Transcriptome sequencing (RNA-Seq) of non-tumor kidney tissues from 36 patients undergoing nephrectomy for exploring the metabolic mechanism of sorafenib and identifying the major transcriptional regulation factors in sorafenib metabolism in kidney
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE93069 | GEO | 2018/01/03
SECONDARY ACCESSION(S): PRJNA359795
REPOSITORIES: GEO
Similar Datasets
Project description:sorafenib is the treatment of reference for hepatocellular carcinoma (HCC). We applied sorafenib on the human HCC cell line Huh7 and the subclone shRb, carrying a stable knock-down of the expression of the RB1 gene, a key regulator of liver carcinogenesis. Our aim was to better understand the physiologic and metabolic consequences of the exposure of HCC cells to sorafenib. We used microarrays to detail the global programme of gene expression at an early time point (9h) after exposure to sorafenib Whole-genome microarrays were used to study the transcriptome of Huh7 cells exposed to Sorafenib
2016-06-30 | E-GEOD-75620 | biostudies-arrayexpress
Project description:In our experiments with a xenograft model, mouse-IFN (mIFN) treatment was suggested to exaggerate the antitumor effects of sorafenib on hepatocellular carcinoma in vivo. We explored how mIFN enhances the in vivo antitumor effects of sorafenib.
2017-11-01 | GSE102863 | GEO
Project description:sorafenib is the treatment of reference for hepatocellular carcinoma (HCC). We applied sorafenib on the human HCC cell line Huh7 and the subclone shRb, carrying a stable knock-down of the expression of the RB1 gene, a key regulator of liver carcinogenesis. Our aim was to better understand the physiologic and metabolic consequences of the exposure of HCC cells to sorafenib. We used microarrays to detail the global programme of gene expression at an early time point (9h) after exposure to sorafenib
2016-06-30 | GSE75620 | GEO
Project description:Hepatocellular carcinoma (HCC) is one of the most common causes of death worldwide and the fourth most prevalent type of cancer. Whereas curative treatments such as liver transplantation, ablation or surgery are optimal for early stages, only paliative treatments are given to intermediate and advanced stages of the disease. Sorafenib is still a suitable therapeutic option for patients in whom immunotherapy is not feasible. To gain information about therapy response, we sequenced HepG2 cells treated with Sorafenib 10 µM (24 hours)
2023-12-01 | GSE225537 | GEO
Project description:Sorafenib resistance up-regulated circRNA_104797 could be transmitted by exosomes and responsible for the spread of Sorafenib resistance among HCC cells. CircRNA_104797 was critical for Sorafenib resistance maintenance and silencing circRNA_104797 could substantially increase the efficacy of Sorafenib by inducing apoptosis. Mechanism dissection unveiled that circRNA_104797 could specifically sponge miR-103a-2-5p and miR-660-3p and act as a competing endogenous RNA (ceRNA), thus competitively activated wnt/β-catenin pathway and induced Sorafenib resistance. Meanwhile, LC-MS/MS also revealed that circRNA_104797 could specifically bind to translation related proteins, which might regulate downstream glycan biosynthesis and lipid metabolism, and finally induce Sorafenib resistance. In vivo experiments portrayed a promising clinical application by locally injection of in vivo-grade siRNA for circRNA_104797 by TACE or other manners, which could intensively enhance Sorafenib efficacy in HCC patients. The clinical application of in vivo-grade siRNA for circRNA_104797 in Sorafenib treated HCC patients might shed bright future for the management of advanced HCC.
2020-07-25 | GSE101850 | GEO
Project description:Knowing the gene expression profiles of drug-metabolizing enzymes and transporters throughout gestation is important for understanding the mechanisms of pregnancy-induced changes in drug pharmacokinetics. In this study, we compared gene expression of drug-metabolizing enzymes and transporters in the maternal liver, kidney, small intestine, and placenta of pregnant mice throughout gestation by microarray analysis. Specifically, we investigated cytochrome P450 (Cyp), UDP-glucuronosyltranserase (Ugt), and sulfotransferase (Sult), as well as ATP-binding cassette (Abc) and solute carrier (Slc) transporters. We found that relatively few Ugt and Sult genes were impacted by pregnancy in maternal tissues and placenta. Cyp1a2, most Cyp2 isoforms, Cyp3a11, and Cyp3a13 in the liver were down-regulated, with the greatest changes occurring on gestation days (gd) 15 and 19 compared to non-pregnant controls (gd 0). However, Cyp2d40, Cyp3a16, Cyp3a41a, Cyp3a41b, and Cyp3a44 in the liver were induced throughout pregnancy. Cyp expression in mid-gestation placenta (gd 10 and 15) was generally greater than that in term placenta (gd 19). There were also notable changes in Abc and Slc transporters. Abcc3 in the liver was down-regulated by 60%, and Abcb1a, Abcc4, and Slco4c1 in the kidney were down-regulated by 30-60% on gd 15 and 19 versus gd 0. Abcc5 in the placenta was induced 3-fold on gd 10 versus gd 15 and 19, whereas Slc22a3 expression in the placenta on gd 10 was 90% lower than that on gd 15 and 19. Overall, this study demonstrates important gestational age-dependent expression of drug-metabolizing enzymes and transporter genes, which may have mechanistic relevance to human pregnancy. Ninety pregnant mice at gestational days 0, 7.5, 10, 15, and 19 (n = 5-6 per gestational age) were used for the maternal liver, kidney, small intestine and placenta. The placentas were collected on gestational days 10, 15, and 19.
2013-10-08 | E-GEOD-41438 | biostudies-arrayexpress
Project description:OBJECTIVE: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterize the role of tumor-initiating cells (T-ICs) and signaling pathways involved in sorafenib resistance. DESIGN: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: 1) Role of T-ICs by in vitro sphere formation and in vivo tumorigenesis assays using NOD/SCID mice, 2) Activation of alternative signaling pathways and 3) Efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, qRT-PCR) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in 2 independent cohorts. RESULTS: Sorafenib-acquired resistance tumors showed significant enrichment of T-ICs (164 cells needed to create a tumor) vs. sorafenib-sensitive tumors (13400 cells) and non-treated tumors (1292 cells), p<0.001. Tumors with sorafenib-acquired resistance were enriched with IGF and FGF signaling cascades (FDR<0.05). In vitro, cells derived from sorafenib-acquired resistant tumors and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumor growth and improved survival in sorafenib-resistant tumors. A sorafenib-resistance 175-gene signature was characterized by enrichment of progenitor-cell features, aggressive tumoral traits and predicted poor survival in 2 cohorts (n=442 HCC patients). CONCLUSION: Acquired resistance to sorafenib is driven by tumor initiating cells with enrichment of progenitor markers and activation of IGF and FGF signaling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression. Transcriptomic profile of subcutaneous Huh7 cells-derived tumors treated with sorafenib that developed acquired resistance to the drug (n=4), remain responsive to sorafenib (n=3) or were treated with brivanib after development of resistance (n=3). Gene profiling of hepatospheres generated from tumors with acquired resistance to sorafenib (n=3) and non-treated tumors (n=3) was also analyzed.
2016-06-16 | E-GEOD-73571 | biostudies-arrayexpress
Project description:We used an expression profiling chip to detect the expression profile of PLC cells after they were treated with sorafenib and sorafenib probe
2018-12-12 | GSE123600 | GEO
Project description:Checkpoint inhibitors combined with sorafenib for hepatocellular carcinoma (HCC) treatment have achieved satisfactory results in many clinical trials. Understanding the mechanism underlying this modality may provide better strategies to eradicate HCC. In the present study, peripheral blood mononuclear cells (PBMCs) from patients who received combination sintilimab and sorafenib treatment were analyzed by single-cell RNA sequencing (scRNA-seq).
2022-10-17 | GSE215428 | GEO
Project description:Tyrosine kinase inhibitors (TKIs), as a class of small-molecule drugs that exert anti-tumor effects by inhibiting tyrosine kinase-catalyzed phosphorylation, have been used in the treatment of various cancers. Sorafenib, as a multi-targeted TKI drug, is the first-line treatment for advanced renal cell carcinoma and unresectable hepatocellular carcinoma. However, sorafenib has repeatedly been reported to cause cardiac events in patients without a history of heart diseases during clinical use, indicating that it has cardiotoxicity. Alternative splicing of cardiac contraction-related genes happens during heart development and cardiac diseases, and is critical for heart function. However, whether alternative splicing plays a role in drug-induced cardiotoxicity remains unexplored. RBM20 is an important cardiac-specific splicing factor, mutations of which cause dilated cardiomyopathy or other cardiac dysfunctions. Rbm20 also mediates alternative splicing of genes essential for heart contraction, which is often negatively affected in drug-induced cardiotoxicity. Existing studies do not fully explain the mechanism of sorafenib cardiotoxicity, and none of the relationship between cardiotoxicity of sorafenib and alternative splicing mediated by tissue-specific splicing factors, such as Rbm20, have been reported. In order to explore whether cardiac-specific alternative splicing plays a role in sorafenib-induced cardiotoxicity, we establish both cell and animal models of cardiotoxicity, and obtain the following results: (1) By constructing a rat animal model administered with sorafenib, we find that sorafenib causes abnormal cardiac function in rats, and the genes that undergo alternative splicing in rat hearts are related to cytoskeleton of actin; (2) Alternatively spliced genes induced by sorafenib in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are enriched in sarcomere, actin filament, calcium transient regulation, mitochondria, all of which are critical for cardiac contraction. These genes are associated with dilated cardiomyopathy, hypertrophic cardiomyopathy and other cardiomyopathy; (3) Sorafenib induces a decrease in the expression of cardiac-specific splicing factor RBM20; (3) Many genes whose splicing are altered by sorafenib overlap with Rbm20 targets, indicating that sorafenib may affect alternative splicing through Rbm20; (4) Sorafenib induces pathogenic alternative splicing of FHOD3, which is a RBM20 target gene and participates in myocardial sarcomere formation. Sorafenib also affects alternative splicing of SLC25A3, which encodes a phosphate transporter on the mitochondrial inner membrane and regulates ATP synthesis; (5) Enhancing the expression of RBM20 rescues the cardiotoxicity of sorafenib by reducing apoptosis and increasing ATP levels, which is mediated by reversing the alternative splicing of FHOD3 and SLC25A3 induced by sorafenib. This paper uncovers that sorafenib reduces the expression of RBM20 to cause pathogenic alternative splicing of genes related to myocardial sarcomere and energy mechanism, resulting in abnormal myocardial function. Increasing the expression of RBM20 reverses the alternative splicing of FHOD3 and SLC25A3 associated with cardiac sarcomeres and mitochondria respectively, rescuing the cardiotoxicity of sorafenib.
2023-12-07 | GSE222642 | GEO