HGF/c‐MET pathway contributes to cisplatin‐mediated PD‐L1 expression in hepatocellular carcinoma

Zhang, Zhansheng; Yang, Ruo-Han; Yao, Xin; Cheng, Yue-Ying; Shi, Hong-Xiang; Yao, Chao-Yan; Gao, Zixuan; Qi, Defei; Zhang, Wenke; Dou, Yuanyuan; Guo, Juan; Hu, Mei‐Chen; Zhao, Hui; Fang, Dong

doi:10.1002/cbin.11697

Cited by 8 publications

(5 citation statements)

References 41 publications

(46 reference statements)

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“…22 Similarly, a study also found that DDP promoted the expression of PD-L1 and p-ERK in liver cancer cells SUN-368 and SUN-739, which affected the tumor inhibitory effect of DDP. 23 In this study, we also found that DDP promoted the expression of PD-1 in HepG2 cells (Fig. 4C) and further studied the effect of DHA combined with DDP.…”

Section: The Expressions Of Yap1 and P-erk/erk Were Inhibited By Dihy...supporting

confidence: 62%

PD-1/PD-L1 Interaction Upregulates YAP1 Expression in HepG2 Cells Through MAPK/ERK Pathway

Li,

Dai,

Wang

et al. 2023

Natural Product Communications

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Background Antibodies, which target programmed cell death protein-1 (PD-1) or its ligand programmed death ligand-1 (PD-L1), can rescue T cells from an exhausted state and resume their immune response to cancer cells. Clinically, the purpose of blocking the PD-1/PD-L1 signaling pathway is to induce immune cells to play an anti-tumor role. However, the effect of intertumor PD-1/PD-L1 signal blocking on tumor cells remains unclear. Methods HepG2 cells were treated with DHA, IFN-γ, BSA, DDP, PD-1-Fc (1 μg/ml), IgG-Fc, nivolumab, or human IgG for 24 h, respectively. GEPIA, cBioPortal, and TIMER databases were used to analyze the correlation between YAP1, PD-1, and PD-L1 and ERK, ERK-5, JNK, and p38. Western blot was used to detect the expression of YAP1 and p-ERK. Results GEPIA, cBioPortal, and TIMER databases analysis showed that YAP1 was positively correlated with ERK. After HepG2 cells were treated with PD98059 (ERK inhibitor), the expression of YAP1 was decreased. In this study, we investigated the inhibitory effect of PD98059 on PD-1/PD-L1 signaling. Our study found that PD-1-Fc (PD-1 fusion protein) promoted the expression of p-ERK/ERK and YAP1 in HepG2 cells. In contrast, nivolumab (PD-1 blocking antibody) reduced the expression of p-ERK/ERK and YAP1 in IFN-γ-pretreated HepG2 cells. In addition, the application of DHA also inhibited the expression of p-ERK/ERK to inhibit YAP1. Furthermore, treatment of HepG2 cells with DHA alone or DHA combined with cisplatin (DDP) both inhibited the expression of p-ERK/ERK and YAP1. Conclusions These results suggested that PD-1/PD-L1 interactions between tumor cells could promote the expression of ERK or YAP1 within tumors. Moreover, the conduction of PD-1/PD-L1 could be reversed using ERK inhibitors.

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Section: The Expressions Of Yap1 and P-erk/erk Were Inhibited By Dihy...supporting

confidence: 62%

PD-1/PD-L1 Interaction Upregulates YAP1 Expression in HepG2 Cells Through MAPK/ERK Pathway

Li,

Dai,

Wang

et al. 2023

Natural Product Communications

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“…Besides, malignant follicular cells also expressed genes for ligands that induce M2-like macrophage polarization, including C3 (binds to C3AR1 ) and ANAX1 (binds to FPR3 ) ( Figure 5C ) ( 26 – 28 ). In turn, myeloid cells expressed hepatocyte growth factor (HGF) that binds to the receptor (MET) in follicular cells ( Figure 5D ), activating the PI3K/Akt signaling pathway involved in cell growth, motility, and metastasis ( 29 , 30 ). Myeloid cells expressed genes ( CXCL10 and CXCL12 ) for chemokines as chemoattractants to recruit T cells expressing CXCR4 and/or CXCR3 in T1 and T2 samples, but not in T3 ( Figure 5E ), which was in accordance with the histological assessment that indicated chronic lymphocytic thyroiditis in T1 and T2 samples ( Supplementary Figure S1 ).…”

Section: Resultsmentioning

confidence: 99%

“…Our analysis indicated that malignant follicular cells also expressed ligands ( C3 and ANAX1 ) that encouraged the polarization of M2-like macrophages. In turn, myeloid cells expressed HGF that binds to the receptor (MET) in follicular cells, activating the PI3K/Akt signaling pathway involved in cell growth, motility, and metastasis ( 29 , 30 ). Moreover, myeloid cells also expressed high levels of arginine (ARG) that binds to intercellular adhesion molecule 1 (ICAM1) in follicular cells, whose expression levels have been shown to be increased in PTC, poorly differentiated thyroid cancer (PDTC), and anaplastic thyroid cancer (ATC) and which has been proven to be an effective therapeutic target in advanced thyroid cancer ( 55 , 56 ).…”

Section: Discussionmentioning

confidence: 99%

Single-Cell Transcriptome Analysis Reveals Inter-Tumor Heterogeneity in Bilateral Papillary Thyroid Carcinoma

Wang

Shi

et al. 2022

Front. Immunol.

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BackgroundThe tumor microenvironment (TME) plays a pivotal role in cancer progression in papillary thyroid carcinoma (PTC), yet the composition and the phenotype of cells within the TME in bilateral PTC are poorly understood.MethodsWe performed unbiased transcriptome-wide single-cell RNA sequencing (scRNA-seq) analysis on 29,561 cells from 3 pairs of bilateral PTC and 1 non-tumor thyroid sample. The results of the analysis were validated by a large-scale bulk transcriptomic dataset deposited in The Cancer Genome Atlas (TCGA) database.ResultsOur integrative analysis of thyroid follicular cells revealed 42 signaling pathways enriched in malignant follicular cells, including cytokine–cytokine receptor interaction, PI3K/Akt signaling pathway, mitogen-activated protein kinase (MAPK) signaling pathway, and tumor necrosis factor (TNF) signaling pathway. A 6-gene signature (CXCL3, CXCL1, IL1A, CCL5, TNFRSF12A, and IL18) in the cytokine–cytokine receptor interaction pathway was constructed to predict the prognosis of patients with PTC, with high risk scores being associated with decreased overall survival [hazard ratio (HR) = 3.863, 95% CI = 2.233−6.682, p < 0.001]. Gene set variation analysis (GSVA) indicated that the pathways enriched in bilateral PTC were significantly different, indicating great heterogeneity in bilateral PTC, even with the same BRAF V600E mutation. Comprehensive analysis of T cells revealed that the proportion of CD8+ tissue-resident memory T cells expressing IFNG decreased in tumor samples with advanced N stage. Within the myeloid compartment, the ratio of suppressive M2-like to pro-inflammatory M1-like macrophages increased with advanced disease stage, which was confirmed in the bulk dataset using transcriptomic profiles. In addition, we also identified numerous biologically critical interactions among myeloid cells, T cells, and follicular cells, which were related to T-cell recruitment, M2-like macrophage polarization, malignant follicular cell progression, and T-cell inhibitory signaling.ConclusionOur integrative analyses revealed great inter-tumor heterogeneity within the TME in bilateral PTC, which will offer assistance for precise diagnosis and treatment.

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“…PIVKA-II was considered as an angiogenic factor through KDR–PLC-γ–MAPK, highly expressed in both HCC cells and vascular endothelial cells. The improved understanding of PIVKA-II at the molecular level might provide potential druggable targets for HCC treatment ( 118 ).…”

Section: Conclusion and Future Prospectivementioning

confidence: 99%

Progression of Prothrombin Induced by Vitamin K Absence-II in Hepatocellular Carcinoma

Yang

et al. 2021

Front. Oncol.

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Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related death worldwide. Due to the lack of efficient tools for early detection, asymptomatic HCC patients are diagnosed at an advanced stage, leading to a poor prognosis. To improve survival, serum biomarker prothrombin induced by vitamin K absence-II (PIVKA-II) was under investigation. PIVKA-II is an abnormal protein produced in HCC. The coagulation function was insufficient due to the lack of Gla residues. Elevated PIVKA-II was associated with bad tumor behavior in terms of proliferation, metastasis, and invasion. Three major signaling pathways were proposed to clarify the mechanism. With the advantages including affordability, minimal invasiveness, convenience, and efficiency, PIVKA-II could improve HCC management consisting of four aspects. First, PIVKA-II was an effective and dynamic tool for improving HCC surveillance in high-risk population. Changes in the serum levels of PIVKA-II provided valuable molecular alteration information before imaging discovery. Second, PIVKA-II offered a complementary approach for HCC early detection. Compared to traditional diagnostic approaches, the combination of PIVKA-II and other biomarkers had better performance. Third, PIVKA-II was an indicator for the assessment of response to treatment in HCC. Preoperative assessment was for selecting personalized therapy, and postoperative measurement was for assessing treatment efficacy. Fourth, PIVKA-II was considered as a prognostic predictor for HCC. Patients with elevated PIVKA-II were more likely to develop microvascular invasion, metastasis, and recurrence.

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HGF/c‐MET pathway contributes to cisplatin‐mediated PD‐L1 expression in hepatocellular carcinoma

Cited by 8 publications

References 41 publications

PD-1/PD-L1 Interaction Upregulates YAP1 Expression in HepG2 Cells Through MAPK/ERK Pathway

PD-1/PD-L1 Interaction Upregulates YAP1 Expression in HepG2 Cells Through MAPK/ERK Pathway

Single-Cell Transcriptome Analysis Reveals Inter-Tumor Heterogeneity in Bilateral Papillary Thyroid Carcinoma

Progression of Prothrombin Induced by Vitamin K Absence-II in Hepatocellular Carcinoma

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