Genetic changes of Hep3B cells with acquired resistance to sorafenib after STIM1 knockout
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE248770 | GEO | 2023/12/09
REPOSITORIES: GEO
Similar Datasets
Project description:Genetic changes of Hep3B cells with acquired resistance to sorafenib after STIM1 knockout
| PRJNA1045975 | ENA
Project description:In order to explore the genetic changes of Hep3B cells after resistance to sorafenib, we used a dose-increasing method to obtain drug-resistant cell lines from parental Hep3B cells by intermittent stimulation with sorafenib.
2023-12-09 | GSE248769 | GEO
Project description:Genetic changes of Hep3B cells after acquired resistance to sorafenib
| PRJNA1045974 | ENA
Project description:Hepatocellular carcinoma (HCC) is the second prominent cause of cancer-associated death worldwide. Usually, HCC is diagnosed in advanced stages, where sorafenib, a multiple target ty-rosine kinase inhibitor, is used as the first line of treatment. Unfortunately, resistance to sorafenib is usually encountered within six months of the treatment. Therefore, there is a critical need to identify the underlying reasons for drug resistance. In the present study, we investigated the proteomic and metabolomics alterations accompanying to sorafenib resistance in hepatocellular carcinoma Hep3B cells by employing ultra-high-performance liquid chromatography quadrupole time of flight mass spectrometry (UHPLC-QTOF-MS). The Bruker Human Metabolome Database (HMDB) library was used to identify the differentially abundant metabolites through MetaboScape 4.0 software (Bruker). For protein annotation and identification, the Uniprot proteome for Homo sapiens (Human) da-tabase was utilised through MaxQuant. The results revealed that 27 metabolites and 18 proteins were significantly dysregulated due to sorafenib resistance in Hep3B cells compared to the parental phenotype. D-alanine, L-proline, o-tyrosine, succinic acid and phosphatidylcholine (PC, 16:0/16:0) were among the significantly altered metabolites. Ubiquitin carboxyl-terminal hydrolase isozyme L1, mitochondrial superoxide dismutase, UDP-glucose-6-dehydrogenase, sorbitol dehydrogenase and calpain small subunit 1 were among the significantly altered proteins. The findings revealed that resistant Hep3B cells demonstrated significant alterations in amino acid and nucleotide met-abolic pathways, energy production pathways and other pathways related to cancer aggressive-ness, migration, proliferation, and drug-resistance. Joint pathway enrichment analysis unveiled unique pathways, including the antifolate resistance pathway and other important pathways that maintain cancer cells' survival, growth, and proliferation. Collectively, the results identified po-tential biomarkers for sorafenib-resistant HCC and gave insights into their role in chemotherapeutic drug resistance, cancer initiation, progression, and aggressiveness, which may contribute to better prognosis and chemotherapeutic outcomes.
2023-01-17 | PXD036785 | Pride
Project description:To investigate the altered glucose and lipid metabolism genes after STIM1 knockout (STIM1 KO) or STIM1 knockout plus Snail1 OE (STIM1 KO+Snail1 OE) in SMMC7721 cells. STIM1 KO-SMMC7721 cells were constructed by CRISPR/Cas9, and STIM1 KO+Snail1 OE-SMMC7721 cells was established via lentiviral Infection of Snail1 overexpression in STIM1 KO-SMMC7721 cells. The cells mentioned above were cultured in DMEM supplemented with 10% (v/v) FBS at 37 °C in 5% CO2. When the cells grow to 60~70% confluent, total RNA was extracted by using Trizol (TAKARA, Japan). Reverse transcription was performed from 1μg total RNA using PrimeScript™ RT reagent Kit with gDNA Eraser (TAKARA), Quantitative real-time PCR were performed (CFX386, BioRad) with 40 cycles at 95 °C for 10 seconds, 59 °C for 20 seconds and 72 °C for 30 seconds.
2020-04-07 | GSE148129 | 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:Sorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients’ survival gain is limited and varies over a wide range depending on patho-genetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucuial to achieve efficient control of HCCs. In this study, we employed a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene ontology and gene set analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum (ER) stress network model combined with in vitro experiments showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low PDI expression group. These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness.
2017-03-19 | GSE96792 | 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: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:Overexpression of SOX4 in various kinds of cancers specimen was associated with poor prognosis of patients; however, the role of SOX4 in angiogenesis or tumor microenvironment modulation remains unclear. Therefore the endogenous SOX4 was knockout and the differential gene expression between Hep3B and Hep3B SOX4-/- cells were examined via genechip. We found that the differentially expressed genes, EzH2, a SOX4-associated partner, and CXCL12, were repressed in Hep3B SOX4-/- cells compared with parental Hep3B; these results were further assessed via qRT-PCR in Hep3B SOX4-/- versus Hep3B cells.
2020-12-01 | GSE141909 | GEO