Effect of Sorafenib on Myeloid-derived suppressor cells in HCC
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ABSTRACT:
PROVIDER: PRJNA1146471 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30192627.fastq.gz | Fastqsanger.gz | |||
| SRR30192628.fastq.gz | Fastqsanger.gz | |||
| SRR30192629.fastq.gz | Fastqsanger.gz | |||
| SRR30192630.fastq.gz | Fastqsanger.gz | |||
| SRR30192631.fastq.gz | Fastqsanger.gz |
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Project description:Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related deaths worldwide. Sorafenib, a multikinase inhibitor, is the first-line systemic therapy approved for advanced HCC, but its impact on the tumor microenvironment, particularly on myeloid-derived suppressor cells (MDSCs), is not fully understood.MDSCs are a heterogeneous population of immune cells that play a crucial role in promoting tumor growth and immune evasion by suppressing T cell function and facilitating an immunosuppressive microenvironment. This study investigates the effects of sorafenib on the function and phenotype of MDSCs in HCC.
2025-02-05 | GSE274470 | GEO
Project description:The aim of the study is to evaluate whether the preoperative level of myeloid-derived suppressor cells is associated with postoperative complications classified by Clavien-Dindo categories. Levels of all MDSC, polymorphonuclear MDSC (PMNMDSC), monocytic MDSC (MMDSC), early-stage MDSC (EMDSC) and monocytic to polymorphonuclear MDSC ratio (M/PMN MDCS) were established and compared in patients with postoperative complications, severe postoperative complications (>= IIIA according to Clavien-Dindo) and severe septic complications.
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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:Acute myeloid leukemia (AML) is a hematologic malignancy with a poor prognosis. We discovered that BMAL1 is a ferroptosis suppressor. Furthermore, it was also found to be overexpressed in AML patients, affecting the cell cycle and promoting tumor cell growth and progression. In this study, we further validated the association of BMAL1 with the progression and survival outcomes of AML. Lipidomic revealed that the levels of ceramide increased in AML cells following the depletion of BMAL1. Ceramide facilitated ferroptosis in AML cells. ASAH2 played a key role in this process. BMAL1 could not directly regulate ASAH2 but instead through IKZF2. Elevated levels of ceramide promoted the degradation of the ferroptosis protection molecule GPX4, ultimately promoting ferroptosis. Furthermore, ceramide treatment has been demonstrated to enhance the responsiveness of AML cells to sorafenib. In summary, this study elucidates that BMAL1 depletion remodels ceramide metabolism to regulate the sensitivity of AML cells to ferroptosis and targeted drug sorafenib.
2025-01-24 | MTBLS11557 | MetaboLights
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:Mitochondrial damage-associated molecular patterns (DAMPs) including mitochondrial DNA (mtDNA), TFAM (transcription factor A, mitochondrial), and ATP, play crucial roles in the regulation of inflammatory environment in human diseases. However, the role of mitochondrial DAMPs in the regulation of tumor microenvironment (TEM) remains unclear. Herein we demonstrate that infiltration of M2 type tumor-associated macrophages (TAMs) was correlated with the resistance of hepatocellular carcinoma (HCC) to sorafenib. We found that cell free mtDNA in the plasma was significantly increased in sorafenib-resistant HCC mice. Sorafenib induced mitochondrial dysfunction and promoted the release of mtDNA into extracellular matrix of HCC. The mtDNAs were retaken by macrophages in the TME of HCC, activated TLR9 signaling on the endosome, and hence promoted the activation of NF-κB and the polarization of TAMs into M2. Application of DNase I to digest mtDNAs or depletion of macrophages with clodronate liposomes reduced the infiltration of M2 macrophage, decreased the growth of HCC, and sensitized the tumors to sorafenib. Furthermore, we showed that blocking the activation of TLR9 enhanced the therapeutic effect of sorafenib in HCC. Together, in the current study, we demonstrate that sorafenib treatment leads to the release of mtDNAs into TME in HCC, which in turn facilitates the polarization of TAMs into M2 macrophages through TLR9 activation and aggravates the resistance of HCC to sorafenib. Our study reveals a novel mechanism underlying circulating mtDAMPs in remodeling HCC microenvironment by reprograming the TAMs and provides a new strategy for improving the therapeutic effect of sorafenib and overcoming its resistance in HCC.
2025-03-12 | GSE270323 | GEO
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: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: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:Finding Sorafenib-Responding Signature in Hepatocellular Carcinoma (HCC)
| PRJNA1204978 | ENA