FGF19/FGFR4-mediated elevation of ETV4 facilitates hepatocellular carcinoma metastasis by upregulating PD-L1 and CCL2

Xie, Meng; Lin, Zhuoying; Ji, Xiaoyu; Luo, Xun-Jiang; Zhang, Zerui; Sun, Mengyu; Chen, Xiaoping; Zhang, Bixiang; Liang, Huifang; Liu, Danfei; Feng, Yangyang; Wang, Yijun; Li, Yiwei; Liu, Bi‐Feng; Huang, Wenjie; Xia, Limin

doi:10.1016/j.jhep.2023.02.036

Cited by 52 publications

(26 citation statements)

References 60 publications

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“…However, whether the phenotype obtained from the subcutaneous tumor model would truly occur under the physiological condition needed further investigation. By using orthotopic xenograft models, Xie et al [41] found that ETV4 upregulated the transcription of programmed cell death-ligand 1 (PD-L1) and C-C motif chemokine ligand 2 (CCL2) and promoted HCC metastasis. Their results may represent the microenvironment in late stage during tumor development since they performed the experiments with the tumor cell line Hepa1-6.…”

Section: Discussionmentioning

confidence: 99%

Transcription factor ETV4 promotes the development of hepatocellular carcinoma by driving hepatic TNF‐α signaling

Qi,

Lu,

et al. 2023

Cancer Communications

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BackgroundHepatic inflammation is the major risk factor of hepatocellular carcinoma (HCC). However, the underlying mechanism by which hepatic inflammation progresses to HCC is poorly understood. This study was designed to investigate the role of ETS translocation variant 4 (ETV4) in linking hepatic inflammation to HCC.MethodsQuantitative real‐time PCR and immunoblotting were used to detect the expression of ETV4 in HCC tissues and cell lines. RNA sequencing and luciferase reporter assays were performed to identify the target genes of ETV4. Hepatocyte‐specific ETV4‐knockout (ETV4fl/fl, alb‐cre) and transgenic (ETV4Hep‐TG) mice and diethylnitrosamine‐carbon tetrachloride (DEN‐CCL4) treatment experiments were applied to investigate the function of ETV4 in vivo. The Cancer Genome Atlas (TCGA) database mining and pathological analysis were carried out to determine the correlation of ETV4 with tumor necrosis factor‐alpha (TNF‐α) and mitogen‐activated protein kinase 11 (MAPK11).ResultsWe revealed that ETV4 was highly expressed in HCC. High levels of ETV4 predicted a poor survival rate of HCC patients. Then we identified ETV4 as a transcription activator of TNF‐α and MAPK11. ETV4 was positively correlated with TNF‐α and MAPK11 in HCC patients. As expected, an increase in hepatic TNF‐α secretion and macrophage accumulation were observed in the livers of ETV4Hep‐TG mice. The protein levels of TNF‐α, MAPK11, and CD68 were significantly higher in the livers of ETV4Hep‐TG mice compared with wild type mice but lower in ETV4fl/fl, alb‐cre mice compared with ETV4fl/fl mice as treated with DEN‐CCL4, indicating that ETV4 functioned as a driver of TNF‐α/MAPK11 expression and macrophage accumulation during hepatic inflammation. Hepatocyte‐specific knockout of ETV4 significantly prevented development of DEN‐CCL4‐induced HCC, while transgenic expression of ETV4 promoted growth of HCC.ConclusionsETV4 promoted hepatic inflammation and HCC by activating transcription of TNF‐α and MAPK11. Both the ETV4/TNF‐α and ETV4/MAPK11 axes represented two potential therapeutic targets for highly associated hepatic inflammation and HCC. ETV4+TNF‐α were potential prognostic markers for HCC patients.

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Section: Discussionmentioning

confidence: 99%

Transcription factor ETV4 promotes the development of hepatocellular carcinoma by driving hepatic TNF‐α signaling

Qi,

Lu,

et al. 2023

Cancer Communications

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“…Therefore, our results, which show an association between CD68 or PD-L1 expression and lenvatinib treatment, require further examination to fully understand the dynamic changes in the phenotype and number of macrophages following MKI treatment. A recent study revealed that E-twenty-six-specific sequence variant 4 (ETV4) increases PD-L1 expression, leading to enhanced TAM infiltration and suppressed T-cell accumulation, ultimately resulting in HCC metastasis [ 28 ]. Importantly, ETV4 expression was upregulated by fibroblast growth factor 19 (FGF19) and fibroblast growth factor receptor 4 (FGFR4).…”

Section: Discussionmentioning

confidence: 99%

Higher Number of Tumor-Infiltrating PD-L1+ Cells Is Related to Better Response to Multikinase Inhibitors in Hepatocellular Carcinoma

Han

Kim

et al. 2023

Diagnostics

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Multikinase inhibitors (MKIs) such as sorafenib and lenvatinib are first-line treatments for unresectable hepatocellular carcinoma (HCC) and are known to have immunomodulatory effects. However, predictive biomarkers of MKI treatment in HCC patients need to be elucidated. In the present study, thirty consecutive HCC patients receiving lenvatinib (n = 22) and sorafenib (n = 8) who underwent core-needle biopsy before treatment were enrolled. The associations of CD3, CD68, and programmed cell death-ligand-1 (PD-L1) immunohistochemistry with patient outcomes, including overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), were evaluated. High and low subgroups were determined according to median CD3, CD68, and PD-L1 values. Median CD3 and CD68 counts were 51.0 and 46.0 per 20,000 µm2, respectively. The median combined positivity score (CPS) of PD-L1 was 2.0. Median OS and PFS were 17.6 and 4.4 months, respectively. ORRs of the total, lenvatinib, and sorafenib groups were 33.3% (10/30), 12.5% (1/8), and 40.9% (9/22), respectively. The high CD68+ group had significantly better PFS than the low CD68+ group. The high PD-L1 group had better PFS than the low subgroup. When we analyzed the lenvatinib subgroup, PFS was also significantly better in the high CD68+ and PD-L1 groups. These findings suggest that high numbers of PD-L1-expressing cells within tumor tissue prior to MKI treatment can serve as a biomarker to predict favorable PFS in HCC patients.

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“…41 To assess the selectivity of HDFGFR4/CMMNPs, we included five drugs in the HDFGFR4/CMMNPs screening system. As shown in Figure 4D, we selected BLU554 42 and BLU9931 as positive drugs for FGFR4 on the cell membrane, and lovastatin, aspirin, and gefitinib were randomly selected as negative control drugs, whose binding sites were not FGFR4. As screening recoveries of BLU9931 on HDFGFR4/CMMNPs and FGFR4/ CMMNPs were 92.56% and 88.46%, respectively.…”

Section: Adsorption Selectivitymentioning

confidence: 99%

Genetically Engineered Cell Membrane-Coated Nanoparticles with High-Density Customized Membrane Receptor for High-Performance Drug Lead Discovery

Bu,

Wu,

Zhao

et al. 2023

ACS Appl. Mater. Interfaces

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Cell membrane coating strategies have been increasingly researched due to their unique capabilities of biomimicry and biointerfacing, which can mimic the functionality of the original source cells in vivo but fail to provide customized nanoparticle surfaces with new or enhanced capabilities beyond natural cells. However, the field of drug lead discovery necessitates the acquisition of sufficient surface density of specific target membrane receptors, presenting a heightened demand for this technology. In this study, we developed a novel approach to fabricate high density of fibroblast growth factor receptor 4 (FGFR4) cell membrane-coated nanoparticles through covalent site-specific immobilization between genetically engineered FGFR4 with HaloTag anchor on cell membrane and chloroalkane-functionalized magnetic nanoparticles. This technique enables efficient screening of tyrosine kinase inhibitors from natural products. And the enhanced density of FGFR4 on the surface of nanoparticles were successfully confirmed by Western blot assay and confocal laser scanning microscopy. Further, the customized nanoparticles demonstrated exceptional sensitivity (limit of detection = 0.3 × 10–3 μg mL–1). Overall, the proposed design of a high density of membrane receptors, achieved through covalent site-specific immobilization with a HaloTag anchor, demonstrates a promising strategy for the development of cell membrane surface engineering. This approach highlights the potential of cell membrane coating technology for facilitating the advanced extraction of small molecules for drug discovery.

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FGF19/FGFR4-mediated elevation of ETV4 facilitates hepatocellular carcinoma metastasis by upregulating PD-L1 and CCL2

Cited by 52 publications

References 60 publications

Transcription factor ETV4 promotes the development of hepatocellular carcinoma by driving hepatic TNF‐α signaling

Transcription factor ETV4 promotes the development of hepatocellular carcinoma by driving hepatic TNF‐α signaling

Higher Number of Tumor-Infiltrating PD-L1+ Cells Is Related to Better Response to Multikinase Inhibitors in Hepatocellular Carcinoma

Genetically Engineered Cell Membrane-Coated Nanoparticles with High-Density Customized Membrane Receptor for High-Performance Drug Lead Discovery

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