loss of RelB significantly inhibited spheroid formation, ALDH expression and activity, chemoresistance, and tumorigenesis in subcutaneous and intrabursal mouse xenograft models of human ovarian cancer. RelB also affected expression of the ALDH gene ALDH1A2 Interestingly, classical NF?B signaling through the RelA transcription factor was equally important for tumorigenesis in the intrabursal model, but had no effect on ALDH. In this case, classical signaling via RelA was essential for proliferating cells, whereas the alternative signaling pathway was not. Our results show how NF?B sustains diverse cancer phenotypes via distinct classical and alternative signaling pathways, with implications for improved understanding of disease recurrence and therapeutic response. Cancer Res; 77(24); 6927-40. ©2017 AACR.

| S-EPMC5732863 | biostudies-literature

Analysis of ARID3A and ARID3B regulated genes by RNA-seq

Project description:In ovarian cancer cells ARID3A, ARID3B, or both genes were expressed exogenously with lentivirus. Cells were sorted based on expression level using fluoescent tags. RNA was isolated and RNA-sequencing was conducted to identify ARID3 regulated genes.

2020-02-05 | GSE129082 | GEO

Anisomycin has the potential to induce human ovarian cancer stem cell ferroptosis by influencing glutathione metabolism and autophagy signal transduction pathways.

Project description:Ovarian cancer is a highly malignant gynecological tumor that seriously endangers women's health. Previously, we demonstrated that anisomycin significantly inhibited the activity of ovarian cancer stem cells (OCSCs) in vitro and in vivo. In this study, anisomycin treatment of OCSCs significantly reduced the content of adenosine triphosphate and total glutathione, increased the extent of lipid peroxidation, and increased malondialdehyde, and Fe2+ levels. The ferroptosis inhibitor Ferr-1 could significantly weaken the cytotoxicity of anisomycin. Subsequently, the cDNA microArray results suggested that anisomycin significantly reduced the transcription levels of gene clusters associated with protection from ferroptosis, such as those encoding members of the glutathione metabolism and autophagy signal transduction pathways. Bioinformatic analyses indicated that genes encoding core factors of these two pathways, and activating transcription factor 4 (ATF4), were significantly expressed in ovarian cancer tissues and correlated with poor prognosis. After overexpression or knockdown of ATF4, the ability of anisomycin to inhibit the proliferation and autophagy of OCSCs increased or decreased, respectively. Finally, analysis using a peripheral blood exosome database indicated that the contents of key factors (e.g., ATF4, GPX4, and ATG3) in peripheral blood exosomes from patients with ovarian cancer, were significantly higher than those of the healthy controls. Therefore, we hypothesized that anisomycin suppressed the expression of members of the glutathione metabolism and autophagy signal transduction pathways by downregulating the expression of ATF4. Moreover, anisomycin has the potential to induce human ovarian cancer stem cell ferroptosis. Overall, we confirmed that anisomycin has multiple targets and many mechanisms of action in inhibiting the activity of OCSCs.

| S-EPMC10197939 | biostudies-literature

Stem cell pathways contribute to clinical chemoresistance in ovarian cancer.

Project description:Within heterogeneous tumors, subpopulations often labeled cancer stem cells (CSC) have been identified that have enhanced tumorigenicity and chemoresistance in ex vivo models. However, whether these populations are more capable of surviving chemotherapy in de novo tumors is unknown.We examined 45 matched primary/recurrent tumor pairs of high-grade ovarian adenocarcinomas for expression of CSC markers ALDH1A1, CD44, and CD133 using immunohistochemistry. Tumors collected immediately after completion of primary therapy were then laser capture microdissected and subjected to a quantitative PCR array examining stem cell biology pathways (Hedgehog, Notch, TGF-?, and Wnt). Select genes of interest were validated as important targets using siRNA-mediated downregulation.Primary samples were composed of low densities of ALDH1A1, CD44, and CD133. Tumors collected immediately after primary therapy were more densely composed of each marker, whereas samples collected at first recurrence, before initiating secondary therapy, were composed of similar percentages of each marker as their primary tumor. In tumors collected from recurrent platinum-resistant patients, only CD133 was significantly increased. Of stem cell pathway members examined, 14% were significantly overexpressed in recurrent compared with matched primary tumors. Knockdown of genes of interest, including endoglin/CD105 and the hedgehog mediators Gli1 and Gli2, led to decreased ovarian cancer cell viability, with Gli2 showing a novel contribution to cisplatin resistance.These data indicate that ovarian tumors are enriched with CSCs and stem cell pathway mediators, especially at the completion of primary therapy. This suggests that stem cell subpopulations contribute to tumor chemoresistance and ultimately recurrent disease.

| S-EPMC3271164 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data