Mitochondrial Plasticity Promotes Resistance to Sorafenib and Vulnerability to STAT3 Inhibition in Human Hepatocellular Carcinoma
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PROVIDER: PRJNA784262 | ENA |
REPOSITORIES: ENA
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Project description:Enhanced expression of mitochondrial ribosomal proteins and marked reprogramming of the mitochondrial network are associated with sorafenib resistance in human cell lines and hepatocarcinoma patients, providing novel actionable targets for increasing therapeutic efficacy.
2021-11-30 | GSE189711 | GEO
Project description:Circular RNAs (circRNAs) are increasingly gaining importance and attention due to their diverse potential functions. Our study aims to explore the novel mechanisms by which exosome-contained circRNAs promote sorafenib resistance in hepatocellular carcinoma (HCC). Here we report that a circular RNA, circRNA-MANBA (a circular RNA upregulated in exosomes derived from sorafenib-resistant HCC cells), plays a significant role in sorafenib resistance in HCC. We identified that circRNA-MANBA is increased in sorafenib-resistant HCC cells, their exosomes, and tumor samples from sorafenib-treated HCC patients. Depletion of circRNA-MANBA substantially increases the cell-killing ability of sorafenib. Co-culture experiments revealed that exosomes from sorafenib-resistant HCC cells carrying large amounts of circRNA-MANBA could transmit drug resistant capacity to parental cells. Further studies revealed that circRNA-MANBA acted as ‘miRNAs sponge’ to absorb miR-1290, which prevented miR-1290 interaction with CD109 and thus upregulated STAT3 phosphorylation subsequently. Using different HCC mouse models, we demonstrated that silencing circRNA-MANBA by injection of siRNA could substantially overcome sorafenib resistance. Our study provides a proof-of-concept demonstration for a potential strategy to overcome sorafenib resistance in HCC patients by targeting circRNA-MANBA.
2023-11-07 | GSE213242 | GEO
Project description: Not available
| S-EPMC8657239 | biostudies-literature
Project description:mRNA-seq was performed in HepG2 hepatocellular carcinoma cells to characterize transcriptional changes driven by ARID1B loss under sorafenib treatment. Wild-type (WT) and ARID1B-knockout (ARID1B-KO) HepG2 cells were treated with sorafenib (5 µM, 48 h) or DMSO vehicle, with three biological replicates per condition. DESeq2 interaction model identified ARID1B-dependent transcriptional responses to sorafenib. Preprint: https://doi.org/10.64898/2026.06.11.731725
2026-06-19 | GSE335769 | GEO
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:Sorafenib is currently the standard treatment for advanced hepatocellular carcinoma (HCC). Epigenetic alterations such as DNA methylation, play a decisive role in the development and progression of HCC. To our knowledge, there are no studies that have analyzed the global DNA methylation changes in HCC cells treated with sorafenib. Using MeDip-chip technologies we analyzed sorafenib effects on the methylome of human HCC cells. We found 1230 differentially methylated genes in HA22T/VGH cells treated with sorafenib compared to untreated cells. Gene ontology and pathway analysis found enriched several GO terms related to transcription factors and different pathways involved in tumorigenesis and cancer progression. Among the genes differentially methylated we found genes related to apoptosis (FOXO3, SMAD2, p21), angiogenesis (EPAS1) and invasion (MMP3, MMP7, RAC1, RHOC), genes belonged to pathways deregulated in HCC such as RAF/MEK/ERK (MAPK3, MAP2K2), JNK (MAPK8, MAP2K7), JAK-STAT (JAK1, STAT3, STAT5, CCND3), PI3K/AKT/mTOR (TSC2, PRKCZ) and NF-κB (IKBKG, MALT1, MAP3K14) and cancer-associated non-coding genes such as MALAT1, miR-149 and miR-675. We found a general trend where oncogenes were hypermethylated and tumor suppressor genes were hypomethylated after sorafenib treatment. Finally, we validated MeDip-chip results on several differentially methylated genes using COBRA and direct bisulfite sequencing and for these genes we evaluated the relationship between methylation level and mRNA expression.Our results suggest that in HCC cells sorafenib could affect the methylation level of genes associated to cancer-related processes and pathways related to sorafenib mechanism of action. These results identified novel sorafenib targets genes which could be targets in a new design of multi-target and combined therapies, and to better understand the emergence of resistance in HCC.
2017-06-30 | GSE72257 | GEO
Project description:Sorafenib, the first targeted therapy for hepatocellular carcinoma (HCC), has been utilized in clinics over a decade. However, its effectiveness is severely hindered by the acquired drug resistance, the mechanisms of which remain largely elusive. In this study, we identify that carbonic anhydrase 2 (CA2) is a key regulator of sorafenib resistance. Mechanistically, sorafenib treatment decreases intracellular pH (pHi) by suppressing monocarboxylate transporter 4 (MCT4) expression, while high levels of CA2 counteract MCT4-mediated pHi dysregulation upon sorafenib treatment, maintaining pHi homeostasis to facilitate cell survival and sorafenib resistance. Targeting CA2 re-sensitizes resistant HCC cells to sorafenib both in vitro and in vivo. Importantly, analysis of clinical samples demonstrates a strong correlation between CA2 expression levels and the therapeutic efficacy of sorafenib in HCC patients. Our findings highlight the significance of CA2 in facilitating sorafenib resistance and propose targeting CA2 as a potential strategy for overcoming sorafenib resistance in HCC patients.
2024-10-24 | PXD056884 | Pride
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:Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, and acquired resistance to sorafenib—the first-line targeted therapy for advanced HCC—remains a major clinical challenge. To investigate the molecular mechanisms underlying sorafenib resistance in HCC, we established sorafenib-resistant sublines of HepG2 and Huh7 cells through continuous exposure to increasing concentrations of sorafenib. We then performed RNA-seq analysis comparing these resistant sublines with their parental sensitive counterparts. Differential gene expression analysis revealed distinct transcriptional signatures associated with sorafenib resistance. Our findings provide a comprehensive transcriptomic resource for understanding sorafenib resistance mechanisms and identify potential candidate genes that may serve as biomarkers or therapeutic targets for overcoming drug resistance in HCC.
2026-06-10 | GSE322742 | GEO
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