Role of heparanase 2 (Hpa2) in gastric cancer

Abstract

BackgroundHeparanase is highly implicated in tumor metastasis due to its capacity to cleave heparan sulfate (HS) and, consequently, remodel the extracellular matrix (ECM) underlying epithelial and endothelial cells. In striking contrast, only little attention was given to its close homolog, heparanase 2 (Hpa2), possibly because it lacks HS-degrading activity typical of heparanase. MethodsWe combined clinical, in vivo and in vitro studies to reveal the role of Hpa2 in gastric cancer. ResultsHere, we report that gastric cancer patients exhibiting high levels of Hpa2 survive longer. Similarly, mice administrated with gastric carcinoma cells engineered to over-express Hpa2 produced smaller tumors and survived longer than mice administrated with control cells. This was associated with increased phosphorylation of AMP-activated protein kinase (AMPK), a kinase that is situated at the center of a tumor suppressor network known to attenuate the growth of various types of cancer including gastric cancer. We also found that MG132, an inhibitor of the proteasome that results in proteotoxic stress, prominently enhances Hpa2 expression. Notably, Hpa2 induction by MG132 appeared to be mediated by AMPK, and AMPK was found to induce the expression of Hpa2, thus establishing a loop that feeds itself where Hpa2 enhances AMPK phosphorylation that, in turn, induces Hpa2 expression, leading to attenuation of gastric tumorigenesis. ConclusionsThese results indicate that high levels of Hpa2 in some tumors but not in others are due to stress conditions that tumors often experience due to their high rates of cell proliferating, high metabolic demands, and changes in the tumor microenvironment. This increase in Hpa2 levels by the stressed tumors appears critically important for the patient's outcome.