RNA-sequencing of HCC patients undergoing sorafenib treatment
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PROVIDER: EGAS00001005662 | EGA |
REPOSITORIES: EGA
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Project description:Whole-exome sequencing of hepatocellular carcinomas at various stages of sorafenib treatment
| EGAS00001005661 | EGA
Project description:Ferroptosis is a new form of regulated, non-apoptotic cell death characterized by excessive lipid peroxidation upon loss of activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4). Sorafenib, an FDA-approved multi-kinase inhibitor drug for treatment of hepatocellular carcinoma (HCC), has been shown to induce ferroptosis. Protein phosphorylation changes upon Sorafenib treatment have been previously reported in patient studies and in cell culture however the early phosphorylation changes during induction of ferroptosis are not completely understood. This work highlights these changes through a time course from 7 to 60 min of Sorafenib treatment in SKHep1 cells to provide insight on the induction of ferroptosis. 6,186 unique phosphosites were quantified from 2,381 phosphoproteins in this study and phosphorylation changes occurred in as early as 30 minutes of Sorafenib treatment. By 60 minutes, significant changes in key regulatory pathways were identified, including sites from ferroptosis-related proteins, indicating the involvement of phospho-regulated signaling during ferroptosis induction.
2019-07-26 | MSV000084140 | MassIVE
Project description:Sorafenib has been a cornerstone in hepatocellular carcinoma (HCC) therapy; however, its efficacy is limited, and identifying patients that will respond to sorafenib is challenging. Gene expression data from 33 HCC tumors treated with sorafenib were analyzed to construct a prediction model aimed at identifying patients with greater benefit from sorafenib treatment. The analysis of transcriptome data revealed a 50-gene signature, KUSS50 (Korea University Sorafenib Signature with 50 genes), that exhibited high predictive power in identifying patients responded to sorafenib treatment in a training cohort. Extensive validation across 2 independent cohorts (IMbrave150 and BIOSTORM) given sorafenib demonstrated KUSS50's high specificity in predicting sorafenib response. Genomic analyses identified distinct molecular characteristics linked with KUSS50 subtypes, including an increased mutation rate and activation of ferroptosis, suggesting increased baseline ferroptotic activity in HCCs, which may sensitize them to sorafenib. The benefit subtype also overlapped with those in previously defined genomic HCC subtypes associated with stemness and aggressiveness. Conversely, the non-benefit subtype correlated with -catenin mutations and increased tumor purity, underscoring the biological significance of the signature. In conclusion, KUSS50 is a clinically actionable biomarker for optimizing HCC patient selection for treatment with sorafenib, providing an opportunity to improve outcomes. Further exploration of KUSS50's underlying biology, particularly the involvement of ferroptosis in sorafenib sensitivity, could provide additional therapeutic insights.
2025-12-31 | GSE285625 | GEO
Project description:The multi-kinase inhibitor drug sorafenib is used as first line treatment for hepatocellular carcinoma and advanced renal cell carcinoma. Sorafenib mainly undergos cytochrome P450 (CYP) 3A4-mediated oxidation and uridine diphosphate glucuronosyl transferase (UGT) 1A9-mediated glucuronidation in liver, but the biotransformation of sorafenib in kidney remains unclear. Therefore, we integrated the mRNA expression data of 36 kidney samples and the corresponding metabolic activities for sorafenib to study the metabolic mechanism of sorafenib in kidney.
2018-01-03 | GSE93069 | GEO
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 a multi-kinase blocker and one of the few suggested drug treatments for aggressive hepatocellular carcinoma (HCC) patients. However, drug resistance to sorafenib may often occur over time and cause further tumor aggression. Recently, cancer stem cells were found in HCC and were speculated to be involved in tumor progression. SOX9 is highly expressed in HCC cancer stem cells and promotes cell proliferation and self-renewal. Meanwhile, HCC patients with higher SOX9 expression show poorer prognosis [1]. Whether SOX9 is involved in sorafenib resistance in HCC is still unclear. Here, we found that sorafenib treatment increased SOX9 expression in HCC cell lines. Overexpression of exogenous SOX9 in HCC increased sorafenib resistance both in vitro and in vivo, whereas down-regulation led to inhibition of sorafenib resistance. Knock-down of SOX9 by RNA interference caused down-regulation of downstream genes, including ATP binding cassette subfamily G member 2 (ABCG2). The drug resistance to sorafenib caused by SOX9 overexpression could be ameliorated by overexpression of SOX9 in combination withby ABCG2 inhibition in HCC cell lines. In the cohort of patients resistant to sorafenib, we found that patients with lower SOX9 expression had more prolonged overall survival (OS) and progression-free survival (PFS). Cox analysis shows that SOX9 expression exerts as an independent risk factor for HCC, and logistic regression analysis reveals that SOX9 expression, tumor capsule deficiency, tumor diameters, and microvascular invasion are risk factors for poor prognosis of HCC patients. These findings demonstrate that SOX9 enhances sorafenib resistance and may regulate this process by modulating ABCG2 expression.
2020-01-13 | GSE143477 | GEO
Project description:Sorafenib is the first-line treatment for advanced stage hepatocellular carcinoma (HCC), but rapid disease re-progression occurs in most treated cases, with molecular mechanism remaining elusive. The resistance to sorafenib has been correlated with inflammation, and here we investigated how the pro-inflammatory TIFA signaling modulates the inflammatory tumor microenvironment to negate sorafenib cytotoxicity and prime for HCC dissemination. We found that the TIFA-NF-κB axis in HCC cells compromised sorafenib cytotoxicity in alliance with pro-tumor M2 macrophages, suggesting an intensive crosstalk between HCCs and M2 macrophages. To identify the key mediators of such crosstalk between HCC cells and macrophages underlying sorafenib resistance, primary macrophages were cocultured with HCC cells and then subjected to targeted RNA-panels for transcriptome analysis of innate immune and inflammatory factors.
2021-12-31 | GSE125825 | GEO
Project description:This study aimed to investigate the transcriptomic changes in subcutaneous Hepa1-6 tumor tissues of mice following intraperitoneal administration of sorafenib, a tyrosine kinase inhibitor, versus a control solvent. Mice were injected with either sorafenib or the control solvent four times, according to the experimental design. After the treatment period, tumor samples were collected and subjected to RNA sequencing (RNA-seq) to analyze the gene expression profiles. The results from this RNA-seq analysis provide insights into the molecular mechanisms underlying the response of Hepa1-6 tumors to sorafenib treatment, potentially identifying novel therapeutic targets and biomarkers for hepatocellular carcinoma.
2025-01-05 | GSE283371 | GEO
Project description:Tumor samples and matching healthy tissue from 23 human hepatocellular carcinoma (HCC) patients and one hepatocellular adenoma patient were collected after surgical resection. Total RNA was harvested and sequenced with a strand-specific single-end RNA-seq protocol.
2021-12-23 | E-MTAB-8915 | biostudies-arrayexpress
Project description:We used array-based comparative genomic hybridization (arrayCGH) of 76 hepatocellular carcinomas (HCCs) to search for genetically disrupted genes.
2012-01-20 | GSE14322 | GEO