Mechanism of sorafenib resistance associated with ferroptosis in HCC

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: June 7, 2023

Hepatocellular carcinoma (HCC) is the most familiar primary hepatic malignancy with a poor prognosis. The incidence of HCC and associated deaths have risen in recent decades. Sorafenib first drug to be approved by Food Drug Administration (FDA) for routine use first-line therapy patients advanced HCC. However, only about 30% will benefited from sorafenib therapy, resistance typically develops within 6 months. In years, mechanisms gained attention growing number researchers. A promising field current studies ferroptosis, which novel form cell death differing apoptosis, necroptosis, autophagy. This process dependent on accumulation intracellular iron reactive oxygen species (ROS). Furthermore, increase levels ROS can significantly observed cells resistant sorafenib. article reviews that are related evaluates relationship between ferroptosis resistance, explores new therapeutic approaches capable reversing through modulation ferroptosis.

Language: Английский

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Circumventing drug resistance in gastric cancer: A spatial multi-omics exploration of chemo and immuno-therapeutic response dynamics

Drug Resistance Updates, Journal Year: 2024, Volume and Issue: 74, P. 101080 - 101080

Published: March 19, 2024

Language: Английский

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Loss of lncRNA LINC01056 leads to sorafenib resistance in HCC

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: April 6, 2024

Abstract Background and aims Sorafenib is a major nonsurgical option for patients with advanced hepatocellular carcinoma (HCC); however, its clinical efficacy largely undermined by the acquisition of resistance. The aim this study was to identify key lncRNA involved in regulation sorafenib response HCC. Materials methods A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) single-guide RNA (sgRNA) synergistic activation mediator (SAM)-pooled library applied screen regulated treatment. role identified mediating HCC examined vitro vivo. underlying mechanism delineated proteomic analysis. significance expression evaluated multiplex immunostaining on human microtissue array. Results CRISPR/Cas9 screening revealed that Linc01056 among most downregulated lncRNAs sorafenib-resistant cells. Knockdown reduced sensitivity cells sorafenib, suppressing apoptosis promoting tumour growth mice Proteomic analysis knockdown sorafenib-treated induced genes related fatty acid oxidation (FAO) while repressing glycolysis-associated genes, leading metabolic switch favouring higher intracellular energy production. FAO inhibition significantly restored sorafenib. Mechanistically, we determined PPARα critical molecule governing upon indeed, tumours Clinically, predicted optimal overall progression-free survival outcomes better response. indicated low level Conclusion Our as epigenetic regulator potential therapeutic target

Language: Английский

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Exosomal miR-223-3p from bone marrow mesenchymal stem cells targets HDAC2 to downregulate STAT3 phosphorylation to alleviate HBx-induced ferroptosis in podocytes

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 20, 2024

Background: Hepatitis B virus associated-glomerulonephritis (HBV-GN) is one of the major secondary renal diseases in China, and microRNAs (miRNAs) bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exo) can attenuate HBV-X protein (HBx)-induced ferroptosis podocytes, but exact mechanism remains unclear. This study aimed to investigate protective miR-223-3p BMSC-Exo HBx-induced podocytes. Methods: The employed human podocyte cells (HPCs), marrow-derived (BMSCs), as well kidney tissue from C57BL/6 mice HBx transgenic mice. Initially, correlation between STAT3 phosphorylation was authenticated through administration signal transducer activator transcription 3 (STAT3) inhibitors both vivo vitro settings. Furthermore, effect HDAC2 overexpression on examined. Subsequently, association carrying miR-223-3p, HDAC2, HPCs injury induced by assessed. interaction confirmed via RNA immunoprecipitation assay. Various techniques such cell counting kit-8 assay, western blot, RT-qPCR, immunofluorescence, flow cytometry, lipid peroxidation assay kit, iron transmission electron microscopy, hematoxylin-eosin staining were visualize extent . Results: attenuation be achieved inhibiting podocytes HBx. Conversely, upregulation enhance phosphorylation, thereby promoting ferroptosis. MiR-223-3p capable directly exerting negative regulation expression. effectively suppress expression ultimately leading reduce targeting with downregulating phosphorylation. Conclusion: evidences potential mediated delivery mitigating offering a novel therapeutic target approach for treating HBV-GN alleviating injury.

Language: Английский

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Cross-talks of GSH, mitochondria, RNA m6A modification, NRF2, and p53 between ferroptosis and cuproptosis in HCC: A review

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 302, P. 140523 - 140523

Published: Feb. 1, 2025

Language: Английский

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Understanding sorafenib-induced ferroptosis and resistance mechanisms: Implications for cancer therapy

European Journal of Pharmacology, Journal Year: 2023, Volume and Issue: 955, P. 175913 - 175913

Published: July 17, 2023

Language: Английский

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Monocytes subsets altered distribution and dysregulated plasma hsa-miR-21-5p and hsa-miR-155-5p in HCV-linked liver cirrhosis progression to hepatocellular carcinoma

Journal of Cancer Research and Clinical Oncology, Journal Year: 2023, Volume and Issue: 149(17), P. 15349 - 15364

Published: Aug. 28, 2023

Abstract Purpose The authors aim to investigate the altered monocytes subsets distribution in liver cirrhosis (LC) and subsequent hepatocellular carcinoma (HCC) association with expression level of plasma Homo sapiens (has)-miR-21-5p hsa-miR-155-5p. A step toward non-protein coding (nc) RNA precision medicine based on immune perturbation manifested as distribution, top LC HCC. Methods Seventy-nine patients diagnosed chronic hepatitis C virus (CHCV) infection were enrolled current study. Patients sub-classified into group without HCC ( n = 40), 39), 15 apparently healthy controls. Monocyte frequencies assessed by flow cytometry. Real-time quantitative PCR was used measure hsa-miR-21-5p hsa-miR-155-5p expression. Results Hsa-miR-21-5p correlated intermediate r 0.30, p 0.007), while negatively non-classical − 0.316, 0.005). ROC curve analysis revealed that combining frequency hsa-miR-21 yielded sensitivity 79.5%, specificity 75%, AUC 0.84. In comparison, AFP a lower 69% 100% 0.85. Logistic regression proved up-regulation independent risk factors for progression HCC, after adjustment co-founders. Conclusion differentiation linked Combined could be considered sensitive indicator Circulating evolution, clinically silico proved. Graphical abstract

Language: Английский

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miR-21-5p Inhibits Ferroptosis in Hepatocellular Carcinoma Cells by Regulating the AKT/mTOR Signaling Pathway through MELK

Journal of Immunology Research, Journal Year: 2023, Volume and Issue: 2023, P. 1 - 20

Published: March 24, 2023

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers, and its incidence rate increasing worldwide. At present, there no ideal treatment for HCC. In recent years, molecular-targeted therapy has shown significant therapeutic benefits patients. Ferroptosis a modality regulated cell death, previous studies have found that inducing ferroptosis in liver cancer cells can inhibit progression cancer. The aim this study to investigate regulatory mechanism miR-21-5p regulating HCC cells. CCK-8 was used measure viability, EdU colony formation were proliferation, Transwell assays migration invasion. RT-qPCR detect level miR-21-5p, Western blotting protein expression level, dual-luciferase reporter gene assay determine targeting relationship between MELK, coimmunoprecipitation interaction MELK AKT. Overexpression facilitated formation, invasion, Downregulation suppressed AKT/mTOR signaling pathway, causing changes levels GPX4, GSH, FTH1, xCT, heme oxygenase 1(HO-1), reactive oxygen species, Fe2+ regulate hepatoma Erastin, an inducer ferroptosis, attenuated repressive influence on summary, demonstrates inhibits by pathway through MELK.

Language: Английский

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Pien-Tze-Huang prevents hepatocellular carcinoma by inducing ferroptosis via inhibiting SLC7A11-GSH-GPX4 axis

Cancer Cell International, Journal Year: 2023, Volume and Issue: 23(1)

Published: June 6, 2023

Abstract Background Malignant transformation from hepatic fibrosis to carcinogenesis may be a therapeutic target for hepatocellular carcinoma (HCC). The aim of this study was evaluate anti-cancer efficacy Pien-Tze-Huang (PZH), and investigate the underlying mechanisms by integrating transcriptional regulatory network analysis experimental validation. Methods A diethylnitrosamine (DEN)-induced HCC model in rats established used PZH. After detecting transcriptomic profiling, “disease-related gene–drug effective target” interaction constructed, candidate targets PZH against malignant were identified verified vitro. Results effectively alleviated pathological changes cirrhosis, inhibited tumor formation growth DEN-induced rats. Additionally, administration reduced levels various function-related serological indicators significantly. Mechanically, ferroptosis-related SLC7A11-GSH-GPX4 axis might one potential HCC. Especially, high SLC7A11 expression associated with poor prognosis patients. Experimentally, markedly increased trivalent iron ferrous ion, suppressed GPX4 proteins, GSH/GSSG ratio liver tissues Conclusions Our data offer an evidence that improve microenvironment prevent occurrence through promoting ferroptosis cells via inhibiting axis, implying drug prevention treatment at early stage.

Language: Английский

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Sodium butyrate induces ferroptosis in endometrial cancer cells via the RBM3/SLC7A11 axis

APOPTOSIS, Journal Year: 2023, Volume and Issue: 28(7-8), P. 1168 - 1183

Published: May 11, 2023

Language: Английский

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