Abstract
Metastasis is the major cause of poor survival and therapeutic failure in gastric cancer (GC). However, the molecular mechanisms underlying GC metastasis remain unclear. Here, we analyzed the expression patterns of sex determining region Y-box 12 (SOX12) in two independent cohorts of paired GC tissues and adjacent nontumor tissues and conducted in vitro and in vivo functional studies to determine the role of SOX12 in GC cells. High SOX12 expression in GC tissues was associated with increased frequency of recurrence and poorer patient survival. SOX12 overexpression increased GC cell migration, invasion and metastasis, whereas SOX12 downregulation decreased these behaviors. Reporter assays revealed that matrix metallopeptidase 7 (MMP7) and insulin-like growth factor 1 (IGF1) are transcriptional targets of SOX12 and indicated their requirement for SOX12-mediated GC metastasis. IGF1 induced SOX12 expression via the PI3K/AKT/CREB pathway, forming an IGF1/CREB/SOX12 feedback loop that contributed to GC metastasis. SOX12 expression correlated with MMP7 and IGF1 expression in GC tissues, and patients expressing SOX12 and either MMP7 or IGF1 had higher metastasis and recurrence rates and shorter survival than patients without that expression pattern. In conclusion, SOX12 is a novel prognostic biomarker and regulator of GC metastasis.