Regorafenib inhibited gastric cancer cells growth and invasion via CXCR4 activated Wnt pathway

AimRegorafenib is an oral small-molecule multi kinase inhibitor. Recently, several clinical trials have revealed that regorafenib has an anti-tumor activity in gastric cancer. However, only part of patients benefit from regorafenib, and the mechanisms of regorafenib’s anti-tumor effect need further demonstrating. In this study, we would assess the potential anti-tumor effects and the underlying mechanisms of regorafenib in gastric cancer cells, and explore novel biomarkers for patients selecting of regorafenib.MethodsThe anti-tumor effects of regorafenib on gastric cancer cells were analyzed via cell proliferation and invasion. The underlying mechanisms were demonstrated using molecular biology techniques.ResultsWe found that regorafenib inhibited cell proliferation and invasion at the concentration of 20μmol/L and in a dose dependent manner. The anti-tumor effects of regorafenib related to the decreased expression of CXCR4, and elevated expression and activation of CXCR4 could reverse the inhibition effect of regorafenib on gastric cancer cells. Further studies revealed that regorafenib reduced the transcriptional activity of Wnt/β-Catenin pathway and led to decreased expression of Wnt pathway target genes, while overexpression and activation of CXCR4 could attenuate the inhibition effect of regorafenib on Wnt/β-Catenin pathway.ConclusionsOur findings demonstrated that regorafenib effectively inhibited cell proliferation and invasion of gastric cancer cells via decreasing the expression of CXCR4 and further reducing the transcriptional activity of Wnt/β-Catenin pathway.

瑞戈非尼（regorafenib）是一种口服小分子多激酶抑制剂。近期多项临床试验表明，瑞戈非尼对胃癌具有抗肿瘤活性。然而，仅部分患者可从瑞戈非尼治疗中获益，其抗肿瘤作用机制尚待进一步阐明。本研究旨在评估瑞戈非尼对胃癌细胞的潜在抗肿瘤效应及其潜在作用机制，并探索可用于指导瑞戈非尼治疗患者筛选的新型生物标志物。
方法：本研究通过细胞增殖与侵袭实验分析瑞戈非尼对胃癌细胞的抗肿瘤效应，并采用分子生物学技术阐明其潜在作用机制。
结果：本研究发现，20μmol/L浓度的瑞戈非尼即可抑制胃癌细胞的增殖与侵袭，且该抑制作用呈剂量依赖性。瑞戈非尼的抗肿瘤效应与CXCR4表达下调相关；CXCR4的过表达与激活可逆转瑞戈非尼对胃癌细胞的抑制作用。进一步研究显示，瑞戈非尼可降低Wnt/β-连环蛋白（Wnt/β-Catenin）通路的转录活性，下调该通路靶基因的表达；而CXCR4的过表达与激活可减弱瑞戈非尼对Wnt/β-连环蛋白通路的抑制效应。
结论：本研究结果证实，瑞戈非尼可通过下调CXCR4的表达，进一步降低Wnt/β-连环蛋白通路的转录活性，从而有效抑制胃癌细胞的增殖与侵袭。