Extracellular Hsp90α clinically correlates with tumor malignancy and promotes migration and invasion in esophageal squamous cell carcinoma

Purpose: Extracellular Hsp90 alpha (eHsp90 alpha) is known to be involved in tumor invasiveness and metastasis, and its prognostic value in many kinds of tumors has been identified. We aimed to evaluate the clinical and functional role of eHsp90 alpha in esophageal squamous cell carcinoma (ESCC). Patients and methods: A total of 193 patients with newly diagnosed ESCC were retrospectively evaluated. The relationship between serum Hsp90 alpha levels before treatment and ESCC malignancy of the patients was analyzed. To test the role of eHsp90 alpha in migration and invasion of ESCC cell lines, transwell assay was performed. Western blotting was used to explore the possible mechanism in which eHsp90 alpha promotes ESCC migration and invasion. Results: We found that the serum Hsp90 alpha level before treatment is positively correlated with ESCC malignancy. Moreover, high serum Hsp90 alpha level before treatment was significantly correlated with positive lymph node (LN) metastasis, which is the main prognostic factor for ESCC patients. Meanwhile, we demonstrated that eHsp90 alpha promoted migration and invasion of ECA109 and ECA9706 in vitro. Further investigations revealed that eHsp90 alpha stabilized MMP-2 and promoted epithelial-to-mesenchymal transition evidenced by downregulation of E-cadherin and upregulation of N-cadherin. On the other hand, Hsp90 alpha neutralizing antibody functionally blocked the secreted Hsp90 alpha and reversed those effects. Conclusion: Our findings prove the critical role of eHsp90 alpha in promoting ESCC migration and invasion, indicating it can be not only a promising predictor for ESCC LN status, but also an effective target in ESCC therapeutics, especially in preventing LN metastasis.