Effect of metastasis associated in colon cancer-1 on vasculogenic mimicry formation in patients with gastric cancer.

e15052 Background: Vasculogenic mimicry (VM) as a blood supplyment pattern is strongly associated with tumor progression. In a previous study, metastasis-associated in colon cancer-1 (MACC1) upregulation predicted a poor prognosis of gastric cancer (GC), and induced epithelial mesenchymal transition (EMT). Recent studies showed that EMT is a key step for VM. The aim of this study was to identify whether both VM and MACC1 expression predict worse clinical outcome, and to explore how MACC1 regulate VM in GC. Methods: Using immunohistochemistry, we analysed both VM and MACC1 expression with clinicopathologically characterised 88 stage IV GC patients. We studied the roles of MACC1 on VM formation in animal models of athymic mice. RNA interference and 3D culture assay were conducted to investigate the effects of Twist1 and Twist2 on MACC1-induced VM in GC cells. Using luciferase reporter gene and co-ip assay, we analysed the effects of MACC1/Twist1 complex on Twist2 promoter activity and some key downstream genes during VM formation. Results: VM positivity was more frequent with differentiation (p=0.018), metastasis (p=0.025) and MACC1 expression (p=0.048) in GC patients. Survival analysis revealed that the three-year survival rate was 8.6% in both VM and MACC1 expression group, whereas 41.7% in non-VM and without MACC1 expression group, and the median survival time was 3.3 versus 32 months. Moreover, MACC1 upregulation was closely correlated with Twist1 (p=0.016) and Twist2 (p=0.001) in GC tissues, which also caused VM formation in animal models. In vitro study demonstrated that MACC1 induced typical pipe-like structures in a 3D culture system, and increased the expression of Twist1 and Twist2 in mRNA and protein levels. RNA interference-mediated silencing of Twist1 or Twist2 inhibited VM formation. MACC1/Twist1 complex enhanced Twist2 promoter activity and transcriptional activation of multiple downstream genes that increased VM, which partially via HGF/c-MET signaling pathway. Conclusions: These findings indicated a novel function for MACC1 in VM formation, and MACC1/Twist1 complex may play a significant role in promoting tumor progression and VM in GC partially through HGF/c-MET pathway.