Macrophage migration inhibitory factor exerts pro‐proliferative and anti‐apoptotic effects via CD74 in murine hepatocellular carcinoma

Wirtz, Theresa H.; Saal, Alena; Bergmann, Irina; Fischer, Petra; Heinrichs, Daniel; Brandt, Elisa Fabiana; Djudjaj, Sonja; Schneider, Kai Markus; Bucala, Richard; Weiskirchen, Ralf; Berres, Marie‐Luise

doi:10.1111/bph.15622

Cited by 26 publications

(21 citation statements)

References 47 publications

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“…The receptor gene CD74 may participate in the regulation of antigen presentation for immune response. The interaction of MIF and CD74 was reported to exert proproliferative and antiapoptotic effects in murine hepatocellular carcinoma [ 28 ].…”

Section: Resultsmentioning

confidence: 99%

Single-Cell RNA-seq Analysis Reveals Dysregulated Cell-Cell Interactions in a Tumor Microenvironment Related to HCC Development

Liu

Zhang

Ouyang³

et al. 2022

Disease Markers

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The heterogeneity of tumor microenvironment (TME) of hepatocellular carcinoma (HCC) may relate to cell-cell interaction event (CCE) dysregulation and would affect therapeutic responses and clinical outcomes. To reveal the differentiation of CCEs in the liver tissue from healthy donors (HD) to HCC, scRNA-seq data of ~62000 cells from HD, paracancerous nontumor tissue (NT), and HCC were analyzed. The microenvironmental CCE landscape was constructed. Dysregulated cell types and changed molecular functions were identified with CCE alterations in HCC. Dysregulated CCEs which function as pivotal roles in tumorigenesis and development of HCC included SPP1-CD44, MIF-TNFRSF14, and VEGFA-NRP1. A CCE-based immune regulatory network was extracted to illustrate the mechanism of TME dysregulation. A prognostic signature based on CCE genes was identified and validated in independent datasets. Our study provided insights into the characteristics of the cross-talk between tumor cells and microenvironment in HCC and established a workflow strategy for CCE analyses based on scRNA-seq data.

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Section: Resultsmentioning

confidence: 99%

Single-Cell RNA-seq Analysis Reveals Dysregulated Cell-Cell Interactions in a Tumor Microenvironment Related to HCC Development

Liu

Zhang

Ouyang³

et al. 2022

Disease Markers

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“…Blocking MIF-CD74 signalling not only inhibits the proliferation of HCC cells but also exerts antitumour effects. Therefore, MIF/CD74 axis inhibition could be an effective treatment for HCC ( 28 ). SPP1 encodes osteopontin (OPN), a phosphorylated glycoprotein expressed in various tissues and cells associated with human diseases ( 29 , 30 ).…”

Section: Resultsmentioning

confidence: 99%

Single-cell transcriptome analysis reveals the metabolic changes and the prognostic value of malignant hepatocyte subpopulations and predict new therapeutic agents for hepatocellular carcinoma

et al. 2023

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BackgroundThe development of HCC is often associated with extensive metabolic disturbances. Single cell RNA sequencing (scRNA-seq) provides a better understanding of cellular behavior in the context of complex tumor microenvironments by analyzing individual cell populations. MethodsThe Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data was employed to investigate the metabolic pathways in HCC. Principal component analysis (PCA) and uniform manifold approximation and projection (UMAP) analysis were applied to identify six cell subpopulations, namely, T/NK cells, hepatocytes, macrophages, endothelial cells, fibroblasts, and B cells. The gene set enrichment analysis (GSEA) was performed to explore the existence of pathway heterogeneity across different cell subpopulations. Univariate Cox analysis was used to screen genes differentially related to The Overall Survival in TCGA-LIHC patients based on scRNA-seq and bulk RNA-seq datasets, and LASSO analysis was used to select significant predictors for incorporation into multivariate Cox regression. Connectivity Map (CMap) was applied to analysis drug sensitivity of risk models and targeting of potential compounds in high risk groups.ResultsAnalysis of TCGA-LIHC survival data revealed the molecular markers associated with HCC prognosis, including MARCKSL1, SPP1, BSG, CCT3, LAGE3, KPNA2, SF3B4, GTPBP4, PON1, CFHR3, and CYP2C9. The RNA expression of 11 prognosis-related differentially expressed genes (DEGs) in normal human hepatocyte cell line MIHA and HCC cell lines HCC-LM3 and HepG2 were compared by qPCR. Higher KPNA2, LAGE3, SF3B4, CCT3 and GTPBP4 protein expression and lower CYP2C9 and PON1 protein expression in HCC tissues from Gene Expression Profiling Interactive Analysis (GEPIA) and Human Protein Atlas (HPA) databases. The results of target compound screening of risk model showed that mercaptopurine is a potential anti-HCC drug.ConclusionThe prognostic genes associated with glucose and lipid metabolic changes in a hepatocyte subpopulation and comparison of liver malignancy cells to normal liver cells may provide insight into the metabolic characteristics of HCC and the potential prognostic biomarkers of tumor-related genes and contribute to developing new treatment strategies for individuals.

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“…MIF has been confirmed to contribute to a variety of facets of tumor growth, including cell proliferation, differentiation, and angiogenesis. MIF can bind to its receptor CD74 in the TME, which is present on TAMs, DCs, Treg cells, and MDSCs, facilitating immunological escape and cancer growth ( 63 , 64 ). For the first time, our study found that MIF may inhibit memory B-cell activity in HCC and that inhibiting the MIF-CD74 axis may be a new treatment strategy.…”

Section: Resultsmentioning

confidence: 99%

Immunosuppressive landscape in hepatocellular carcinoma revealed by single-cell sequencing

et al. 2022

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Background/AimsHepatocellular carcinoma (HCC), accounting for 75-85% of primary liver cancer cases, is the third leading cause of cancer-related death worldwide. The purpose of this research was to examine the tumor immune microenvironment (TIME) in HCC.MethodsWe investigated the HCC TIME by integrated analysis of single-cell and bulk-tissue sequencing data to reveal the landscape of major immune cell types.ResultsRegulatory T(Treg) cells were found to be specifically distributed in the TIME of HCC. Several immune checkpoints, including TNFRSF4, TIGIT and CTLA4, were found to be uniquely overexpressed in Treg cells, and the glycolysis/gluconeogenesis pathway was enriched in Treg cells. We also discovered the presence of two NK-cell subsets with different cytotoxic capacities, one in an activated state with antitumor effects and another with an exhausted status. In addition, memory B cells in HCC were found to exist in a unique state, with high proliferation, low differentiation, and low activity, which was induced by overexpression of PRAP1 and activation of the MIF-CD74 axis.ConclusionsWe revealed the TIME landscape in HCC, highlighting the heterogeneity of major immune cell types and their potential mechanisms in the formation of an immunosuppressive environment. Hence, blocking the formation of the TIME could be a useful therapeutic strategy for HCC.

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Macrophage migration inhibitory factor exerts pro‐proliferative and anti‐apoptotic effects via CD74 in murine hepatocellular carcinoma

Abstract: The data that support the findings of this study are available from the corresponding author upon reasonable request. Some data may not be made available because of privacy or ethical reasons.

Cited by 26 publications

References 47 publications

Single-Cell RNA-seq Analysis Reveals Dysregulated Cell-Cell Interactions in a Tumor Microenvironment Related to HCC Development

Single-Cell RNA-seq Analysis Reveals Dysregulated Cell-Cell Interactions in a Tumor Microenvironment Related to HCC Development

Single-cell transcriptome analysis reveals the metabolic changes and the prognostic value of malignant hepatocyte subpopulations and predict new therapeutic agents for hepatocellular carcinoma

Immunosuppressive landscape in hepatocellular carcinoma revealed by single-cell sequencing

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