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. Lipid reprogramming is utilized by tumor cells to maintain rapid proliferation, migration, and invasion. Therefore, it is important to investigate novel therapeutic targets and mechanisms in gastric cancer (GC). Methods Clinicopathological data and corresponding immunohistochemistry data were collected to explore the role of SDC4 in patients with GC. Cell progression and lipid reprogramming were assessed using functional experiments, and the molecular mechanisms involved were determined using western blotting. Moreover, cholesterol-induced lipotoxic environments in vivo and in vitro were constructed to explore the underlying positive loop circuit. Results SDC4 expression was upregulated in GC tissues compared to that in normal tissues and was associated with tumor differentiation. GC patients with high SDC4 expression were positively correlated with high circulating tumor cell (CTC) and vascular endothelial growth factor (VEGF) levels. Moreover, SDC4 significantly promotes cell progression by activating transforming growth factor-beta 1 (TGF-β1/TGFB1)-induced lipid synthesis and contributes to a positive loop circuit in GC cells. However, the core of this circuit is dependent on Smad3. In addition, a cholesterol-induced lipotoxic environment further upregulated SDC4 expression by activating the RAS signaling pathway in GC. Conclusions These findings highlight SDC4 as a therapeutic target for GC and identify actionable positive loop circuits.