Proinflammatory TIFA-NF-κB axis drives intrinsic survival signaling and acquires macrophage niches via DAMPs to promote HCC resistance to sorafenib
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ABSTRACT:
PROVIDER: PRJNA517656 | ENA |
REPOSITORIES: ENA
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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:To better identify the key gene involved in sorafenib-resistant HCC cells and uncover potential targets for HCC therapy, the microarray analysis was used to screen the differentially expressed genes in sorafenib-resistant HCC cells, xenograft model and the corresponding counterparts.
2021-10-11 | GSE121153 | GEO
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:Objective: Advanced HCC patients have few choices for life-prolonging therapy due to the high incidence of drug resistance. This study aimed to clarify the mechanism of sorafenib resistance and seek more effective treatments.Design:Two sorafenib-resistant (SR) cell lines were established to study the mechanism of drug resistance. RNA sequencing was used to characterize the global transcriptional consequences of sorafenib resistance, and immunoprecipitation-mass spectrometry (IP-MS) was performed to identify specific acetylation sites.Results： We found that Rho-GTPases were upregulated in SR cells and that PLEKHG5 was most abundantly expressed among all Rho GEFs (activators of Rho-GTPases). PLEKHG5 knockdown increased HCC cell sensitivity to sorafenib and inhibited the activation of Rac1 and downstream AKT/NF-κB signaling, while overexpression of PLEKHG5 reduced sorafenib sensitivity, which suggested that PLEKHG5 activation could be targeted to limit sorafenib resistance. IP-MS confirmed that three lysine sites in PH domain of PLEKHG5 could be acetylated, and their acetylation levels were correlated with PLEKHG5 stability. Further study demonstrated that HDAC2 interacted with PLEKHG5 to deacetylate lysine sites within the PH domain and maintain its stability. Finally, both knockout of HDAC2 and treatment with the selective HDAC2 inhibitor CAY10683 reduced PLEKHG5 protein levels and thereby enhanced the sensitivity of HCC to sorafenib in vivo and in vitro.Conclusion.:PLEKHG5 plays a key role in the occurrence of sorafenib resistance by activating Rac1/AKT/NF-κB signaling. HDAC2 regulates PLEKHG5 protein stability by regulating the acetylation level of its PH domain, and thus HDAC2 may be a potential therapeutic target for overcoming PLEKHG5-mediated sorafenib resistance in HCC.
2021-06-05 | GSE176151 | GEO
Project description:RNA-sequencing of hepatocellular carcinomas at various stages of sorafenib treatment
| EGAS00001005662 | EGA
Project description:Whole-exome sequencing of hepatocellular carcinomas at various stages of sorafenib treatment
| EGAS00001005661 | EGA
Project description:Sorafenib resistance up-regulated circRNA_104797 could be transmitted by exosomes and responsible for the spread of Sorafenib resistance among HCC cells. CircRNA_104797 was critical for Sorafenib resistance maintenance and silencing circRNA_104797 could substantially increase the efficacy of Sorafenib by inducing apoptosis. Mechanism dissection unveiled that circRNA_104797 could specifically sponge miR-103a-2-5p and miR-660-3p and act as a competing endogenous RNA (ceRNA), thus competitively activated wnt/β-catenin pathway and induced Sorafenib resistance. Meanwhile, LC-MS/MS also revealed that circRNA_104797 could specifically bind to translation related proteins, which might regulate downstream glycan biosynthesis and lipid metabolism, and finally induce Sorafenib resistance. In vivo experiments portrayed a promising clinical application by locally injection of in vivo-grade siRNA for circRNA_104797 by TACE or other manners, which could intensively enhance Sorafenib efficacy in HCC patients. The clinical application of in vivo-grade siRNA for circRNA_104797 in Sorafenib treated HCC patients might shed bright future for the management of advanced HCC.
2020-07-25 | GSE101850 | GEO
Project description:We used an expression profiling chip to detect the expression profile of PLC cells after they were treated with sorafenib and sorafenib probe
2018-12-12 | GSE123600 | GEO
Project description:Candidate genes were successfully screened by Cancer PathwayFinder PCR Array Cancer PathwayFinder PCR Array was applied to compare gene changes in xenograft tumor samples of HCC model. A total of 12 samples were examined with 6 from Sorafenib treated group and 6 from control.
2011-11-11 | E-GEOD-33621 | biostudies-arrayexpress
Project description:Sorafenib is associated with cardiac adverse effects, including left ventricular dysfunction. However, the precise mechanism remains unclear. Here, we aimed to establish the genes responsible for this cardiotoxicity using zebrafish. A pigmentless zebrafish line expressing green fluorescent protein in the heart were treated with or without sorafenib. In vivo fluorescent cardiac imaging revealed that the ventricular dimension of the longitudinal axis in zebrafish treated with sorafenib was significantly lower than in those without sorafenib. Transcriptome analysis of zebrafish hearts revealed that expression of stanniocalcin1 (stc1) in zebrafish treated with sorafenib was significantly lower than that without sorafenib treatment. We were able to demonstrate that the ventricular dimension of the longitudinal axis in stc1 morphant was significantly smaller than that of control zebrafish and that forced expression of stc1 normalized the decrease in ventricular diameter in stc1 morphant and zebrafish treated with sorafenib. These data suggest that stc1 is the gene responsible for sorafenib-induced cardiotoxicity. Gene expression regulated by sorafenib in zebrafish at 4 dpf was measured. Four independent experiments were performed for each group.
2014-12-04 | E-GEOD-61155 | biostudies-arrayexpress