Research On The Molecular Mechanism Of The Function Of Secreted Hsp90α On Tumorigenesis And Metastasis

Heat shock protein 90-α(Hsp90α) is an intracellular molecular chaperone. It functions to maintain the normal protein folding environment and promote the cell survival under stress conditions. In tumor cells, the chaperoning activity of Hsp90αis subverted to retain the functions of mutant proteins and thus facilitate the malignant transformation. Meanwhile, Hsp90αcan also be secreted by tumor cells, but the functions of this extracellular form remains far from clear. Therefore, my study focuses on the functions of secreted Hsp90αon tumor cells and the underlying mechanisms. We demonstrate that secreted Hsp90αcan promote tumor invasiveness and is highly correlated with tumor malignancy. The blockage of secreted Hsp90αresults in significant inhibition on tumor invasion and complete prevention of lymph node metastasis. In addition, the level of plasma Hsp90αis positively correlated with tumor malignancy in cancer patients, indicating it is a potential diagnostic marker for tumor malignancy in clinical application.Since we found that the secreted Hsp90αis highly correlated with tumor malignancy, we next investigated the mechanism behind this phenomenon. It is reported that secreted Hsp90αinteracts with MMP-2 and the inhibition of extracellular Hsp90αreduces the activity of MMP-2. In the present study, by the means of over-expressing, knocking down and also antibody blockage, we demonstrate that the pro-invasiveness activity of extracellular Hsp90αis dependent on MMP-2. But the regulatory mechanism of Hsp90αon the activity of MMP-2 is still unknown. We find that Hsp90αcan stabilize MMP-2 and prevent the proteolytic processing of MMP-2 via directly binding to the hemopexin domain. We further demonstrated that Hsp90αcan be secreted by endothelial cells and is a positive regulator of angiogenesis. Moreover, the antibody of Hsp90αpromotes MMP-2 processing and thus retards the angiogenesis and tumor invasiveness in vitro and in vivo.In sum, here we reveal that secreted Hsp90αfunctions as a pro-invasiveness factor extracellularly and its level in plasma is positively correlated with the tumor malignancy, especially tumor metastasis. Meanwhile, we demonstrate that extracellular Hsp90αstabilizes MMP-2 and prevent its proteolytic processing via binding to the hemopexin domain, providing novel mechanistic explanations for both the function of extracellular Hsp90αand the regulatory mechanism of MMP-2 activity.