The effects of sorafenib treatment on the Hep1-6 tumor tissue
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PROVIDER: PRJNA1193538 | ENA |
REPOSITORIES: ENA
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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:Hepatocellular carcinoma (HCC) activates platelets through the action of adjacent sinusoidal cells. Activated platelets bind to tumor-associated endothelial cells and release growth factors that promote tumor progression. We hypothesized that tumor inhibitors encapsulated in platelets would function as drug carriers for tumor therapy. We propose a therapeutic strategy for HCC using autologous platelets encapsulating multiple tyrosine kinase inhibitors in a rat chemically-induced HCC model. Sorafenib or lenvatinib was encapsulated in platelets isolated from tumor-bearing rats in vitro. The rats were divided into groups that received repeated intravenous injections (twice a week for 10 weeks) of the following materials: placebo, sorafenib (SOR), lenvatinib (LEN), autologous platelets, autologous platelets encapsulating sorafenib (SOR-PLT), and autologous platelets encapsulating lenvatinib (LEN-PLT). The therapeutic effect was then analyzed by ultrasonography (US) and histopathological analysis. Histopathological and US analysis demonstrated extensive tumor necrosis in the tumor tissue of SOR-PLT or LEN-PLT, but not in other experimental groups. By liquid chromatography-mass spectrometry, more abundant sorafenib was detected in tumor tissues after SOR-PLT administration than in surrounding normal tissues, but no such difference in sorafenib level was observed with SOR administration. Therefore, the use of autologous platelets encapsulating drugs might be a novel therapeutic strategy for HCC. We investigated the effect of the drug encapsulation process on the degradation of resident mRNA inherited from megakaryocytes in platelets.
2021-12-15 | GSE190863 | 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
Project description:To investigate the impact of sorafenib treatment on gene expression in Treg cells, we performed RNA sequencing on Treg cells treated with sorafenib and on control Treg cells that were not treated with sorafenib. Specifically, our study focused on the expression of immune-suppressive related genes, and we observed an upregulation in the expression of Tgf-β1 (Transforming Growth Factor-β1), Prf1 (Perforin 1), Gzma (Granzyme A), and Il10 (Interleukin 10).
2025-01-05 | GSE280126 | 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.
2016-06-16 | GSE73571 | GEO
Project description:To address how serum cholesterol affected tumor progression, C57BL/6J mice were placed on either normal diet or high cholesterol diet for 4 weeks, and then Hep1-6 cells were subcutaneously injected into the right flanks of mice. We performed transcriptome sequencing analysis (RNA-seq) on tumor tissues from ND and HCD groups.
2019-02-03 | GSE124599 | GEO
Project description:We observed an increasing trend of nuclear SLC29A2 expression associated with high histological de-differentiation grades, metastasis and poor patient prognosis by immunohistochemical analysis of HCC tumors. Treatments of dipyridamole to SLC29A2 expressing SK-hep1 cells reduced cell viability and cell migration. To examine the anticancer activities of dipyridamole, transcriptome analysis was performed to detect the modulations of oncogenic SLC29A2 and the downstream signaling pathways.
2020-10-23 | GSE139583 | GEO
Project description:Background: Malignant peripheral nerve sheath tumors (MPNST) are soft-tissue sarcomas that can arise either sporadically or in association with neurofibromatosis type 1 (NF1). These aggressive malignancies confer poor survival, with no effective therapy available. Methods: We generated five patient-derived MPNST orthoxenograft models (three NF1-related and two sporadic) and performed an exhaustive histological and molecular characterization of primary MPNSTs and their corresponding orthoxenografts. Finally, orthoxenografts models were used as an in vivo pre-clinical platform to test several treatment strategies. Results: MPNST orthoxenografts recapitulate the histopathological properties and preserve the genomic and transcriptomic status of their parental primary tumors. Additionally, they mimic distal dissemination properties in mice. Compatible with an origin in a catastrophic event and subsequent stabilization, MPNSTs contained highly altered genomes that remained remarkably stable in orthoxenograft establishment and along passages. Although preliminary, the results presented here point to clear differences between NF1-associated and sporadic MPNSTs. In accordance, mutation frequency in sporadic MPNSTs was an order of magnitude higher than in NF1-associated MPNSTs and unsupervised cluster analysis and principal component analysis (PCA) using a MPNST signature perfectly divided the samples between NF1 and sporadic MPNST. Finally, different therapeutic approaches tested in the validated orthoxenograft MPNST models, reveal that sorafenib, or in combination with doxorubicin or rapamycin caused a great tumor reduction in all models. Conclusion: The development of a well-characterized and standardized preclinical model for MPNSTs has laid the foundations for evaluating novel therapeutic strategies in the clinical setting. Moreover, results obtained strongly support the clinical evaluation of Sorafenib in this subset of patients. Primary MPNSTs were implanted in the sciatic nerve of nude mices to create orthoxenograft MPNST models. Several orthoxenograft passages were created. The primary tumor (when available) and passages 1 and 4 were selected for gene expression profiling to demonstrate that the orthoxenografts closely resemble their primary tumors and are stable along xenograft passages.
2015-04-15 | E-GEOD-60082 | biostudies-arrayexpress
Project description:Porphyromonas gingivalis strain:tumor tissue | isolate:tumor tissue Genome sequencing
| PRJNA974917 | ENA
Project description:Sorafenib, a multiple-kinase inhibitor, has been widely used as a first-line anticancer drug for advanced hepatocellular carcinoma (HCC). However, the development of drug resistance to sorafenib is frequently observed in clinical applications. Potential non-kinase targets of sorafenib have not been well documented and may provide insights into reversing drug resistance. Herein, we report that sorafenib exerted its anticancer effects by activating metallothionein 1G (MT1G) expression. MT1G served as a novel marker in HCC and correlated well with patient survival. MT1G overexpression suppressed the cellular proliferation, migration, invasion, and tumor formation of HCC, and sensitized cells to sorafenib treatment. However, the disruption of MT1G attenuated sorafenib’s anticancer effects. Mechanistically, sorafenib upregulated MT1G expression via hypomethylation of its promoter region by binding and inhibiting DNA methyltransferase 1 (DNMT1) and increasing its promoter accessibility in HCC cells. The activation of MT1G also inhibited CA9 transcription through the degradation of HIF1a as mediated by KLF4. Our collective data revealed that sorafenib exerted its anticancer effects through epigenetic regulation of the DNMT1/MT1G/KLF4/CA9 axis in HCC, and that the activation of MT1G might constitute a strategy for reversing sorafenib resistance.
2022-04-30 | GSE192771 | GEO