Browse
Submit Data
Databases
API
Help

Dataset Information

19 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Feedback activation of GATA1/miR-885-5p/PLIN3 pathway decreases sunitinib sensitivity in clear cell renal cell carcinoma.

ABSTRACT: Sunitinib is the most commonly used first-line therapy for the treatment of advanced renal cell carcinoma (RCC), but intrinsic and extrinsic resistance to targeted therapies dramatically compromise the benefit of clinical outcome. Dissecting the underlying mechanisms and discovering reliable predictive biomarkers are urgently needed in clinic. Here, we discovered miR-885-5p was notably decreased after sunitinib treatment and associated with poor disease progression in clear cell renal cell carcinoma (ccRCC). In vitro and in vivo studies identified miR-885-5p inhibition contributed to sunitinib resistance. Mechanistically, sunitinib treatment reduced GATA1 expression, which in turn reduced its binding to MIR885 promoter and resulted in miR-885-5p downregulation in transcriptional level. In addition, PLIN3 was confirmed to be directly targeted by miR-885-5p and its upregulation significantly increased lipid droplets formation to decrease sunitinib sensitivity. Therefore, GATA1/miR-885-5p/ PLIN3 pathway may serve as a potential therapeutic strategy and a biomarker for sunitinib treatment in ccRCC.

SUBMITTER: Yao D

PROVIDER: S-EPMC7513838 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

miR-96-5p targets PTEN to mediate sunitinib resistance in clear cell renal cell carcinoma.

Project description:A multiple receptor tyrosine kinase inhibitor, sunitinib, is a first-line therapy for clear cell renal cell carcinoma (CCRCC). Unfortunately, it has the major challenges of low initial response rate and resistance after about one year of treatment. Here we evaluated a microRNA (miRNA) and its target responsible for sunitinib resistance. Using miRNA profiling, we identified miR-96-5p upregulation in tumors from sunitinib-resistant CCRCC patients. By bioinformatic analysis, PTEN was selected as a potential target of miR-96-5p, which showed low levels in tumors from sunitinib-resistant CCRCC patients. Furthermore, PTEN and miR-96-5p levels were negatively correlated in a large The Cancer Genome Atlas kidney renal clear cell carcinoma cohort and high miR-96 and low PTEN represented poor prognosis in this cohort. Additionally, four-week sunitinib treatment increased miR-96-5p and decreased PTEN only in tumors from a sunitinib-resistant patient-derived xenograft model. We found a novel miR-96-5p binding site in the PTEN 3' UTR and confirmed direct repression by luciferase reporter assay. Furthermore, we demonstrated that repression of PTEN by miR-96-5p increased cell proliferation and migration in sunitinib-treated cell lines. These results highlight the direct suppression of PTEN by miR-96-5p and that high miR-96-5p and low PTEN are partially responsible for sunitinib resistance and poor prognosis in CCRCC.

| S-EPMC8894382 | biostudies-literature

Impact of sunitinib resistance on clear cell renal cell carcinoma therapeutic sensitivity <i>in vitro</i>.

Project description:Sunitinib resistance creates a major clinical challenge for the treatment of advanced clear cell renal cell carcinoma (ccRCC) and functional and metabolic changes linked to sunitinib resistance are not fully understood. We sought to characterize the molecular and metabolic changes induced by the development of sunitinib resistance in ccRCC by developing and characterizing two human ccRCC cell lines resistant to sunitinib. Consistent with the literature, sunitinib-resistant ccRCC cell lines presented an aberrant overexpression of Axl and PD-L1, as well as a metabolic rewiring characterized by enhanced OXPHOS and glutamine metabolism. Therapeutic challenges of sunitinib-resistant ccRCC cell lines in vitro using small molecule inhibitors targeting Axl, AMPK and p38, as well as using PD-L1 blocking therapeutic antibodies, showed limited CTL-mediated cytotoxicity in a co-culture model. However, the AMPK activator metformin appears to sensitize the effect of PD-L1 blocking therapeutic antibodies and to enhance CTLs' cytotoxic effects on ccRCC cells. These effects were not broadly observed with the Axl and the p38 inhibitors. Taken together, these data suggest that targeting certain pathways aberrantly activated by sunitinib resistance such as the AMPK/PDL1 axis might sensitize ccRCC to immunotherapies as a second-line therapeutic approach.

| S-EPMC11005810 | biostudies-literature

Identification of dysregulated serum miR-508-3p and miR-885-5p as potential diagnostic biomarkers of clear cell renal carcinoma.

Project description:Clear cell renal cell carcinoma (ccRCC), the most common subtype, accounts for approximately 80% of all RCC cases. ccRCC patients typically present with an advanced stage at the time of diagnosis resulting in a poor patient prognosis. The present study aimed to identify novel potential microRNAs (miRNAs or miRs) in peripheral blood as biomarkers for the detection of ccRCC. Candidate miRNAs were selected through integrated analysis of the Gene Expression Omnibus (GEO) database, The Cancer Genome Atlas (TCGA) database, and from clinical samples. The expression levels of miRNAs were quantified using reverse transcription?quantitative PCR. Receiver operating characteristic (ROC) curve analysis was used to explore the diagnostic values of the miRNAs. Bioinformatic analysis of candidate miRNAs was conducted by using the STRING database. After an integrated analysis of the GEO and TCGA databases, four miRNAs were found to be consistently dysregulated in ccRCC tissues. Then, their expression levels in serum and diagnostic utilities were further explored. We discovered that serum miR?508?3p and miR?885?5p were significantly dysregulated in ccRCC patients with marked diagnostic values. The area under the ROC curve (AUC) of serum miR?508?3p and miR?885?5p was 0.80 (95% CI, 0.73?0.87) and 0.87 (95% CI, 0.79?0.95), respectively. Functional enrichment analysis revealed that both miR?508?3p and miR?885?5p were closely associated with cellular metabolic processes. In conclusion, serum miR?508?3p and miR?885?5p are novel potential biomarkers for the diagnosis of ccRCC.

| S-EPMC6854552 | biostudies-literature

Impact of sunitinib resistance on clear cell renal cell carcinoma therapeutic sensitivity in vitro

2024-04-17 | GSE216494 | GEO

AUY922 improves sensitivity to sunitinib in clear cell renal cell carcinoma based on network pharmacology and in vitro experiments.

Project description:Clear Cell Renal Cell Carcinoma (ccRCC), the most prevalent form of renal cell carcinoma (RCC), poses a significant threat to human health due to its rising morbidity and mortality rates. Sunitinib, a pivotal targeted drug for the treatment of ccRCC, presents a significant challenge due to the high susceptibility of ccRCC to resistance. HSP90 inhibitor AUY922 has demonstrated anti-tumor activity in a range of cancer types. However, its efficacy in combination with sunitinib for ccRCC treatment has not been evaluated. In this study, we employed bioinformatics, network pharmacology, and in vitro assays to verify that AUY922 inhibits cell viability, proliferation, and migration of ccRCC cell lines 786-O and ACHN, with IC50s of 91.86 μM for 786-O and 115.5 μM for ACHN. The effect of AUY922 enhancing the inhibitory effect of sunitinib on ccRCC was further confirmed. The CCK-8 assay demonstrated that the IC50 of sunitinib was reduced from 15.10 μM to 11.91 μM for 786-O and from 17.65 μM to 13.66 μM for ACHN, after the combined application of AUY922. The EdU assay and wound healing assay indicated that AUY922 augmented the inhibitory impact of sunitinib on the proliferation and migration of ccRCC cells. Western blot and RT-PCR analyses demonstrated that AUY922 increased the sensitivity of ccRCC cells to sunitinib by targeting the HIF-1α/VEGFA/VEGFR pathway. Our study represents the first investigation into the role and mechanism of AUY922 in enhancing the sensitivity of ccRCC to sunitinib. In conclusion, the findings indicate the potential for AUY922 to enhance the therapeutic efficacy of sunitinib and overcome sunitinib resistance in ccRCC.

| S-EPMC11324986 | biostudies-literature

Role of IL13RA2 in Sunitinib Resistance in Clear Cell Renal Cell Carcinoma.

Project description:Vascular endothelial growth factor (VEGF) and mammalian target of rapamycin are well-known therapeutic targets for renal cell carcinoma (RCC). Sunitinib is an agent that targets VEGF receptors and is considered to be a standard treatment for metastatic or unresectable clear cell RCC (ccRCC). However, ccRCC eventually develops resistance to sunitinib in most cases, and the mechanisms underlying this resistance are not fully elucidated. In the present study, we established unique primary xenograft models, KURC1 (Kyoto University Renal Cancer 1) and KURC2, from freshly isolated ccRCC specimens. The KURC1 xenograft initially responded to sunitinib treatment, however finally acquired resistance. KURC2 retained sensitivity to sunitinib for over 6 months. Comparing gene expression profiles between the two xenograft models with different sensitivity to sunitinib, we identified interleukin 13 receptor alpha 2 (IL13RA2) as a candidate molecule associated with the acquired sunitinib-resistance in ccRCC. And patients with high IL13RA2 expression in immunohistochemistry in primary ccRCC tumor tends to have sunitinib-resistant metastatic site. Next, we showed that sunitinib-sensitive 786-O cells acquired resistance in vivo when IL13RA2 was overexpressed. Conversely, shRNA-mediated knockdown of IL13RA2 successfully overcame the sunitinib-resistance in Caki-1 cells. Histopathological analyses revealed that IL13RA2 repressed sunitinib-induced apoptosis without increasing tumor vasculature in vivo. To our knowledge, this is a novel mechanism of developing resistance to sunitinib in a certain population of ccRCC, and these results indicate that IL13RA2 could be one of potential target to overcome sunitinib resistance.

| S-EPMC4482605 | biostudies-literature

RNF7 inhibits apoptosis and sunitinib sensitivity and promotes glycolysis in renal cell carcinoma via the SOCS1/JAK/STAT3 feedback loop.

Project description:BackgroundRING finger protein 7 (RNF7) is a highly conserved protein that functions as an E3 ubiquitin ligase. RNF7 overexpression is indicated in multiple human cancers, but its role in renal cell carcinoma (RCC) and the mechanisms underlying how it regulates the initiation and progression of RCC have not been explored.MethodsBioinformatics analysis, quantitative reverse-transcription polymerase chain reaction (RT-PCR), and Western blot were conducted to determine the expression of RNF7 in RCC tissues and cell lines. Knockdown and overexpression experiments were performed to examine the effects of RNF7 on cell viability, apoptosis, and glycolysis in vitro and on tumor growth in nude mice in vivo.ResultsThe elevated RNF7 expression in tumor tissues of patients with RCC was correlated with poor survival. RNF7 overexpression inhibited apoptosis and promoted glycolysis in vitro and increased tumor growth in vivo by activating the JAK/STAT3 signaling pathway by ubiquitination of SOCS1. Moreover, RNF7 overexpression affected the sensitivity of RCC cells to sunitinib. Finally, STAT3 activation was necessary for transcriptional induction of RNF7.ConclusionThese results demonstrate that RNF7 inhibited apoptosis, promoted glycolysis, and inhibited sunitinib sensitivity in RCC cells via ubiquitination of SOCS1, thus activating STAT3 signaling. These suggest the potential for targeting the RNF7-SOCS1/JAK/STAT3 pathway for RCC treatment.

| S-EPMC9107170 | biostudies-literature

CXCL7 is a predictive marker of sunitinib efficacy in clear cell renal cell carcinomas.

Project description:Sunitinib is one of the first-line standard treatments for metastatic clear cell renal cell carcinoma (ccRCC) with a median time to progression shorter than 1 year. The objective is to discover predictive markers of response to adapt the treatment at diagnosis.Prospective phase 2 multi-centre trials were conducted in ccRCC patients initiating sunitinib (54 patients) or bevacizumab (45 patients) in the first-line metastatic setting (SUVEGIL and TORAVA trials). The plasmatic level of CXCL7 at baseline was correlated with progression-free survival (PFS).The cut-off value of CXCL7 for PFS was 250?ng?ml-1. Patients with CXCL7 plasmatic levels above the cut-off at baseline (250?ng?ml-1) had a significantly longer PFS (hazard ratio 0.323 (95% confidence interval 0.147-0.707), P=0.001). These results were confirmed in a retrospective validation cohort. The levels of CXCL7 did not influence PFS of the bevacizumab-treated patients.CXCL7 may be considered as a predictive marker of sunitinib efficacy for ccRCC patients.

| S-EPMC5625677 | biostudies-literature

Sphingosine kinase 1 overexpression contributes to sunitinib resistance in clear cell renal cell carcinoma.

Project description:Sphingosine kinase 1 (SphK1) is the major source of the bioactive lipid and GPCR agonist sphingosine 1-phosphate (S1P). Although alterations in SphK1 expression and activity have been detected in various human malignancies, its potential molecular mechanisms in the development and sunitinib resistance of clear cell renal cell carcinoma (ccRCC) remain obscure. In this study, we aim to evaluate the clinical significance of SphK1 and to explore the therapeutic implications of combination approach for ccRCC patients. We identify upregulation of SphK1 significantly associated with poor prognosis of large cohort of ccRCC patients, which contributing to cell proliferation, colony formation, migration and survival. Suppression of SphK1 activity either by shRNA or pharmacologic inhibitior FTY720 suppresses cell growth in vitro and in vivo. A comprehensive phosphoprotein antibody array reveals that SphK1 overexpression promoted RCC progression by regulating the Akt/mTOR pathway. Moreover, FTY720 administration enhanced tumor growth inhibition effect of sunitinib treatment on RCC cells in vitro and in vivo. Our results unraveled that increased SphK1 kinase activation defines an important mechanism for sunitinib resistance, therefore contributes to tumour development and represents therapeutic targets for ccRCC.

| S-EPMC6279321 | biostudies-literature

PPARα mediates sunitinib resistance via NF-κB activation in clear cell renal cell carcinoma.

Project description:Sunitinib is used as standard treatment for metastatic or unresectable clear cell renal cell carcinoma (ccRCC). However, ccRCC eventually develops resistance to sunitinib in most cases, and the mechanisms underlying such resistance have not been fully determined. Nuclear receptors (NRs) are a class of transcription factors that regulate many cellular functions by controlling gene expression, and they also play important roles in tumor development, proliferation and progression in various types of cancers. In the present study, we aimed to explore the mechanisms underlying sunitinib resistance in RCC and the potential role of NRs in sunitinib resistance. The expression profile of NRs was obtained from the Gene Expression Omnibus (GEO) RNAseq database. A total of 138 patients from GSE65615 were examined in this study. From the GEO metadata, we found that the expressions of three genes, encoding peroxisome proliferator activated receptor alpha (PPARα), androgen receptor (AR) and PPARγ, were significantly increased in sunitinib-treated samples compared with control samples. RT-PCR analysis showed that the PPARα expression at the mRNA level was significantly increased in sunitinib-resistant A498, CaKi-1 and 780-O ccRCC lines compared with their sunitinib-sensitive parental cells. Furthermore, knockdown of PPARα significantly inhibited cell proliferation in all three sunitinib-resistant ccRCC lines, successfully overcoming the resistance to sunitinib. Our results also showed that nuclear factor kappa B (NF-κB) signaling pathway was activated in sunitinib-resistant ccRCC lines, indicating that PPARα and NF-κB inhibition could play a synergistic role to modulate sunitinib resistance and suggesting that PPARα could be used as a potential target to overcome sunitinib resistance via the NF-κB pathway.

| S-EPMC6958248 | 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