Upregulation of Serine Proteinase Inhibitor Clade B Member 3 (SERPINB3) Expression by Stromal Cell-Derived Factor (SDF-1)/CXCR4/Nuclear Factor kappa B (NF-κB) Promotes Migration and Invasion of Gastric Cancer Cells.

BACKGROUND Serine proteinase inhibitor clade B member 3 (SERPINB3) is a neutral glycoprotein. Its overexpression is related to the promotion of cell proliferation and activation via the nuclear factor kappa B (NF-kappaB) pathway in several tumors. Whether it can participate in stromal cell-derived factor (SDF-1)/NF-kappaB-induced metastasis of gastric cancer has not been reported. MATERIAL AND METHODS We analyzed the ability of SDF-1 to induce migration and invasion in vitro by knocking down the expression of SERPINB3 with siRNAs in gastric cancer cells. We also explored the effects of a CXCR4 antagonist and NF-kappaB inhibitor on SERPINB3 expression. We verified the effect of SERPINB3 on prognosis in gastric cancer specimens by immunohistochemistry. RESULTS In vitro experiments confirmed that SDF-1 upregulated the expression of SERPINB3 and promoted metastasis in gastric cancer cells. This phenomenon was reversed by knockdown of SERPINB3, a chemokine receptor 4 (CXCR4) antagonist, and an NF-kappaB inhibitor, which downregulated the expression of SERPINB3. In patients with gastric cancer, a significant positive correlation was observed between CXCR4 and SERPINB3 expression (r=0.222, P=0.029). Moreover, double positivity for SERPINB3 and CXCR4 was certified to be an independent prognostic factor (HR=3.332, P<0.001). CXCR4-positive patients who also expressed SERPINB3 were inclined to suffer from lymph node metastasis, confirming that SERPINB3 is a downstream molecule of CXCR4. CONCLUSIONS In vitro and pathological results showed that SDF-1/CXCR4 activated the NF-kappaB pathway and upregulated SERPINB3 to facilitate the migration and invasion of gastric cancer cells.