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

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.(c) 2023 Elsevier Inc. All rights reserved.

Automated summary

Our study shows that FBXW7 loss of function is crucial in esophageal cancer, but its mechanism in promoting the disease remains unclear. By screening in esophageal squamous cell carcinoma (ESCC), we identified ANXA2 as a potential target of FBXW7. In vitro experiments demonstrated that FBXW7 loss of function could restore ANXA2 expression and enhance the malignant characteristics of ESCC cells. Additionally, ANXA2 up-regulation was found to activate the ERK pathway in ESCC. Moreover, we observed high expression of ANXA2 in ESCC tissues, which was associated with poor tumor staging. Furthermore, a combination regimen targeting ANXA2 and the ERK pathway showed promising inhibitory effects on xenograft tumor growth in vivo. Overall, this study provides evidence that FBXW7 loss of function promotes esophageal cancer through ANXA2 overexpression, suggesting a potential target for ESCC treatment.