Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA348449 | ENA |
REPOSITORIES: ENA
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Project description:Gene mutations play critical roles during cancer development and progression, and therefore represent targets for precision medicine. Here we recapitulated the pharmacogenomic data to delineate novel candidates for actionable mutations and therapeutic target drugs. As a proof-of-concept, we demonstrated that the loss-of-function of SULF2 by mutation (N491K) or inhibition enhanced sorafenib sensitivity in liver cancer cells and in vivo mouse models. This effect was mediated by deregulation of EGFR signaling and downstream expression of LCN2. We also report that the liver cancer patients non-responding to sorafenib treatment exhibit higher expression of SULF2 and LCN2. In conclusion, we suggest that SULF2 plays a key role in sorafenib susceptibility and resistance in liver cancer via deregulation of LCN2. Diagnostic or therapeutic targeting of SULF2 (e.g., OKN-007) and/or LCN2 can be a novel precision strategy for sorafenib treatment in cancer patients.
2018-05-15 | GSE88744 | GEO
Project description:We investigated whether brusatol, an Nrf2 inhibitor, has dual effects as anti-HCV and anti-hepatocellular carcinoma (HCC) and whether brusatol can enhance the similar dual effects of sorafenib. We showed that brusatol has dual effects as anti-HCV and anti-HCC and can enhance the similar in vitro effect by sorafenib and that there is potential of combination therapy of brusatol and sorafenib for HCV-related HCC.
2018-06-01 | GSE98920 | 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:Objective: identify novel and relevant aspects of Sorafenib action on liver cancer cells. We found that in rat hepatocholangiocarcinoma (LCSC-2) cells, exposure to the MEK/multikinase inhibitor sorafenib did not inhibit ERK phosphorylation nor induced appreciable cell death in the low micromolar range; instead, the drug elicited a raise of intracellular reactive oxygen species (ROS) accompanied by a severe decrease of oxygen consumption and intracellular ATP levels, all changes consistent with mitochondrial damage. Moreover, Sorafenib induced depolarization of isolated rat liver mitochondria, indicating a possible direct effect on the organelle. Microarray analysis of gene expression in sorafenib-trated cells revealed a metabolic reprogramming toward aerobic glycolysis, that likely accounts for resitance to drug toxicity in this cell line. Importantly, cytotoxicity was strongly potentiated by glucose withdrawal from the culture medium or by the glycolytic inhibitor 2-deoxy-glucose, a finding also confirmed in the highly malignant melanoma cell line B16F10. Mechanistic studies revealed that ROS are pivotal to cell killing by the Sorafenib + 2DG combination, and that a low content of intracellular oxidants is associated with resistance to the drug; instead, Thr172phosphorylation/activation of the AMP-activated protein kinase (AMPK), induced by Sorafenib, may exert protective effects, since cytotoxicity was enhanced by an AMPK specific inhibitor and prevented by the AMPK activator Metformin. Overall, this study identifies novel and relevant aspects of Sorafenib action on liver cancer cells, including mitochondrial damage, induction of ROS and a metabolic cell reprogramming towards “glucose addiction”, potentially exploitable in therapy.
2015-02-04 | GSE43053 | GEO
Project description:The expression of the extracellular sulfatase, SULF2, has been strongly associated with increased hepatocellular carcinoma (HCC) tumor growth and poorer patient survival. However, to date, the molecular mechanisms underlying this phenomenon remain in part unclear. To address this issue, we developed a transgenic mouse overexpressing Sulf2 in hepatocytes under the control of the transthyretin promoter. In this mouse model Sulf2 overexpression potentiated DEN-induced HCC. Further analysis demonstrated a central role for the zinc finger transcription factor Gli1 as a mediator of Sulf2 during HCC development. The cross of the Sulf2 transgenic with Gli1 knockout mice showed that the inactivation of this transcription factor impaired Sulf2-induced HCC. Transcriptomic analysis revealed a Stat3 gene signatures associated with Sulf2 overexpression. Interestingly, Gli1 knockout abrogates Sulf2-induction of several Stat3 target genes including Socs2/3, Pim1 and Flt4. Human orthologues were similarly regulated by SULF2 and dependent on intact GLI1 and STAT3 function in human HCC cells. SULF2 overexpression not only resulted in GLI1 and STAT3 interaction, but also promoted enrichment of GLI1 and STAT3 at consensus sites at the target gene promoters. Interestingly, GLI1 was found to be enriched at select STAT3 consensus sites with SULF2 overexpression and vice versa. siRNA-mediated knockdown of STAT3 or GLI1 reduced promoter binding of GLI1 and STAT3 respectively. Finally, chromatin capture PCR confirmed long-range co-regulation of SOCS2 and FLT3 through changes in promoter conformation. Thus, these findings define a novel mechanism by which SULF2 drives HCC and highlights the role of GLI1-STAT3 transcriptional complex as an effector of this sulfatase.
2019-10-25 | GSE139374 | GEO
Project description:To profile determinants of sensitivity and resistance towards the multikinase inhibitor sorafenib in liver cancer (HCC), we generated HCCs with elevated MYC expression and activated Raf-MEK-ERK signaling. To trigger tumor development, we co-delivered transposable elements encoding for Myc and oncogenic NrasG12V via hydrodynamic injection into the hepatocytes of C57BL/6 wildtype mice. To characterize the response of Myc/NrasG12V HCCs towards sorafenib, we analyzed their transcriptomes after three weeks of sorafenib or carrier treatment.
2020-12-01 | GSE162322 | GEO
Project description:Objective: identify novel and relevant aspects of Sorafenib action on liver cancer cells. We found that in rat hepatocholangiocarcinoma (LCSC-2) cells, exposure to the MEK/multikinase inhibitor sorafenib did not inhibit ERK phosphorylation nor induced appreciable cell death in the low micromolar range; instead, the drug elicited a raise of intracellular reactive oxygen species (ROS) accompanied by a severe decrease of oxygen consumption and intracellular ATP levels, all changes consistent with mitochondrial damage. Moreover, Sorafenib induced depolarization of isolated rat liver mitochondria, indicating a possible direct effect on the organelle. Microarray analysis of gene expression in sorafenib-trated cells revealed a metabolic reprogramming toward aerobic glycolysis, that likely accounts for resitance to drug toxicity in this cell line. Importantly, cytotoxicity was strongly potentiated by glucose withdrawal from the culture medium or by the glycolytic inhibitor 2-deoxy-glucose, a finding also confirmed in the highly malignant melanoma cell line B16F10. Mechanistic studies revealed that ROS are pivotal to cell killing by the Sorafenib + 2DG combination, and that a low content of intracellular oxidants is associated with resistance to the drug; instead, Thr172phosphorylation/activation of the AMP-activated protein kinase (AMPK), induced by Sorafenib, may exert protective effects, since cytotoxicity was enhanced by an AMPK specific inhibitor and prevented by the AMPK activator Metformin. Overall, this study identifies novel and relevant aspects of Sorafenib action on liver cancer cells, including mitochondrial damage, induction of ROS and a metabolic cell reprogramming towards “glucose addiction”, potentially exploitable in therapy. Microarray analysis of gene expression in sorafenib-trated cells. LCSC-2 cells were incubated with sorafenib 2.5 mM under serum deprivation for 12 hours. The total RNA was isolated from LCSC2, 24h after treatment, using the RNeasy mini kit (Qiagen, Hilden, Germany), RNA was quantified using a UV spectrophotometer and RNA quality and integrity were assessed Agilent 2100 Bioanalyzer (Agilent, Santa Clara, CA, USA). The resulting total RNA was then used to create the biotin-labeled library to be hybridized on GeneChip Rat Gene expression 1.0 st Array (Affymetrix, Santa Clara, CA, USA), according to the recommended experimental protocols provided by the suppliers. The CEL files resulting from the hybridization were analyzed using the Partek® Genomic Suite™ (Partek GS). Gene-level calculation was performed by Robust Multichip Average and normalization by quantile sketch.
2015-02-04 | E-GEOD-43053 | biostudies-arrayexpress
Project description:Pharmacogenomic identification of targets for adjuvant therapy with the topoisomerase poison camptothecin. The response of tumor cells to the unusual form of DNA damage caused by topoisomerase poisons such as camptothecin (CPT) is poorly understood, and knowledge regarding which drugs can be effectively combined with CPT is lacking. To better understand the response of tumor cells to CPT and to identify potential targets for adjuvant therapy, we examined global changes in mRNA abundance in HeLa cells after CPT treatment using Affymetrix U133A GeneChips, which include all annotated human genes (22,283 probe sets). Statistical analysis of the data using a Bayesian/Cyber t test and a modified Benjamini and Hochberg correction for multiple hypotheses testing identified 188 probe sets that are induced and 495 that are repressed 8 h after CPT treatment at a False Discovery Rate of <0.05 and a minimum 3-fold change. This pharmacogenomic approach led us to identify two pathways that are CPT induced: (a) the epidermal growth factor receptor; and (b) nuclear factor-kappaB-regulated antiapoptotic factors. Experiments using HeLa cells in our lab and prior animal model studies performed elsewhere confirm that inhibitors of these respective pathways super-additively enhance CPT's cytotoxicity, suggesting their potential as targets for adjuvant therapy with CPT. Cancer Res. 2004 Mar 15;64(6):2096-104
2007-07-29 | E-GEOD-1417 | biostudies-arrayexpress
Project description:Analysis of changes in gene expression upon Sorafenib treatment. Looking for candidates, that could potentially be up- or down-regulated upon Sorefanib treatment. Total RNA were optained from whole liver lysates of vehicle 14d-, Sorafenib 14d- and LT Sorafenib-treated iAST mice
2014-06-20 | E-GEOD-54857 | biostudies-arrayexpress
Project description:Introduction: Hepatocellular carcinoma stands as the most common cause of global cancer-related mortality. The actin-binding protein Girdin exhibits elevated expression in diverse tumors, fostering tumorigenesis and progression. Nevertheless, the precise mechanism by which Girdin regulates liver cancer remains elusive. Methods: This study comprehensively analyzed the expression level of Girdin in liver cancer and adjacent tissue, along with the correlation between Girdin expression and the clinical characteristics and prognosis of liver cancer. The analysis involved the integration of data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Clinical Proteomic Tumor Analysis Consortium (CPTAC) database, and immunohistochemistry. Subsequently, the expression level of Girdin was knocked down to elucidate its role in the progression of liver cancer. Transcriptome sequencing was employed to investigate the mechanistic underpinnings of Girdin's regulatory impact on liver cancer. Additionally, the Comparative Toxicogenomics Database (CTD) was utilized to identify potential drugs or molecules for liver cancer treatment. Results: The findings revealed elevated Girdin expression in liver cancer tissues, and heightened Girdin expression correlated with adverse clinical features and prognosis. Silencing of Girdin markedly impeded the proliferation and migration of hepatocellular carcinoma cells. Moreover, transcriptome sequencing demonstrated that silencing Girdin led to differential expression of 176 genes and inhibition of the PI3K/Akt signaling pathway. Ultimately, we propose that Imatinib Mesylate, Orantinib, Resveratrol, Sorafenib, and Curcumin mayinteract with Girdin, potentially contributing to the treatment of liver cancer. Conclusion: This study reveals the association between Girdin and hepatocellular carcinoma, providing novel clues for future research and treatment of hepatocellular carcinoma.
2023-12-25 | GSE251899 | GEO