SLC7A1 Overexpression Is Involved in Energy Metabolism Reprogramming to Induce Tumor Progression in Epithelial Ovarian Cancer and Is Associated with Immune-Infiltrating Cells

Abstract

Cationic amino acid transporters (SLC7A1/CAT1) are highly expressed in human ovarian cancer (OC) tissues. However, the specific biological functions and mechanisms involved remain unclear. We used bioinformatics analysis to explore SLC7A1 expression level, prognostic value, and tumor mutation burden (TMB) in ovarian cancer (OC) tissues. We performed in vitro experiments to identify the expression and biological function of SLC7A1 in epithelial ovarian cancer (EOC) tissues and cells. An amino acid autoanalyzer was used to detect the effect of SLC7A1 on amino acid metabolism in EOC cells. Finally, SLC7A1 in OC was evaluated for cell-to-cell signalling and immune infiltration using online databases. We found that increased SLC7A1 expression in EOC cells and tissues was associated with poorer survival outcomes ( P < 0.05 ) but not with tumor stage or grade of OC ( P > 0.05 ). SLC7A1 is involved in the transport of phenylalanine and arginine in EOC cells, and its knockdown reduced the proliferation and migration of EOC cells and the resistance of cells to cisplatin. Furthermore, the TIMER database indicated that SLC7A1 overexpression was significantly positively correlated with levels of CD4+ memory resting cells, CD8+ effector memory cells, M0 macrophages, and cancer-associated fibroblasts (CAFs) in OC ( P < 0.05 ) and significantly negatively correlated with CD4+ memory-activated cells ( P < 0.05 ). Cell immunofluorescence indicated that SLC7A1 overexpression may affect the distribution of immune-infiltrating lymphocytes in tumors by inhibiting the expression of CCL4. Therefore, we concluded that SLC7A1 is involved in the metabolic remodelling of amino acids in EOC to promote tumor development and cisplatin resistance and is related to the tumor-infiltrating immune microenvironment of OC. SLC7A1 is a biomarker for predicting EOC progression and cisplatin resistance and represents a promising target for EOC treatment.

Deregulated Metabolic Pathways in Ovarian Cancer: Cause and Consequence

“…CAT-1 is overexpressed in EOC and it is involved in transporting phenylalanine and arginine. The expression of CAT-1 is associated with poorer survival rate in EOC patients and it was shown to promote proliferation and migration in EOC [182]. Arginine is synthesized de novo by the urea cycle.…”

Tyramine promotes colon cancer risk and development by inducing DNA damage and inflammation

“…Reduced expression of DHRS3 has been previously shown in gastric cancer, and its ectopic expression was found to inhibit cell proliferation and migration (Sumei et al, 2021). Expression of genes involved in glucose metabolism such as HKDC1 (Zapater et al, 2022) and amino acid metabolism such as SLC7A1 (You et al, 2022), were elevated, suggesting an impact of tyramine on cell energy metabolism.…”

High expression of SLC7A1 in high‐grade serous ovarian cancer promotes tumor progression and is involved in MAPK/ERK pathway and EMT

“…3.1 | SLC7A1 is highly expressed in the stroma of HGSOC Our previous bioinformatics analysis showed that overexpression of SLC7A1 was correlated with decreased progression-free survival (PFS) in OC patients, and SLC7A1 expression in OC was closely correlated with CAFs (p < 0.05). 20 To further clarify the relationship between SLC7A1 and the interstitial of ovarian cancer, immunohistochemical results showed significant SLC7A1 interstitial deposition in HGSOC samples (Figure 1A). However, perhaps due to the small number of immunohistochemical cases, we did not find significant differences in the expression of SLC7A1 in different stages of HGSOC.…”

“…Our previous studies have shown that SLC7A1 is highly expressed in EOC cells and is involved in tumor progression, platinum resistance, and amino acid metabolic remodeling in EOC, and is associated with poor progression‐free survival (PFS) in OC patients. 20 Meanwhile, the database evaluation found that there was a significant positive correlation between SLC7A1 and CAFs in OC ( p = 0.00015). However, the expression and mechanism of SLC7A1 in CAFs remain unclear.…”