Abstract
BackgroundPeritoneal metastasis (PM) occurs frequently in patients with gastric cancer (GC) and confers poor survival. Lipid metabolism acts as a non‐negligible regulator in epithelial–mesenchymal transition (EMT), which is crucial for the metastasis of GC. As apolipoprotein C2 (APOC2) is a key activator of lipoprotein lipase for triglyceride metabolism, the exact mechanism of APOC2 remains largely unknown in GC.MethodsTandem mass tags identified differentially expressed proteins between human PM and GC tissues, and showed that APOC2 overexpressed in PM tissues, which was further confirmed by immunoblotting, immunohistochemistry, and ELISA. Global gene expression changes were identified in APOC2 knockdown cells via RNA‐sequencing. The role of APOC2 in lipid metabolism of GC cells was assessed via the Seahorse XF analyzer and lipid staining assays. The biological role of APOC2 in GC cells was determined by 3D Spheroid invasion, apoptosis, colony formation, wound healing, transwell assay, and mouse models. The interaction between APOC2 and CD36 was analyzed by co‐immunoprecipitation and biolayer interferometry. The underlying mechanisms were investigated using western blot technique.ResultsAPOC2 overexpressed in GC PM tissues. Upregulation of APOC2 correlated with a poor prognosis in GC patients. APOC2 promoted GC cell invasion, migration, and proliferation via CD36‐mediated PI3K/AKT/mTOR signaling activation. Furthermore, APOC2‐CD36 axis upregulated EMT markers of GC cells via increasing the phosphorylation of PI3K, AKT, and mTOR. Knockdown either APOC2 or CD36 inhibited the malignant phenotype of cancer cells, and delayed GC PM progression in murine GC models.ConclusionAPOC2 cooperates with CD36 to induce EMT to promote GC PM via PI3K/AKT/mTOR pathway. APOC2‐CD36 axis may be a potential target for the treatment of aggressive GC.
Highlights
Peritoneal metastasis (PM) occurs frequently in patients with gastric cancer (GC) and confers poor survival
GC and PM types have not been compared systematically at the tissue proteomic level, and the differentiation between PM and primary GC is of fundamental clinical importance for therapeutic stratification; we explored the possibility of identifying biomarkers for proteomic diagnosis
Apolipoprotein C-II (APOC2) knockdown markedly inhibited the TC (Fig. 3I, 3J) and TG (Fig. 3K, 3L) synthesis in GC cells. These results suggested that APOC2 plays a key role in lipid metabolism and transportation, we speculated that regulating its expression in GC cells would affect their bioenergetic profile
Summary
Peritoneal metastasis (PM) occurs frequently in patients with gastric cancer (GC) and confers poor survival. Lipid metabolism and epithelial-mesenchymal transition (EMT) play an important role in GC metastasis. As Apolipoprotein C-II (APOC2) is a key protein in lipid metabolism, few studies have investigated the role of APOC2 in PM. This study aims to elucidate the potential molecular mechanism of APOC2 in the PM of GC. Gastric cancer (GC) is a major health problem worldwide, especially in China. It ranks third in cancer related deaths worldwide and is associated with huge health costs and patient pain, especially in eastern Asia, mainly because of the high incidence of recurrence and metastasis [1, 2]. In-depth mechanistic research is required to discover the driving factors of PM and develop an effective treatment
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