Apolipoprotein C‐II induces EMT to promote gastric cancer peritoneal metastasis via PI3K/AKT/mTOR pathway

Abstract

Background Peritoneal 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. Methods Tandem 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. Results APOC2 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. Conclusion APOC2 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.

Tumor metastasis: Mechanistic insights and therapeutic interventions

“…More and more molecules regulating lipid metabolism have been proved to promote tumor metastasis by regulating EMT, including apolipoprotein C, sterol regulatory element‐binding transcription protein 1, stromal‐interaction molecule 1, human hydroxysteroid dehydrogenase‐like 2, and cytosolic phospholipase A2α. 243 , 244 , 245 , 246 In triple‐negative breast cancer, nicotinamide adenine dinucleotide phosphate (NADP) steroid dehydrogenase‐like (NSDHL), a cholesterol metabolic enzyme, has been reported to be a potential metastatic driver. 247 The functions of NSDHL rely on its enzyme activity in the biosynthesis of cholesterol and is mediated by the NSDHL‐TGFβR2 signaling pathway.…”

Stanniocalcin 1 promotes metastasis, lipid metabolism and cisplatin chemoresistance via the FOXC2/ITGB6 signaling axis in ovarian cancer

“…The PI3K signaling pathway has long been a focus of interest in cancer due to its role in cancer cell proliferation, migration and metabolism. It is also related to lipid metabolism in many cancers such as gastric cancer [ 57 ], hepatocellular carcinoma [ 58 ] and breast cancer [ 59 ]. Recent reports have showed that the activation of the PI3K signaling pathway is linked to lipid synthesis [ 43 ] and lipid droplet accumulation [ 60 ] in OC.…”

Identification of Immune Subtypes of Esophageal Adenocarcinoma to Predict Prognosis and Immunotherapy Response

“…In addition, overexpression of TNFAIP6 was also found to increase with tumor invasion and lymph node metastasis in gastric cancer [ 44 ]. Apolipoprotein C2 (APOC2) is a lipoprotein lipase activator involved in fatty acid metabolism [ 45 ]. Most differentially expressed lncRNAs, such as AL121906.2 [ 46 ], AC092910.3 [ 47 ], AC005332.4 [ 48 ], and CASC9 [ 49 ], were upregulated in EAC subtype 1 and had been previously reported as prognostic biomarkers in multiple tumors.…”