Overexpression of Annexin A2 promotes proliferation by forming a Glypican 1/c-Myc positive feedback loop: prognostic significance in human glioma

Xin Li,Jiajia Liu,Yuxi Song,Shengdan Nie,Gaoya Zhou,Ziyang Lv,Xin Hu,Zhongxu Hu,Zhiqiang Liu,Shan Wang,Zhijie Dai,Tao Song,Lingran Ma

doi:10.1038/s41419-021-03547-5

Abstract

In order to set up a reliable prediction system for the tumor grade and prognosis in glioma patients, we clarify the complicated crosstalk of Annexin A2 (ANXA2) with Glypican 1 (GPC1) and demonstrate whether combined indexes of ANXA2 and GPC1 could improve the prognostic evaluation for glioma patients. We found that ANXA2-induced glioma cell proliferation in a c-Myc-dependent manner. ANXA2 increased the expression of GPC1 via c-Myc and the upregulated GPC1 further promoted the c-Myc level, forming a positive feedback loop, which eventually led to enhanced proliferation of glioma cells. Both mRNA and protein levels of ANXA2 were upregulated in glioma tissues and coincided with the overexpression of GPC1. Besides, we utilized tissue microarrays (TMAs) and immunohistochemistry to demonstrate that glioma patients with both high expression of ANXA2 and GPC1 tended to have higher rate of tumor recurrence and shorter overall survival (OS). In conclusion, the overexpression of ANXA2 promotes proliferation of glioma cells by forming a GPC1/c-Myc positive feedback loop, and ANXA2 together with its downstream target GPC1 could be a potential “combination biomarker” for predicting prognosis of glioma patients.

Highlights

Glioma, with varying grades of malignancy, is the most common primary brain tumor[1,2]
We found that Annexin A2 (ANXA2) increased the expression of Glypican 1 (GPC1) via c-Myc and that the upregulated GPC1 further promoted the c-Myc level, forming a positive feedback loop, which eventually led to enhanced proliferation of glioma cells
The levels of Ki67, PCNA, and c-Myc were correspondingly enhanced. All these increases could be effectively reversed by a specific inhibitor of c-Myc, 10058-F4 (Fig. 1E–H), indicating that c-Myc is a key modulator in ANXA2-induced glioma cell proliferation

Summary

Introduction

With varying grades of malignancy, is the most common primary brain tumor[1,2]. Researchers have identified various proliferation-associated biomarkers as prognostic indicators for glioma patients[5,6,7], such as Par[6], chromobox protein homolog 3 (CBX3) and nucleolar and spindle-associated protein 1 (NUSAP1), Glypicans (GPCs), a family of heparan sulfate proteoglycans (HSPGs), are anchored to the external surface of the plasma membrane by a glycosylphosphatidylinositol anchor[8,9,10]. Six members of this family (GPC1–6) have been identified[11,12]. It was reported that overexpression of GPC1 in U87 glioma cells enhanced FGF-2-stimulated

Methods

Results

Conclusion