Heparanase is highly implicated in tumor metastasis due to its capacity to cleave heparan sulfate and, consequently, remodel the extracellular matrix underlying epithelial and endothelial cells. In striking contrast, only little attention was given to its close homolog, heparanase 2 (Hpa2), possibly because it lacks heparan sulfate-degrading activity typical of heparanase. We subjected sections of gastric carcinoma to immunostaining and correlated Hpa2 immunoreactivity with clinical records, including tumor grade, stage and patients' status. We over-expressed Hpa2 in gastric carcinoma cell lines and examined their tumorigenic properties in vitro and in vivo. We also evaluated the expression of Hpa2 by gastric carcinoma cells following inhibition of the proteasome, leading to proteotoxic stress, and the resulting signaling responsible for Hpa2 gene regulation. Here, 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. 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. These results indicate that high levels of Hpa2 in some tumors are due to stress conditions that tumors often experience due to their high rates of cell proliferation and high metabolic demands. This increase in Hpa2 levels by the stressed tumors appears critically important for patient outcomes.

乙酰肝素酶与肿瘤转移高度相关，因为它具有裂解硫酸乙酰肝素的能力，因此可以重塑上皮细胞和内皮细胞下的细胞外基质。与之形成鲜明对比的是，它的密切同源物乙酰肝素酶 2 (Hpa2) 几乎没有受到关注，这可能是因为它缺乏乙酰肝素酶典型的硫酸乙酰肝素降解活性。我们对胃癌切片进行免疫染色，并将 Hpa2 免疫反应性与临床记录相关联，包括肿瘤分级、分期和患者状态。我们在胃癌细胞系中过表达 Hpa2，并在体外和体内检测了它们的致瘤特性。我们还评估了抑制蛋白酶体后胃癌细胞对 Hpa2 的表达，导致蛋白质毒性应激，以及由此产生的负责 Hpa2 基因调控的信号传导。在这里，我们报告表现出高水平 Hpa2 的胃癌患者存活时间更长。类似地，给予过度表达Hpa2的胃癌细胞的小鼠产生的肿瘤更小，并且比给予对照细胞的小鼠存活时间更长。这与 AMP 活化蛋白激酶 (AMPK) 的磷酸化增加有关，AMPK 是一种位于肿瘤抑制网络中心的激酶。我们还发现 MG132 是一种导致蛋白毒性应激的蛋白酶体抑制剂，显着增强了 Hpa2 的表达。值得注意的是，MG132 对 Hpa2 的诱导似乎是由 AMPK 介导的，并且发现 AMPK 诱导 Hpa2 的表达，从而建立了一个自给自足的环，其中 Hpa2 增强了 AMPK 磷酸化，进而，诱导 Hpa2 表达，导致胃肿瘤发生减弱。这些结果表明，某些肿瘤中的高水平 Hpa2 是由于肿瘤由于其高细胞增殖率和高代谢需求而经常经历的压力条件。受压肿瘤导致的 Hpa2 水平升高似乎对患者预后至关重要。