ANXA2 as a novel substrate of FBXW7 promoting esophageal squamous cell carcinoma via ERK phosphorylation

Zongfei Li  ¹ , Yunzhi Pan  ² , Jiayi Yao  ³ , Yingyin Gao  ⁴ , Yulan Qian  ⁵ , Minxue Zheng  ⁶ , Sai Ma  ⁷

Affiliations

Affiliations

• ¹ 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.
• ² Department of Pharmacy, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, 215007, China.
• ³ The First Affiliated Hospital of Suzhou University, Suzhou, 215000, China.
• ⁴ Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Traditional Chinese Medicine, Nanjing, 210023, China.
• ⁵ Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
• ⁶ 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. Electronic address: minxue.zheng@sibet.ac.cn.
• ⁷ Gusu School, Nanjing Medical University, Suzhou, 215008, China; Department of Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215008, China. Electronic address: marseillems@outlook.com.

• PMID: 36758484
• DOI: 10.1016/j.bbrc.2023.01.082

Abstract

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.

Keywords: ANXA2; ERK; Esophageal squamous cell carcinoma (ESCC); FBXW7; Ubiquitination.