Browse
Submit Data
Databases
API
Help

Dataset Information

18 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CircRNA Microarray Profiling Reveals hsa_circ_0058493 as a Novel Biomarker for Imatinib-Resistant CML.

ABSTRACT: Background: CircRNA has appeared as a critical molecular in the development of various cancers. However, the cellular function of circRNAs and exosomal circRNAs has not been well explored in Chronic myeloid leukemia (CML). Methods: Differentially expressed circRNAs were identified by a human circRNA microarray analysis. The expression of hsa_circ_0058493 in peripheral blood mononuclear cells (PBMCs) and exosomes was verified using quantitative real-time PCR. Short hairpin RNAs against hsa_circ_0058493 were constructed to silence the expression of circ_0058493. CCK8, flow cytometry and EdU assay were performed to investigate the biological functions of circ_0058493. Results: Hsa_circ_0058493 was significantly overexpressed in the PBMCs of CML patients and high level of circ_0058493 was associated with the poor clinical efficacy of imatinib. Silencing the expression of circ_0058493 significantly inhibited the development of imatinib-resistant CML cells. miR-548b-3p was overexpressed in circ_0058493-downregulated CML cells. Bioinformatic analysis revealed that circ_0058493 might exert its regulatory function acting as a "sponge" of miR-548b-3p. Moreover, hsa_circ_0058493 was significantly enriched in the exosomes derived from imatinib-resistant CML cells. Conclusion: Hsa_circ_0058493 in PBMCs could be a promising prognostic biomarker and might provide a therapeutic target for CML treatment.

SUBMITTER: Zhong AN

PROVIDER: S-EPMC8473700 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

CircRNA microarray profiling identifies a novel circulating biomarker for detection of gastric cancer.

Project description:CircRNA expression profiles for gastric cancer (GC) were screened using plasma samples from 10 GC patients with different TNM stages and 5 healthy individuals as controls. Results showed lower expression of circ-KIAA1244 in GC tissues, plasmas, and cells compare to normal controls. Further clinical data analysis demonstrated that a decreased expression of circ-KIAA1244 in plasmas was negatively correlated with TNM stage and lymphatic metastasis, and a shorter overall survival time of GC patients. Moreover, we found that circ-KIAA1244 could be detected in GC plasma exosomes and showed no obvious significance compared to the expression level in the corresponding plasmas. This study revealed a GC-tissues-derived circ-KIAA1244 could serve a novel circulating biomarker for detection of GC.

| S-EPMC6147053 | biostudies-literature

Plasma circRNA microarray profiling identifies novel circRNA biomarkers for the diagnosis of ovarian cancer

Project description:Background Circular RNA (circRNA), a class of RNA with a covalent closed circular structure that widely existed in serum and plasma, has been considered an ideal liquid biopsy marker in many diseases. In this study, we employed microarray and qRT-PCR to evaluate the potential circulating circRNAs with diagnostic efficacy in ovarian cancer. Methods We used microarray to explore the circRNA expression profile in ovarian cancer patients’ plasma and quantitative real-time (qRT)-PCR approach to assessing the candidate circRNA’s expression. Then the receiver operating characteristic (ROC) curve was employed to analyze the diagnostic values of candidate circRNAs. The diagnostic model circCOMBO was a combination of hsa_circ_0003972 and hsa_circ_0007288 built by binary logistic regression. Then bioinformatic tools were used to predict their potential mechanisms. Results Hsa_circ_0003972 and hsa_circ_0007288 were downregulated in ovarian cancer patients’ plasma, tissues, and cell lines, comparing with the controls. Hsa_circ_0003972 and hsa_circ_0007288 exhibited diagnostic values with the Area Under Curve (AUC) of 0.724 and 0.790, respectively. circCOMBO showed a better diagnostic utility (AUC: 0.781), while the combination of circCOMBO and carbohydrate antigen 125 (CA125) showed the highest diagnostic value (AUC: 0.923). Furthermore, the higher expression level of hsa_circ_0007288 in both plasma and ovarian cancer tissues was associated with lower lymph node metastasis potential in ovarian cancer. Conclusions Our results revealed that hsa_circ_0003972 and hsa_circ_0007288 may serve as novel circulating biomarkers for ovarian cancer diagnosis. Supplementary information The online version contains supplementary material available at 10.1186/s13048-022-00988-0.

| S-EPMC9097182 | biostudies-literature

Proteomic analysis of imatinib-resistant CML-T1 cells reveals calcium homeostasis as a potential therapeutic target.

Project description:Chronic myeloid leukemia (CML) therapy has markedly improved patient prognosis after introduction of imatinib mesylate for clinical use. However, a subset of patients develops resistance to imatinib and other tyrosine kinase inhibitors (TKIs), mainly due to point mutations in the region encoding the kinase domain of the fused BCR-ABL oncogene. To identify potential therapeutic targets in imatinib‑resistant CML cells, we derived imatinib-resistant CML-T1 human cell line clone (CML-T1/IR) by prolonged exposure to imatinib in growth media. Mutational analysis revealed that the Y235H mutation in BCR-ABL is probably the main cause of CML-T1/IR resistance to imatinib. To identify alternative therapeutic targets for selective elimination of imatinib-resistant cells, we compared the proteome profiles of CML-T1 and CML-T1/IR cells using 2-DE-MS. We identified eight differentially expressed proteins, with strongly upregulated Na+/H+ exchanger regulatory factor 1 (NHERF1) in the resistant cells, suggesting that this protein may influence cytosolic pH, Ca2+ concentration or signaling pathways such as Wnt in CML-T1/IR cells. We tested several compounds including drugs in clinical use that interfere with the aforementioned processes and tested their relative toxicity to CML-T1 and CML-T1/IR cells. Calcium channel blockers, calcium signaling antagonists and modulators of calcium homeostasis, namely thapsigargin, ionomycin, verapamil, carboxyamidotriazole and immunosuppressive drugs cyclosporine A and tacrolimus (FK-506) were selectively toxic to CML-T1/IR cells. The putative cellular targets of these compounds in CML-T1/IR cells are postulated in this study. We propose that Ca2+ homeostasis can be a potential therapeutic target in CML cells resistant to TKIs. We demonstrate that a proteomic approach may be used to characterize a TKI-resistant population of CML cells enabling future individualized treatment options for patients.

| S-EPMC4968618 | biostudies-literature

Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML.

Project description:Occurrence of the BCR-ABL(T315I) gatekeeper mutation is among the most pressing challenges in the therapy of chronic myeloid leukemia (CML). Several BCR-ABL inhibitors have multiple targets and pleiotropic effects that could be exploited for their synergistic potential. Testing combinations of such kinase inhibitors identified a strong synergy between danusertib and bosutinib that exclusively affected CML cells harboring BCR-ABL(T315I). To elucidate the underlying mechanisms, we applied a systems-level approach comprising phosphoproteomics, transcriptomics and chemical proteomics. Data integration revealed that both compounds targeted Mapk pathways downstream of BCR-ABL, resulting in impaired activity of c-Myc. Using pharmacological validation, we assessed that the relative contributions of danusertib and bosutinib could be mimicked individually by Mapk inhibitors and collectively by downregulation of c-Myc through Brd4 inhibition. Thus, integration of genome- and proteome-wide technologies enabled the elucidation of the mechanism by which a new drug synergy targets the dependency of BCR-ABL(T315I) CML cells on c-Myc through nonobvious off targets.

| S-EPMC4038039 | biostudies-literature

Lyn regulates creatine uptake in an imatinib-resistant CML cell line.

Project description:BackgroundImatinib mesylate (imatinib) is the first-line treatment for newly diagnosed chronic myeloid leukemia (CML) due to its remarkable hematologic and cytogenetic responses. We previously demonstrated that the imatinib-resistant CML cells (Myl-R) contained elevated Lyn activity and intracellular creatine pools compared to imatinib-sensitive Myl cells.MethodsStable isotope metabolic labeling, media creatine depletion, and Na+/K+-ATPase inhibitor experiments were performed to investigate the origin of creatine pools in Myl-R cells. Inhibition and shRNA knockdown were performed to investigate the specific role of Lyn in regulating the Na+/K+-ATPase and creatine uptake.ResultsInhibition of the Na+/K+-ATPase pump (ouabain, digitoxin), depletion of extracellular creatine or inhibition of Lyn kinase (ponatinib, dasatinib), demonstrated that enhanced creatine accumulation in Myl-R cells was dependent on uptake from the growth media. Creatine uptake was independent of the Na+/creatine symporter (SLC6A8) expression or de novo synthesis. Western blot analyses showed that phosphorylation of the Na+/K+-ATPase on Tyr 10 (Y10), a known regulatory phosphorylation site, correlated with Lyn activity. Overexpression of Lyn in HEK293 cells increased Y10 phosphorylation (pY10) of the Na+/K+-ATPase, whereas Lyn inhibition or shRNA knockdown reduced Na+/K+-ATPase pY10 and decreased creatine accumulation in Myl-R cells. Consistent with enhanced uptake in Myl-R cells, cyclocreatine (Ccr), a cytotoxic creatine analog, caused significant loss of viability in Myl-R compared to Myl cells.ConclusionsThese data suggest that Lyn can affect creatine uptake through Lyn-dependent phosphorylation and regulation of the Na+/K+-ATPase pump activity.General significanceThese studies identify kinase regulation of the Na+/K+-ATPase as pivotal in regulating creatine uptake and energy metabolism in cells.

| S-EPMC7055176 | biostudies-literature

Genetic and pharmacologic inhibition of ?-catenin targets imatinib-resistant leukemia stem cells in CML.

Project description:A key characteristic of hematopoietic stem cells (HSCs) is the ability to self-renew. Genetic deletion of ?-catenin during fetal HSC development leads to impairment of self-renewal while ?-catenin is dispensable in fully developed adult HSCs. Whether ?-catenin is required for maintenance of fully developed CML leukemia stem cells (LSCs) is unknown. Here, we use a conditional mouse model to show that deletion of ?-catenin after CML initiation does not lead to a significant increase in survival. However, deletion of ?-catenin synergizes with imatinib (IM) to delay disease recurrence after imatinib discontinuation and to abrogate CML stem cells. These effects can be mimicked by pharmacologic inhibition of ?-catenin via modulation of prostaglandin signaling. Treatment with the cyclooxygenase inhibitor indomethacin reduces ?-catenin levels and leads to a reduction in LSCs. In conclusion, inhibiting ?-catenin by genetic inactivation or pharmacologic modulation is an effective combination therapy with imatinib and targets CML stem cells.

| S-EPMC3339412 | biostudies-literature

Berbamine exhibits potent antitumor effects on imatinib-resistant CML cells in vitro and in vivo.

Project description:AimThe aim of this study was to explore the effects and mechanism of berbamine on imatinib-resistant BCR-ABL-positive human leukemia K562 (K562-r) cells in vitro and in vivo.MethodsCell viability was measured by MTT assay, and apoptotic morphology changes were detected by fluorescence microscopy. The apoptosis rate was measured by flow cytometric assay. mdr-1 mRNA levels were determined by RT-PCR. Bcl-2 family proteins, cytochrome c(cyt C), poly (ADP-ribose) polymerase (PARP), and P-glycoprotein were detected by Western blot. BALB/c nu/nu mice were injected with K562-r cells subcutaneously. Tumor-bearing mice were treated intravenously with berbamine.ResultsMTT tests revealed that berbamine significantly inhibited K562-r cell proliferation and increased the chemo-sensitivity of K562-r cells to imatinib. The apoptosis rate was significantly increased following treatment with 21.2 micromol/L berbamine; formation of typical apoptotic blebs was apparent, as observed by fluorescence microscopy. Expression levels of mdr-1 mRNA and P-gp protein were high in untreated K562-r cells and significantly down-regulated by berbamine treatment. Berbamine-treated K562-r cells also exhibited down-regulated expression of the anti-apoptotic proteins Bcl-2 and Bcl-x(L), up-regulated expression of the apoptotic proteins Bax and cytoplasmic cyt C, and stimulated proteolytic cleavage of PARP. In addition, berbamine also suppressed the growth of K562-r xenotransplanted tumors in vivo.ConclusionBerbamine inhibited proliferation of K562-r cells both in vitro and in vivo. Berbamine-induced apoptosis in K562-r cells appeared to occur through a mechanism involving Bcl-2 family proteins, as well as mdr-1 mRNA and P-gp protein. Berbamine in combination with imatinib restored the chemo-sensitivity of K562-r cells to imatinib. Our findings suggest that berbamine may be useful in treating imatinib-resistant CML patients.

| S-EPMC4002272 | biostudies-literature

Wogonin induces cell cycle arrest and erythroid differentiation in imatinib-resistant K562 cells and primary CML cells.

Project description:Wogonin, a flavonoid derived from Scutellaria baicalensis Georgi, has been demonstrated to be highly effective in treating hematologic malignancies. In this study, we investigated the anticancer effects of wogonin on K562 cells, K562 imatinib-resistant cells, and primary patient-derived CML cells. Wogonin up-regulated transcription factor GATA-1 and enhanced binding between GATA-1 and FOG-1, thereby increasing expression of erythroid-differentiation genes. Wogonin also up-regulated the expression of p21 and induced cell cycle arrest. Studies employing benzidine staining and analyses of cell surface markers glycophorin A (GPA) and CD71 indicated that wogonin promoted differentiation of K562, imatinib-resistant K562, and primary patient-derived CML cells. Wogonin also enhanced binding between GATA-1 and MEK, resulting in inhibition of the growth of CML cells. Additionally, in vivo studies showed that wogonin decreased the number of CML cells and prolonged survival of NOD/SCID mice injected with K562 and imatinib-resistant K562 cells. These data suggested that wogonin induces cycle arrest and erythroid differentiation in vitro and inhibits proliferation in vivo.

| S-EPMC4226676 | biostudies-literature

circRNA, a novel diagnostic biomarker for coronary heart disease.

Project description:ObjectiveThis study aimed to identify the potential diagnostic biomarkers of coronary heart disease (CHD) from exosome-derived circRNA.MethodsThe microarray data of circRNA derived from the exosomes of patients with CHD and mRNA in acute myocardial infarction was retrieved from exoRBase website and GEO database (GSE61144), respectively, to identify the differentially expressed genes (DEGs). Our findings detected the differentially expressed circRNAs and mRNAs and predicted their correlation with microRNAs using the microRNA target prediction website, thus ascertaining the corresponding circ-microRNA and micro-mRNAs. Then, we performed systematic Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis on the differentially expressed mRNA. Protein-Protein Interactions (PPI) of these DEGs were examined using STRING. The receiver operator characteristic (ROC) curve was used to validate the diagnostic efficacy of circRNA in patients with CHD. Finally, the RNAs identified in this study were verified by quantitative real-time polymerase chain reaction (qRT-PCR).ResultsA total of 85 differentially expressed circRNAs (4 up-regulated and 81 down-regulated) were identified by screening the circRNAs in exosome of CHD patients. Based on the prediction data of circRNA, mRNA, and the corresponding microRNA, a ceRNA network was constructed, including 7 circRNA nodes, 5 microRNA nodes, and 2 mRNA nodes. Finally, validated by qRT-PCR testing, we found circRNA0001785, circRNA0000973, circRNA0001741, and circRNA0003922 to be the promising candidate for the effective prediction of CHD. These potential diagnostic markers can provide insight for further research on the occurrence of CHD or even acute coronary syndrome (ACS).

| S-EPMC9928865 | biostudies-literature

A novel circRNA-miRNA-mRNA network reveals hsa-circ-0040039 as a biomarker for intervertebral disc degeneration.

Project description:ObjectiveAlterations in the structure and function of intervertebral discs by multifaceted chronic processes can result in intervertebral disc degeneration (IDD). The mechanisms involved in IDD are still unknown.MethodsWe investigated the possible mechanisms underlying IDD using a bioinformatics analysis of publicly available microarray expression datasets and built a circular RNA-microRNA-mRNA (circRNA-miRNA-mRNA) network based on the results. Datasets GSE67566 and GSE116726 were downloaded from the Gene Expression Omnibus (GEO) and analyzed using the limma package in R. The CircInteractome database was used to detect miRNAs related to circRNA, and TargetScan, miRDB, and miRTarBase were used to predict target mRNAs. Key target genes were annotated using Gene Ontology terms.ResultsThe circRNA hsa-circ-0040039 was found to have the top log fold-change score. Analysis using Metascape showed that the associated genes were enriched mainly in the cell cycle. The Cytoscape plugin MCODE predicted that two members of the RAS oncogene family-RAB1A and RAB1B-and multiple coagulation factor deficiency (MCFD2) may play key roles in IDD.ConclusionOur results suggested that hsa-circ-0040039 and the related network may be potential biomarkers for IDD.

| S-EPMC8733709 | 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