Changes of cytokines in patients with liver cirrhosis and advanced hepatocellular carcinoma treated by sorafenib

Nagai, Hidenari; Kanekawa, Takenori; Kobayashi, Kojiro F.; Mukozu, Takanori; Matsui, Daigo; Matsui, Teppei; Kanayama, Masahiro; Wakui, Noritaka; Momiyama, Kouichi; Shinohara, Mie; Ishii, Koji; Igarashi, Yoshinori; Sumino, Yasukiyo

doi:10.1007/s00280-013-2344-1

Cited by 8 publications

(7 citation statements)

References 30 publications

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“…The diagnosis of liver fibrosis and HCC was based on the criteria of the American Association for the Study of Liver Diseases (AASLD) [64]. An initial sorafenib dosage of 400 mg was administered orally twice daily, after breakfast and dinner [65]. Subsequently, discontinuations and dosage reductions of sorafenib were based on tolerance [65].…”

Section: Human Liver Specimensmentioning

confidence: 99%

“…An initial sorafenib dosage of 400 mg was administered orally twice daily, after breakfast and dinner [65]. Subsequently, discontinuations and dosage reductions of sorafenib were based on tolerance [65]. Treatment was continued until clinical disease progression or unacceptable drugrelated toxicity occurred, or upon withdrawal of consent [65].…”

Section: Human Liver Specimensmentioning

confidence: 99%

“…Subsequently, discontinuations and dosage reductions of sorafenib were based on tolerance [65]. Treatment was continued until clinical disease progression or unacceptable drugrelated toxicity occurred, or upon withdrawal of consent [65]. Informed consent in writing was obtained from patients.…”

Section: Human Liver Specimensmentioning

confidence: 99%

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Activation of ferritinophagy is required for the RNA-binding protein ELAVL1/HuR to regulate ferroptosis in hepatic stellate cells

et al. 2018

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Ferroptosis is a recently recognized form of regulated cell death that is characterized by lipid peroxidation. However, the molecular mechanisms regulating ferroptosis are largely unknown. In this study, we report that the RNA-binding protein ELAVL1/HuR plays a crucial role in regulating ferroptosis in liver fibrosis. Upon exposure to ferroptosis-inducing compounds, ELAVL1 protein expression was remarkably increased through the inhibition of the ubiquitin-proteasome pathway. ELAVL1 siRNA led to ferroptosis resistance, whereas ELAVL1 plasmid contributed to classical ferroptotic events. Interestingly, upregulated ELAVL1 expression also appeared to increase autophagosome generation and macroautophagic/autophagic flux, which was the underlying mechanism for ELAVL1-enhanced ferroptosis. Autophagy depletion completely impaired ELAVL1-mediated ferroptotic events, whereas autophagy induction showed a synergistic effect with ELAVL1. Importantly, ELAVL1 promoted autophagy activation via binding to the AU-rich elements within the F3 of the 3'-untranslated region of BECN1/Beclin1 mRNA. The internal deletion of the F3 region abrogated the ELAVL1-mediated BECN1 mRNA stability, and, in turn, prevented ELAVL1-enhanced ferroptosis. In mice, treatment with sorafenib alleviated murine liver fibrosis by inducing hepatic stellate cell (HSC) ferroptosis. HSC-specific knockdown of ELAVL1 impaired sorafenib-induced HSC ferroptosis in murine liver fibrosis. Noteworthy, we retrospectively analyzed the effect of sorafenib on HSC ferroptosis in advanced fibrotic patients with hepatocellular carcinoma receiving sorafenib monotherapy. Attractively, ELAVL1 upregulation, ferritinophagy activation, and ferroptosis induction occurred in primary human HSCs from the collected human liver tissue. Overall, these results reveal novel molecular mechanisms and signaling pathways of ferroptosis, and also identify ELAVL1-autophagy-dependent ferroptosis as a potential target for the treatment of liver fibrosis. Abbreviations: ACTA2/alpha-SMA: actin, alpha 2, smooth muscle, aorta; ACTB/beta-actin: actin beta; ARE: AU-rich element; ATG: autophagy related; BDL: bile duct ligation; BECN1: beclin 1; BSO: buthionine sulfoximine; COL1A1: collagen type I alpha 1 chain; ELAVL1/HuR: ELAV like RNA binding protein 1; FDA: fluorescein diacetate; FTH1: ferritin heavy chain 1; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic-pyruvic transaminase; GPX4: glutathione peroxidase 4; GSH: glutathione; HCC: hepatocellular carcinoma; HSC: hepatic stellate cell; LCM: laser capture microdissection; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MDA: malondialdehydep; NCOA4: nuclear receptor coactivator 4; PTGS2: prostaglandin-endoperoxide synthase 2; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TBIL: total bilirubin; TEM: transmission electron microscopy; TGFB1: trasforming growth factor beta 1; UTR: untranslated region; VA-Lip-ELAVL1-siRNA: vitamin A-coupled liposomes carrying ELAVL1-siRNA.

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Section: Human Liver Specimensmentioning

confidence: 99%

Section: Human Liver Specimensmentioning

confidence: 99%

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Activation of ferritinophagy is required for the RNA-binding protein ELAVL1/HuR to regulate ferroptosis in hepatic stellate cells

et al. 2018

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“…For example, IFN- γ is capable of controlling T cell expansion via signaling in dendritic cells [ 33 ]. TNF- α induces tumor cell apoptosis by binding to tumor necrosis factor-related ligands, while binding of Fas ligands on cytotoxic T lymphocytes with their receptors elicits apoptosis [ 34 ]. Collectively, these data suggest that the ex vivo culture of SN isolated from the original environment could enhance the antitumor immunological function of T cells.…”

Section: Discussionmentioning

confidence: 99%

Immune Characters and Plasticity of the Sentinel Lymph Node in Colorectal Cancer Patients

Tang

et al. 2021

Journal of Immunology Research

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Purpose. This study is aimed at immunologically characterizing sentinel lymph nodes (SNs) in colorectal cancer (CRC) patients and identifying changes in immunological phenotype and function of SNs isolated from the tumor immunosuppressive microenvironment. Methods. A total of 53 pairs of matched SNs and non-SNs (NSNs) were collected by using a lymph node tracer dye. Flow cytometry was performed to detect the immunophenotype of T cells as well as the expression of activation and inhibitory markers. Differential expression and distribution of characteristic immune cell markers were analyzed by multiplex immunohistochemistry (mIHC). Transcriptomics analysis was conducted to compare the differences in the expression of immune-related genes among lymph nodes. The ex vivo culture of lymph nodes was carried out to examine changes in immunological phenotypes and functions. Results. Compared with NSNs, SNs harbored a significantly higher percentage of regulatory T cells (Tregs) but a lower proportion of MoMDSCs. As indicated in the mIHC assays, Tregs, T follicular helper (Tfh) cells, and M2 macrophages were mainly distributed in cortical areas, germinal centers, and subcapsular sinus areas, respectively, while significantly higher numbers of Tregs and Tfh cells were detected in SNs as compared to NSNs. Moreover, GSEA revealed that T cell activation genes and CD8+ T cell exhaustion-related genes are enriched in SNs and NSNs, respectively. The ex vivo culture led to an increase in the proportion of CD4+ cells, while activating T cells in SNs. In addition, SNs displayed a higher increase in the expression of cytokines IFN-γ, TNF-α, and sFas than NSNs. Conclusion. SNs are shown to be in an immune active state in vivo, while highly expressing inhibitory cytokines and suppressive markers. The ex vivo culture enhanced antitumor immunological function of SN-T cells, providing a starting material for adoptive cell therapy for CRC.

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“…In this immunoassay, concomitant measurement of seven sFas L standards with known concentrations (0.16, 0.31, 0.63, 1.25, 2.5, 5, and 10 ng/ml) was performed together with patient samples and the detection limit for sFas L was <50 pg/ml. Each assay was performed according to the manufacturer's recommendations [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

Host Immunological Effects of Partial Splenic Embolization in Patients with Liver Cirrhosis

Matsukiyo

Nagai

Matsui

et al. 2018

Journal of Immunology Research

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Purpose Restoration of the balance between T lymphocyte subsets and between Th1/Th2 cytokines together with improvement of antitumor immunity has been reported after hepatosplenectomy in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC). However, the detailed effects of partial splenic embolization (PSE) on host immunity are unknown. Accordingly, this study evaluated host immunity in patients with cirrhosis receiving PSE for thrombocytopenia. Methods Twenty-three adult Japanese patients with cirrhosis and thrombocytopenia underwent PSE using straight coils at our hospital between 2010 and 2015. Blood samples were collected before PSE and 4 weeks after PSE. Results The platelet counts were significantly higher 4 weeks after PSE compared with before PSE. The white blood cell count (neutrophils, lymphocytes, and monocytes) also increased significantly after PSE. Furthermore, Th1 cells and Th2 cells showed a significant increase at 4 weeks after PSE compared with before PSE, although there was no significant change of Treg cells. Moreover, serum levels of TNF-alpha, soluble TNF receptor I, and soluble Fas were significantly increased after PSE. There was no significant change of the Child-Pugh score. Conclusions In patients with cirrhosis and thrombocytopenia, PSE not only promoted the recovery of leukopenia and thrombocytopenia but also induced activation of host immunity.

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Changes of cytokines in patients with liver cirrhosis and advanced hepatocellular carcinoma treated by sorafenib

Abstract: These findings suggest that treatment with sorafenib at doses ≥400 mg/day might promote TNF-related or Fas-related apoptosis by increasing the circulating level of TNF-alpha or decreasing that of sFas.

Cited by 8 publications

References 30 publications

Activation of ferritinophagy is required for the RNA-binding protein ELAVL1/HuR to regulate ferroptosis in hepatic stellate cells

Activation of ferritinophagy is required for the RNA-binding protein ELAVL1/HuR to regulate ferroptosis in hepatic stellate cells

Immune Characters and Plasticity of the Sentinel Lymph Node in Colorectal Cancer Patients

Host Immunological Effects of Partial Splenic Embolization in Patients with Liver Cirrhosis

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