Abstract
BackgroundGastric cancer (GC) has a clear predilection for metastasis toward the omentum which is primarily composed of adipose tissue, indicating that fatty acids may contribute to this phenomenon. However their function remains poorly understood in GC. In this study, we investigated the role of palmitate acid (PA) and its cellular receptor CD36 in the progression of GC.MethodsImmunohistochemical (IHC) staining was performed to detect CD36 expression in GC tissues and its clinical significance was determined statistically. CD36 over-expression and knock-down expression cell models were developed and tested in vitro. Wound-healing assays, migration assays, and invasion assays were performed and peritoneal implants into nude mice were done to assess the biological effects of PA and CD36. The underlying mechanisms were investigated using western blot, immunofluorescence (IF), quantitative real-time PCR (qRT-PCR) and antibody blocking assays.ResultsPA promoted the metastasis of GC by phosphorylation of AKT, which facilitated the nuclear localization of β-catenin through inactivation of GSK-3β via phosphorylation. This tumor-promoting effect of PA was mediated by CD36, a cell surface receptor of fatty acids (FAs). The higher the CD36 expression levels in GC tissues correlated with the poorer the prognosis of patients according to the TCGA database, the GEO database and our own clinical data.ConclusionsOur experiments established CD36 as a key mediator of FA-induced metastasis of GC via the AKT/GSK-3β/β-catenin signaling pathway. CD36 might, therefore, constitute a potential therapeutic target for clinical intervention in GC.
Highlights
Gastric cancer (GC) has a clear predilection for metastasis toward the omentum which is primarily composed of adipose tissue, indicating that fatty acids may contribute to this phenomenon
CD36 is highly expressed in human GC tissues and associated with GC TNM staging and poor prognosis To understand the role of CD36 in GC metastasis, we measured CD36 expression in GC tissues by IHC, and analyzed the relationship between the level of CD36 in GC tissues and patients’ clinico-pathological characteristics
We further validated these results using the the cancer genome atlas (TCGA) database which showed that the expression level of CD36 in tumor tissues was significantly associated with depth of local tumor invasion and higher TNM stage of GC, and with lymph node involvement (Fig. 1h, i and j)
Summary
Gastric cancer (GC) has a clear predilection for metastasis toward the omentum which is primarily composed of adipose tissue, indicating that fatty acids may contribute to this phenomenon. Their function remains poorly understood in GC. We investigated the role of palmitate acid (PA) and its cellular receptor CD36 in the progression of GC. Fatty acid (FA) metabolism has recently been reported to play a vital role in the initiation and progression of multiple types of cancer both in vitro and in vivo [4,5,6].
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