OxLDL promotes lymphangiogenesis and lymphatic metastasis in gastric cancer by upregulating VEGF‑C expression and secretion

Abstract

Gastric cancer is one of the most malignant tumor types, and its metastasis is a notable cause of mortality. Among the methods of tumor metastasis, lymphatic metastasis is the predominant one in gastric cancer. A previous study reported that the plasma oxidized low-density lipoprotein (oxLDL) is the risk factor associated with the development of tumors in patients with abnormal lipid metabolism, but the influence of plasma oxLDL in the lymphatic metastasis of gastric cancer remains unclear. In the present study, the concentration of plasma oxLDL from patients with gastric cancer was detected with an ELISA kit, and the lymphatic vessel density in gastric cancer tissues was determined by D2-40 staining. The correlation analysis of oxLDL concentration and lymphatic vessel density demonstrated that plasma oxLDL was positively correlated with lymphatic metastasis in patients with gastric cancer. Subsequently, the popliteal lymph node metastasis animal experiment with nude mice confirmed that oxLDL could promote the lymphatic metastasis of gastric cancer. Following this, the western blotting and ELISA data demonstrated that oxLDL promoted the expression and secretion of vascular endothelia growth factor (VEGF)-C in gastric cancer cell lines. Finally, blocking the lectin-like oxLDL-1 (LOX-1) receptor, a specific receptor for oxLDL, and the nuclear factor (NF)-κB signaling pathway following oxLDL (50 µg/ml) treatment in HGC-27 cells revealed that oxLDL could activate the NF-κB signaling pathway mediated by LOX-1, with subsequent upregulation of VEGF-C expression, and secretion in and from gastric cancer cells, and finally that it could promote the lymphatic metastasis of gastric cancer. These data indicate the association between the plasma oxLDL and the lymphatic metastasis of gastric cancer, and indicate that oxLDL elimination may be a potential therapeutic target for the prevention and intervention of early lymph node metastasis in gastric cancer.

Inconspicuous offender

“…Overexpression of LOX-1 has also been observed in several other metabolic diseases including endothelial dysfunction, atherosclerosis and obesity (55,56). In these disorders, These findings were also confirmed by clinical data demonstrating that plasma oxLDL levels positively correlated with lymphatic metastasis in patients with gastric cancer (60).…”

Identification of the Differentially Expressed Genes and Prognostic Associations in Single-Cell RNA Sequencing Data of Gastric Cancer

“…As the P value of FAM3D in TCGA was close to 0.05 and no studies have shown that FAM3D is associated with GC, the relationship between FAM3D and GC was worthy of further study. Studies have shown that OLR1 is positively correlated with lymph node metastasis of GC 34 .…”

A predictive model for assessing prognostic risks in gastric cancer patients using gene expression and methylation data

“…VEGFC has been reported to be a key regulator in GC progression and its encoded protein facilitates angiogenesis and endothelial cell growth. In addition, oxidised low-density lipoprotein (oxLDL) is a risk factor in the pathogenesis of cancers linked to its roles in abnormal lipid metabolism, and has been shown to promote lymphatic metastasis of GC via the up-regulated expression and secretion of VEGFC [ 15 ]. microRNA (miR)-27b acts as a potential tumour suppressor in GC and targets VEGFC expression [ 16 ], while miR-101 promotes cisplatin (DPP)-induced apoptosis partly via its targeting of VEGFC in DDP-resistant GC cells [ 17 ].…”