Syndecan-4 promotes gastric cancer progression through activating TGF-β1 induced lipid reprogramming and contributes positive loop circuits.

BACKGROUND: Syndecan-4 (SDC4) plays a pivotal role in tumorigenesis through cell signaling, adhesion and matrix interactions. Lipid reprogramming is a core strategy for malignant tumors to drive progression and invasion through reshaping immunity, stromal and vascular ecology in microenvironment. However, the regulatory mechanism of SDC4 in lipid reprogramming has not yet been elucidated. Therefore, it is important to investigate underlying mechanisms and develop novel therapeutic targets for gastric cancer (GC). METHODS: Clinicopathological data and corresponding immunohistochemistry were collected to explore the role of SDC4 in patients with GC. Functional experiments were performed to assess tumor progression and lipid reprogramming. Moreover, western blot assay was performed to verify the molecular mechanisms. In addition, cholesterol-induced lipotoxic environments both in vivo and in vitro were constructed to explore the underlying positive loop circuit. RESULTS: SDC4 expression was upregulated in tumor tissues compared to normal gastric tissues and was associated with differentiation grades. Patients with high SDC4 expression were positively correlated with high circulating tumor cell (CTC) levels, vascular endothelial growth factor (VEGF) levels and poor prognosis. Moreover, SDC4 significantly promoted tumor progression by activating transforming growth factor-beta 1 (TGF-β1/TGFB1)-induced lipid reprogramming and contributed a positive loop circuit in GC cells. However, the core of this circuit was dependent on Smad3. In addition, a cholesterol-induced lipotoxic environment upregulated SDC4 expression by activating the RAS signaling pathway and further indicated a positive loop circuit between SDC4 and lipid reprogramming in GC. CONCLUSIONS: These findings highlight SDC4 as a therapeutic target for GC and identify actionable positive loop circuits.