Extracellular matrix protein 1 promotes cell metastasis and glucose metabolism by inducing integrin β4/FAK/SOX2/HIF-1α signaling pathway in gastric cancer

Extracellular matrix protein 1 (ECM1) is related to strong invasiveness and poor prognosis in major malignancies, but the underlying mechanism remains unknown. Here we aimed to elucidate the function of ECM1 on cell metastasis and glucose metabolism in gastric cancer (GC). The level of ECM1 in sera and tissues of patient with GC were positively correlated with tumor invasion and recurrence. Genetic manipulation of ECM1 expression affected cell metastasis and glucose metabolism in GC cell lines. Enhanced ECM1 expression facilitated gene expression levels associated with epithelial-mesenchymal transition (EMT) and glucose metabolism. Interestingly, our results indicated that ECM1 directly interacted with integrin beta 4 (ITGB4) and activated ITGB4/focal adhesion kinase (FAK)/glycogen synthase kinase 3 beta signaling pathway, which further induced the expression of transcription factor SOX2. Aberrant expression of SOX2 altered gene expression of EMT factors and glucose metabolism enzymes. Furthermore, SOX2 enhanced hypoxia-inducible factor alpha (HIF-1 alpha) promoter activity to regulate glucose metabolism. The micro-positron emission tomography/computed tomography imaging of xenograft model showed that ECM1 substantially increased F-18-fluorodeoxyglucose uptake in xenograft tumors. Using in vivo mouse tail vein injection experiments, ECM1 was also found to increase in lung surface metastasis. These findings provide evidence that ECM1 regulates GC cell metastasis and glucose metabolism by inducing ITGB4/FAK/SOX2/HIF-1 alpha signal pathway and have important implications for the development of therapeutic target to prevent tumor metastasis and recurrence.