Overexpression of Annexin A2 Promotes Proliferation by Forming a Glypican 1 / c-Myc Positive Feedback Loop: Prognostic Significance in Human Glioma

Abstract

Background: Glioma, with varying malignancy grades, is the most common primary brain tumor. It is urgent to set up a reliable prediction system for the tumor grade and prognosis in glioma patients. We aimed to 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.Methods: The role of ANXA2 and GPC1 in proliferation and their relationship were validated in glioma cells. 164 glioma samples were analyzed for association between co-expression of ANXA2 and GPC1 and patient clinicopathological features and prognosis. Results: We found that ANXA2 induced glioma cellular 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 quantitative reverse transcription-polymerase chain reaction (qRT-RCR) and immunohistochemistry revealed that ANXA2 was upregulated in glioma tissues and coincided with the overexpression of GPC1. Glioma patients with high both ANXA2 and GPC1 tended to have higher rate of tumor recurrence and shorter overall survival (OS). Multivariate analyses revealed that the combination of ANXA2 and GPC1 was an independent prognostic indicator for time to recurrence and OS. Conclusions: The overexpression of ANXA2 promotes proliferation by forming a GPC1/c-Myc positive feedback loop, and ANXA2 and its downstream target GPC1 could be a potential “combination biomarker” for predicting prognosis of glioma.