MiR-146a downregulation contributes to sunitinib-induced cardiac dysfunction
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA518091 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The left ventricle tissue of mice underwent microarray assaying to reveal the miRNA alterations induced by SNT.
2019-01-31 | GSE125952 | GEO
Project description:The main adverse effect of tyrosine kinase inhibitors, such as sunitinib, is cardiac contractile dysfunction; however, the molecular mechanisms of this effect remain largely obscure. MicroRNAs (miRNAs) are key regulatory factors in both cardiovascular diseases and the tyrosine kinase pathway. Therefore, we analyzed the differential expression of miRNAs in the myocardium in mice after exposure to sunitinib using miRNA microarray. A significant downregulation of miR-146a was observed in the myocardium of sunitinib-treated mice, along with a 20% decrease in left ventricle ejection fraction (LVEF). The downregulation of miR-146a was further validated by RT-qPCR. Among the potential targets of miR-146a, we focused on Pln and Ank2, which are closely related to cardiac contractile dysfunction. Results of luciferase reporter assay confirmed that miR-146a directly targeted the 3' untranslated region of Pln and Ank2. Significant upregulation of PLN and ANK2 at the mRNA and protein levels was observed in the myocardium of sunitinib-treated mice. Cardiac-specific overexpression of miR-146a prevented the deteriorate effect of SNT on calcium transients, thereby alleviating the decreased contractility of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). SiRNA knockdown of PLN or ANK2 prevented sunitinib-induced suppression of contractility in hiPSC-CMs. Therefore, our in vivo and in vitro results showed that sunitinib downregulated miR-146a, which contributes to cardiac contractile dysfunction by regulating the downstream targets PLN and ANK2, and that upregulation of miR-146a alleviated the inhibitory effect of SNT on cardiac contractility. Thus, miR-146a could be a useful protective agent against sunitinib-induced cardiac dysfunction.
| S-EPMC6716347 | biostudies-literature
Project description:MicroRNAs (miRNAs) are small non-coding RNAs that function as modulators of gene expression. We previously showed that miR-146a-5p is upregulated in pancreatic islets treated with pro-inflammatory cytokines and in pancreatic sections from organ donors with type 1 diabetes (T1D). Other studies have associated overexpression of miR-146a-5p with β cell apoptosis and impaired insulin secretion; however, the molecular mechanisms mediating these effects remain elusive. To investigate the role of miR-146a-5p in β cell function, we developed stable MIN6 cell lines transduced with lentiviral vectors to either overexpress or inhibit the expression of miR-146a-5p. Monoclonal cell populations were treated with pro-inflammatory cytokines (IL1β, IFNg, and TNFα) to model T1D in vitro. We found that overexpression of miR-146a-5p increased the cell death of MIN6 cells under inflammatory stress, whereas inhibition of miR-146a-5p reversed these effects. Additionally, inhibition of miR-146a-5p increased mitochondrial DNA copy number, respiration rate, and ATP production, suggesting that miR-146a-5p inhibition improves mitochondrial function. In support of this finding, we also observed that miR-146a-5p is enriched in the mitochondria of MIN6 cells treated with cytokines. Consistently, bioinformatic analysis of RNA sequencing data using MIN6 stable cells showed enrichment of pathways related to insulin secretion, apoptosis, and mitochondrial function when the expression levels of miR-146a-5p were altered. Overall, the findings from our study show for the first time that miR-146a-5p upregulation during inflammatory stress may promote β cell dysfunction and death by suppressing mitochondrial function.
2024-04-10 | GSE255756 | GEO
Project description:miR-146a-5p contributes to inflammation-mediated β cell mitochondrial dysfunction and apoptosis
| PRJNA1076462 | ENA
Project description:miR-146a is a NF-κB induced microRNA that serves as a feedback regulator of this critical pathway. In mice, deficiency of miR-146a results in hematolymphoid cancer at advanced ages as a consequence of constitutive NF-κB activity. In this study, we queried whether the deficiency of miR-146a contributes to B-cell oncogenesis. Combining miR-146a deficiency with transgenic expression of c-Myc led to the development of highly aggressive B-cell malignancies. Mice transgenic for c-Myc and deficient for miR-146a were characterized by significantly shortened survival, increased lymph node involvement, differential involvement of the spleen and a mature B-cell phenotype. High-throughput sequencing of the tumors revealed significant dysregulation of approximately 250 genes. Amongst these, the transcription factor Egr1 was consistently upregulated in mice deficient for miR-146a. Interestingly, transcriptional targets of Egr1 were enriched in both the high-throughput dataset and in a larger set of miR-146a-deficient tumors. miR-146a overexpression led to downregulation of Egr1 and downstream targets with concomitant decrease in cell growth. Direct targeting of the human EGR1 by miR-146a was seen by luciferase assay. Together our findings illuminate a bona fide role for miR-146a in the modulation of B-cell oncogenesis and reveal the importance of understanding microRNA function in a cell- and disease-specific context.
2016-03-20 | GSE67113 | GEO
Project description:Renal cell carcinoma (RCC) represents about 2-3% of all cancers with over 400,000 new cases per year. Sunitinib, a vascular endothelial growth factor tyrosine kinase receptor inhibitor, has been used mainly for first-line treatment of metastatic clear-cell RCC with good or intermediate prognosis. However, about one third of metastatic RCC patients do not respond to sunitinib, leading to disease progression. Here we aim to find and characterize proteins associated with poor sunitinib response in a pilot proteomics study. 16 RCC tumors from patients responding (8) vs. non-responding (8) to sunitinib in 3 months after treatment initiation, together with their adjacent non-cancerous tissues, were analyzed using data independent acquisition mass spectrometry. Proteomics analysis quantified 1996 protein groups (q<0.01) and revealed 27 proteins deregulated between tumors non-responding vs. responding to sunitinib, representing a pattern of deregulated proteins potentially contributing to sunitinib resistance. Gene set enrichment analysis showed up-regulation of epithelial-to-mesenchymal transition with transgelin as one of the most significantly abundant protein. Transgelin expression was silenced by CRISPR/Cas9 and RNA interference, and the cells with reduced transgelin level exhibited significantly slower proliferation. Our data indicate that transgelin is an essential protein supporting RCC cell proliferation which could contribute to intrinsic sunitinib resistance.
2021-11-03 | PXD027065 | Pride
Project description:To gain insights into the mechanisms of dihydroberberine, sunitinib and dihydroberberine plus sunitinib on inhibition to A549 cells, we have employed whole genome microarray expression profiling as a discovery platform to identify different genes between dihydroberberine, sunitinib and dihydroberberine plus sunitinib-treated sample and control.
2015-06-26 | GSE70282 | GEO
Project description:To gain insights into the mechanisms of dihydroberberine, sunitinib and dihydroberberine plus sunitinib on inhibition to A549 cells, we have employed whole genome microarray expression profiling as a discovery platform to identify different genes between dihydroberberine, sunitinib and dihydroberberine plus sunitinib-treated sample and control. A549 cells were cultivated in the absence or presence of 25?mol/L dihydroberberine, 2?mol/L sunitinib, 25?mol/L dihydroberberine plus 2?mol/L sunitinib for 48 h, followed by the Agilent Whole Human Genome Oligo Microarray
2015-06-26 | E-GEOD-70282 | biostudies-arrayexpress
Project description:Cystathionine γ-lyase downregulation contributes to hepatocyte injury and dysfunction via multiple signaling pathways by regulation of histone lysine methylation
| PRJNA1172652 | ENA
Project description:Despite the promise of targeted tyrosine kinase inhibitors (TKIs), such as sunitinib, in the extension of survival time in patients with clear cell renal cell carcinoma (ccRCC) progression or metastasis, the patients eventually succumb to inevitable drug resistance. Protein degradation executed by the ubiquitin-dependent proteasome system played an important role in determining the sensitivity of ccRCC to sunitinib. Here, we applied the bioinformatic analysis to identify that E3 ligase RBCK1 was elevated in the sunitinib-resistant renal cancer cell lines or patient specimens. The subsequent in vitro or in vivo studies demonstrated that RBCK1 contributed to decreasing the sensitivity of ccRCC to sunitinib. Then, we showed that inhibition of RBCK1 activated the AKT and MAPK signaling pathways, which might be one of the main reasons why RBCK1 induces sunitinib resistance in ccRCC cells. Mechanistically, our results indicated that RBCK1 promotes the degradation of ANKRD35 and that ANKRD35 destabilizes MITD1 by binding with SUMO2 in ccRCC cells. In addition, we showed that the RBCK1-ANKRD35-MITD1-ANXA1 axis regulates the phosphorylation of AKT and ERK and contributes to the dysregulation of sunitinib in ccRCC cells. Therefore, we identified a novel mechanism for regulating the sensitivity of sunitinib in ccRCC. Therefore, we elucidated a novel mechanism by which RBCK1 regulates sunitinib sensitivity in ccRCC.
2025-10-02 | GSE214635 | GEO