SLC39A1 Overexpression is Associated with Immune Infiltration in Hepatocellular Carcinoma and Promotes Its Malignant Progression

Abstract

Background: Solute carrier family 39 member 1 (SLC39A1) has been identified as a zinc ion transport protein that possesses oncogenic properties in various types of cancers. However, its potential function in hepatocellular carcinoma (HCC) remains unknown. This study aimed to investigate the expression profile and potential mechanisms of SLC39A1 in HCC. Methods: SLC39A1 expression was analyzed using multiple databases. The clinical significance and associated biological pathways of SLC39A1 were investigated using bioinformatics analysis. Potential correlations between SLC39A1 expression and tumor immunity in HCC were also evaluated using single-sample gene set enrichment analysis (GSEA). Sixty paired HCC samples were used to verify the expression pattern of SLC39A1. In vitro studies were performed to investigate the oncogenic effects of SLC39A1 in HCC. Western blot analysis was conducted to further investigate the possible involved signaling pathways. Results:The overexpression of SLC39A1 in HCC was determined by bioinformatics analysis and was confirmed in tissues from our center. SLC39A1 overexpression was also significantly correlated with worse prognosis, advanced TNM stage, and histological grade. GSEA analysis demonstrated that SLC39A1 overexpression was involved in various tumor-related pathways, such as the cell cycle and Wnt signaling pathway. SLC39A1 knockdown repressed the proliferation, invasion, and migration abilities of HCC cells. Furthermore, SLC39A1 knockdown decreased the expression of the tumor progression-related proteins (eg, cyclin D1 and MMP2) and Wnt signaling pathway-related proteins (eg, Wnt3A and β-catenin). In addition, SLC39A1 overexpression may be associated with impaired tumor immunity in HCC, as evidenced by the increased infiltration of Th2 cells and reduced infiltration of cytotoxic cells. Conclusion: These findings preliminarily suggested the crucial effect of SLC39A1 overexpression on HCC tumor progression and immunosuppression, suggesting its potential as a novel prognostic and therapeutic target in HCC.

Zinc Transporters Serve as Prognostic Predictors and their Expression Correlates with Immune Cell Infiltration in Specific Cancer: A Pan-cancer Analysis

“…The GO and KEGG enrichment analyses conducted in our study demonstrated the enrichment of zinc transporter-related genes in various biological processes, including cell metabolism, cell cycle regulation, and other essential processes. These findings are consistent with previous studies that have highlighted the importance of zinc transporters in these cellular processes 27 , 32 , 33 .…”

“…The expression of SLC39A4 was also linked to chemotherapeutic response in CESC. It was found that the knockdown of SLC39A4 can significantly improve the sensitivity of CESC to cisplatin treatment 27 . Moreover, we found that the genetic alteration rate of SLC39A4 in PAAD is up to 10% and it is highly associated with a reduced OS in PAAD patients.…”

Identification of tumor-associated antigens and immune subtypes of lower-grade glioma and glioblastoma for mRNA vaccine development

“…SLC39A1 may play an important role in tumor progression [29]. SLC39A1 could significantly decreased the level of Zn2 + in cancer tissue, thereby reducing the level of citrate, and ultimately resulting in the malignant progression of prostate cancer and glioma [30]. MMP-9, a member of the matrix metalloproteinases (MMP) family known to confer invasive behavior to cancer cells.…”

Upregulated Solute Carrier SLC39A1 Promotes Gastric Cancer Proliferation and Indicates Unfavorable Prognosis

“…Their bioinformatics analyses and experimental data found that SLC39A1 knockdown suppressed the expression of cyclin D1, MMP2, Wnt3A, and β -catenin and subsequently inhibited HCC progression. Moreover, overexpressing SLC39A1 may affect tumor immunity in HCC, as indicated by the enhanced infiltration of Th2 cells and impaired infiltration of cytotoxic cells [ 13 ]. Of note, involvement of SLC39A1 in modulating infiltration of immune cells was also suggested in glioma microenvironment [ 14 ].…”

“…Considering that exogenous zinc has significant effect on cell viability and apoptosis [ 11 , 12 ], its potential role in carcinogenesis is attracting more and more attention. Recently, hyper-expression of SLC39A1 has been reported to participate in the malignant progression of hepatocellular carcinoma and glioma [ 13 , 14 ]. However, its role in gastric cancer remains unknown.…”