Aspartate beta-hydroxylase domain containing 1 as a prognostic marker associated with immune infiltration in skin cutaneous melanoma

Abstract

Abstract Background Skin 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. Methods The 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. Results The 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. Conclusion The 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.

Keywords

• ASPHD1
• Skin cutaneous melanoma
• CTLA4
• Tumor immune microenvironment
• Biomarkers