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Identification of Therapeutic Targets and Prognostic Biomarkers Among Chemokine (C-C Motif) Ligands in the Liver Hepatocellular Carcinoma Microenvironment.

ABSTRACT: Background: Liver hepatocellular carcinoma (LIHC) is the third leading cause of cancer-related death and the sixth most common solid tumor worldwide. In the tumor microenvironment, the cross-talk between cancer cells, immune cells, and stromal cells exerts significant effects on neoplasia and tumor development and is modulated in part by chemokines. Chemokine (C-C motif) ligands (CCL) can directly target tumor cells and stromal cells, and they have been shown to regulate tumor cell proliferation, cancer stem-like cell properties, cancer invasiveness and metastasis, which directly and indirectly affect tumor immunity and influence cancer progression, therapy and patient outcomes. However, the prognostic values of chemokines CCL in LIHC have not been clarified. Methods: In this study, we comprehensively analyzed the relationship between transcriptional chemokines CCL and disease progression of LIHC using the ONCOMINE dataset, GEPIA, UALCAN, STRING, WebGestalt, GeneMANIA, TRRUST, DAVID 6.8, LinkedOmics, TIMER, GSCALite, and Open Targets. We validated the protein levels of chemokines CCL through western blot and immunohistochemistry. Results: The transcriptional levels of CCL5/8/11/13/15/18/20/21/25/26/27/28 in LIHC tissues were significantly elevated while CCL2/3/4/14/23/24 were significantly reduced. A significant correlation was found between the expression of CCL14/25 and the pathological stage of LIHC patients. LIHC patients with low transcriptional levels of CCL14/21 were associated with a significantly poor prognosis. The functions of differentially expressed chemokines CCL were primarily related to the chemokine signaling pathway, cytokine-cytokine receptor interactions, and TNF-α signaling pathway. Our data suggested that RELA/REL, NFKB1, STAT1/3/6, IRF3, SPI1, and JUN were key transcription factors for chemokines CCL. We found significant correlations among the expression of chemokines CCL and the infiltration of six types of immune cells (B cells, CD8⁺ T cells, CD4⁺ T cells, macrophages, neutrophils, and dendritic cells) and immune checkpoints (PD-1. PD-L1, and CTLA-4). The western blot and immunohistochemistry results showed that protein expression levels of CCL5 and CCL20 were upregulated in LIHC. CCL5 and CCL20 were significantly correlated with the clinical outcome of patients with LIHC, and could be negatively regulated by some drugs or small molecules. Conclusions: Our results may provide novel insights for the potential suitable targets of immunological therapy and prognostic biomarkers for LIHC.

SUBMITTER: Jiang Z

PROVIDER: S-EPMC8685337 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHepatocellular carcinoma (HCC) is predominant among all types of primary liver cancers characterised by high morbidity and mortality. Genes in the mediator complex (MED) family are engaged in the tumour-immune microenvironment and function as regulatory hubs mediating carcinogenesis and progression across diverse cancer types. Whereas research studies have been conducted to examine the mechanisms in several cancers, studies that systematically focused on the therapeutic and prognostic values of MED in patients with HCC are limited.MethodsThe online databases ONCOMINE, GEPIA, UALCAN, GeneMANIA, cBioPortal, OmicStudio, STING, Metascape, and TIMER were used in this study.ResultsThe transcriptional levels of all members of the MED family in HCC presented an aberrant high expression pattern. Significant correlations were found between the MED1, MED6, MED8, MED10, MED12, MED15, MED17, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, and MED27 expression levels and the pathological stage in the patients with HCC. The patients with high expression levels of MED6, MED8, MED10, MED17, MED19, MED20, MED21, MED22, MED24, and MED25 were significantly associated with poor prognosis. Functional enrichment analysis revealed that the members of the MED family were mainly enriched in the nucleobase-containing compound catabolic process, regulation of chromosome organisation, and transcriptional regulation by TP53. Significant correlations were found between the MED6, MED8, MED10, MED17, MED19, MED20, MED21, MED22, MED24, and MED25 expression levels and all types of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells). B cells and MED8 were independent predictors of overall survival. We found significant correlations between the somatic copy number alterations of the MED6, MED8, MED10, MED20, MED21, MED22, MED24, and MED25 molecules and the abundance of immune infiltrates.ConclusionsOur study delineated a thorough landscape to investigate the therapeutic and prognostic potentials of the MED family for HCC cases, which yielded promising results for the development of immunotherapeutic drugs and construction of a prognostic stratification model.

Project description:Background Several studies have indicated that CXC chemokines influence the prognosis and therapy in patients with hepatocellular carcinoma (HCC). However, there are limited studies on the roles of CXC chemokines in HCC based on data acquired from various databases. This study aimed to conduct an in-depth and comprehensive bioinformatic analysis of the expression and functions of CXC chemokines in HCC. Methods Data was obtained from various databases including ONCOMINE, UALCAN, STRING, GeneMinia, DAVID, Kaplan-Meier plotter, TIMER, GSCALite and NetworkAnalyst for the analysis of the expression and functions of the CXC chemokines in HCC. Results Analysis of the differential expression levels of CXC chemokines between HCC and adjacent normal tissues revealed that the mRNA expression levels of CXCL1/2/5/6/7/12/14 were significantly lower in HCC tissues than those in adjacent normal tissues, whereas the mRNA expression levels of CXCL9/16/17 were significantly higher in HCC tissues. Analysis of the relationship between CXC chemokines and overall survival revealed that high mRNA expression levels of CXCL1/3/5/6/8 were associated with poor overall survival, whereas high mRNA expression levels of CXCL2/4/7/9/10/12 were associated with better overall survival. The functions of CXC chemokines and related genes were associated with cytokine-cytokine receptor interactions and chemokine signaling pathway. Analysis of the association between CXC chemokines and activity of cancer pathways indicated that the DNA damage response and hormone androgen receptor (AR) signaling pathways were inhibited, whereas apoptosis, epithelial-mesenchymal transition (EMT) and Ras/mitogen-activated protein kinase (MAPK) signaling pathways were activated. The expression of CXC chemokines was positively correlated with the infiltration of six types of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells). Conclusions This study has demonstrated that CXC chemokines can influence survival of patients with HCC by recruiting different types of immune cells into the tumor microenvironment.

Project description:Immunosuppressive tumor microenvironment in hepatocellular carcinoma (HCC) is critical in tumor development. C-type (Ca2+ -dependent) lectin (CLEC) receptors, essential in innate pattern recognition, have potential regulatory effects on immune cell trafficking and modulatory effects on cancer cell activity. However, information on the expression and prognostic value of CLECs in HCC is scanty. Herein, we explored the potential role of CLECs in HCC based on TCGA, ONCOMINE, GEPIA, UALCAN, cBioPortal, Metascape, TRRUST, and TIMER databases. Results demonstrated a significantly higher mRNA level of CLEC4A and CLEC4L in HCC tissues than normal liver tissues. Contrarily, we found significantly low CLEC4G/H1/H2/M expression in HCC tissues. The IHC analysis revealed the following: Absence of CLEC4A/J/K/M in normal and liver cancer tissues; high CLEC4C expression in HCC tissues; low expression and zero detection of CLEC4D/E/H1/H2/L in HCC tissues and normal tissues, respectively. And the HepG2 and LX-2 were used to verify the expression level of CLEC4s via qRT-PCR in vitro. Furthermore, the expression of CLEC4H1 (ASGR1) and CLEC4H2 (ASGR2) exhibited a significant relation to clinical stages. However, the expression of CLEC4A, CLEC4D, CLEC4E, CLEC4J (FCER2), CLEC4K (CD207), CLEC4G, CLEC4H1, CLEC4M, and CLEC4H2 decreased with tumor progression. Patients expressing higher CLEC4H1/H2 levels had longer overall survival than patients exhibiting lower expression. Moreover, CLEC4A/D/E/J/K/G/H1/M/H2 had significant down-regulated levels of promoter methylation. The expression level of CLEC4s was correlated with the infiltration of B cells, CD8 + T cells, CD4 + T cells, macrophage cells, neutrophil cells, and dendritic cells. Functional analysis revealed the potential role of CLECL4s in virus infection, including COVID-19. Also, hsa-miR-4278 and hsa-miR-324-5p, two potential miRNA targets of CLEC4s, were uncovered. This article demonstrates that CLEC4 is crucial for the development of HCC and is associated with infiltration of various immune cells, providing evidence for new immunotherapy targets in HCC.

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Identification of Therapeutic Targets and Prognostic Biomarkers Among Chemokine (C-C Motif) Ligands in the Liver Hepatocellular Carcinoma Microenvironment.

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