School of Biomedical Engineering (Suzhou), Division of Life Science and Technology, University of Science and Technology of China, Hefei, 230026, China; Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, 215163, China.
Department of Pharmacy, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, 215007, China.
Biochem Biophys Res Commun. 2023 Mar 15;649:93-100. doi: 10.1016/j.bbrc.2023.01.082. Epub 2023 Jan 27.
Our recent study suggests that FBXW7 loss of function plays a critical function in esophageal cancer. However, the mechanism of FBXW7 in promoting esophageal cancer is still unclear. Here, we explored the interaction protein of FBXW7 by screening of GST-pulldown and LC-MS/MS analysis in esophageal squamous cell carcinoma (ESCC) and identified ANXA2 as a potential target of FBXW7. FBXW7 loss of function could restore the expression of ANXA2 and promote the malignant biological characteristics of ESCC cells in vitro. Up-regulation of ANXA2 enhances the ERK pathway in ESCC. Furthermore, the 23rd tyrosine residue of ANXA2, phosphorylated by SRC, was regarded as playing important roles in the FBXW7-related degradation system. In clinical samples, we found that ANXA2 had high expression in ESCC tissues. High ANXA2 was associated with poor tumor staging. More importantly, we designed a combination regimen including SCH779284, a clinical ERK inhibitor against the phosphorylation of EKR and siRNA targeting ANXA2 by intratumor injection, and it produced potent inhibitory effects on the growth of xenograft tumors in vivo. In conclusion, this study provided evidence that FBXW7 loss of function could promote esophageal cancer through ANXA2 overexpression, and this novel regulation pathway may be used as an efficient target for ESCC treatment.
我们最近的研究表明，FBXW7 功能丧失在食管癌中起着关键作用。然而，FBXW7 促进食管癌的机制仍不清楚。在这里，我们通过 GST-pulldown 和 LC-MS/MS 分析筛选出 FBXW7 的互作蛋白，鉴定 ANXA2 为 FBXW7 的潜在靶标。FBXW7 功能丧失可以恢复 ANXA2 的表达，并促进 ESCC 细胞的体外恶性生物学特征。ANXA2 的上调增强了 ESCC 中的 ERK 通路。此外，SRC 磷酸化的 ANXA2 的第 23 个酪氨酸残基被认为在 FBXW7 相关降解系统中发挥重要作用。在临床样本中，我们发现 ANXA2 在 ESCC 组织中高表达。高表达的 ANXA2与肿瘤分期不良相关。更重要的是，我们设计了一种联合方案，包括 SCH779284（一种针对 ERK 磷酸化的临床 ERK 抑制剂）和针对 ANXA2 的 siRNA 通过瘤内注射，它在体内对异种移植肿瘤的生长产生了强大的抑制作用。总之，这项研究提供了证据表明，FBXW7 功能丧失可以通过 ANXA2 过表达促进食管癌的发生，这种新的调控途径可能被用作 ESCC 治疗的有效靶点。
