Dataset Information

Interleukin-18 Is a Prognostic Biomarker Correlated with CD8+ T Cell and Natural Killer Cell Infiltration in Skin Cutaneous Melanoma.

ABSTRACT: Interleukin-18 (IL-18) is a cytokine that enhances innate and adaptive immune responses. Although there are conflicting reports about the roles of IL-18 in melanoma progression, the clinical relevance of IL-18 expression has not been comprehensively studied. In this study, we investigated IL-18 expression and its correlation with patient survival and immune cell infiltration in melanoma using cancer gene expression data publicly available through various databases. IL18 mRNA expression was found to be significantly lower in melanoma tissues than normal tissues. Kaplan-Meier survival analysis showed that IL18 expression was positively correlated with patient survival. To investigate the possible mechanisms by which IL18 expression increased patient survival, we then assessed the correlation between IL18 expression and immune cell infiltration levels. Infiltration of various immune cells, especially CD8+ T and natural killer (NK) cells, which are cytolytic effector cells, was significantly increased by IL18 expression. Additionally, the expression levels of two cytolytic molecules including perforin and granzyme B were significantly positively correlated with IL18 expression. Collectively, this study provides the first evidence that IL18 expression has prognostic value for melanoma patient survival and is strongly correlated with CD8+ T and NK cell infiltration, suggesting the role of IL-18 as a biomarker for predicting melanoma prognosis.

SUBMITTER: Gil M

PROVIDER: S-EPMC6912818 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Interleukin-18 Is a Prognostic Biomarker Correlated with CD8<sup>+</sup> T Cell and Natural Killer Cell Infiltration in Skin Cutaneous Melanoma.

Gil Minchan M Kim Kyung Eun KE

Journal of clinical medicine 20191115 11

Interleukin-18 (IL-18) is a cytokine that enhances innate and adaptive immune responses. Although there are conflicting reports about the roles of IL-18 in melanoma progression, the clinical relevance of IL-18 expression has not been comprehensively studied. In this study, we investigated IL-18 expression and its correlation with patient survival and immune cell infiltration in melanoma using cancer gene expression data publicly available through various databases. <i>IL18</i> mRNA expression wa ...[more]

PMID: 31731729

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Project description:BackgroundSkin cutaneous melanoma (SKCM) is the most threatening type of skin cancer. Approximately 55,000 people lose their lives every year due to SKCM, illustrating that it seriously threatens human life and health. Homeodomain-only protein homeobox (HOPX) is the smallest member of the homeodomain family and is widely expressed in a variety of tissues. HOPX is involved in regulating the homeostasis of hematopoietic stem cells and is closely related to the development of tumors such as breast cancer, nasopharyngeal carcinoma, and head and neck squamous cell carcinoma. However, its function in SKCM is unclear, and further studies are needed.MethodsWe used the R language to construct ROC (Receiver-Operating Characteristic) curves, KM (Kaplan‒Meier) curves and nomograms based on databases such as the TCGA and GEO to analyze the diagnostic and prognostic value of HOPX in SKCM patients. Enrichment analysis, immune scoring, GSVA (Gene Set Variation Analysis), and single-cell sequencing were used to verify the association between HOPX expression and immune infiltration. In vitro experiments were performed using A375 cells for phenotypic validation. Transcriptome sequencing was performed to further analyze HOPX gene-related genes and their signaling pathways.ResultsCompared to normal cells, SKCM cells had low HOPX expression (p < 0.001). Patients with high HOPX expression had a better prognosis (p < 0.01), and the marker had good diagnostic efficacy (AUC = 0.744). GO/KEGG (Gene Ontology/ Kyoto Encyclopedia of Genes and Genomes) analysis, GSVA and single-cell sequencing analysis showed that HOPX expression is associated with immune processes and high enrichment of T cells and could serve as an immune checkpoint in SKCM. Furthermore, cellular assays verified that HOPX inhibits the proliferation, migration and invasion of A375 cells and promotes apoptosis and S-phase arrest. Interestingly, tumor drug sensitivity analysis revealed that HOPX also plays an important role in reducing clinical drug resistance.ConclusionThese findings suggest that HOPX is a blocker of SKCM progression that inhibits the proliferation of SKCM cells and promotes apoptosis. Furthermore, it may be a new diagnostic and prognostic indicator and a novel target for immunotherapy in SKCM patients.

Project description:BackgroundSkin cutaneous melanoma (SKCM) is an extremely malignant tumor and accounts for the majority of skin cancer deaths. Aspartate beta-hydroxylase domain containing 1 (ASPHD1) may participate in cancer progression through controlling α-ketoglutarate-dependent dioxygenases. However, its role in skin cutaneous melanoma (SKCM) has not been well studied.MethodsThe gene expression data of ASPDH1 and differentially expressed genes (DEGs) from TCGA and GTEx were evaluated, and verified via the GEO database. Then, we performed GO/KEGG, GSEA, PPI network analysis to analyze the functional implications of the DEGs related to ASPHD1. Then, the association between the ASPHD1 expression and clinical parameters was investigated by Cox regression analysis. Subsequently, the survival time of SKCM patients was evaluated by plotting Kaplan-Meier curves. Moreover, we investigated the correlation between the ASPHD1 expression and lymphocytic infiltration by using the data from TISIDB and TIMER 2.0. Next, we explored the association between ASPHD1 expression and drug sensitivity. Finally, we validate the expression differences by analyzing the results of qPCR, Western blot from human normal epidermal melanocytes and melanoma cells, and immunohistochemistry (IHC) from non-tumor skin as well as melanoma tissues.ResultsThe ASPHD1 expression level was significantly upregulated in several cancers, including SKCM especially SKCM-metastasis tissues, and patients with an increased ASPHD1 expression had longer overall survival time than low expression ones. The functional enrichment analysis of ASPHD1-related DEGs showed an association with cell development regulation and tumorigenic pathways. Furthermore, the increased ASPHD1 expression level was associated with the level of immunostimulors, immunoinhibitors, chemokines, and TILs, such as CD4+, CD8+ T cell, mast cell, Th2 cell, and dendritic cell. More interesting, we found that ASPHD1 expression was tightly associated with CTLA4 and CD276 which are immune checkpoint markers. Moreover, the upregulated expression of ASPHD1 exhibited higher IC50 values for 24 chemotherapy drugs, including doxorubicin, and masitinib. Finally, the differential expression of ASPHD1 in SKCM was validated by the results of qPCR, Western blot, and IHC.ConclusionThe expression of ASPHD1 in SKCM patients is closely related to patient survival. ASPHD1 may participate in the regulation of tumor immune microenvironment. Additionally, it may serve as a prognostic biomarker for SKCM and future in-depth studies are necessary to explore its value.

Dataset Information

Interleukin-18 Is a Prognostic Biomarker Correlated with CD8+ T Cell and Natural Killer Cell Infiltration in Skin Cutaneous Melanoma.

Publications

Interleukin-18 Is a Prognostic Biomarker Correlated with CD8<sup>+</sup> T Cell and Natural Killer Cell Infiltration in Skin Cutaneous Melanoma.

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