Yang Yiyuan, Yuan Fengyan, Zhou Huiqin, Quan Jing, Liu Chongyang, Wang Yi, Xiao Fen, Liu Qiao, Liu Jie, Zhang Yujing, Yu Xing
Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China.
J Cell Physiol. 2023 May;238(5):896-917. doi: 10.1002/jcp.30995. Epub 2023 Mar 16.
Heparanase (HPSE; heparanase-1) is an endo-β-glucuronidase capable of degrading the carbohydrate moiety of heparan sulfate proteoglycans, thus modulating and facilitating the remodeling of the extracellular matrix and basement membrane. HPSE activity is strongly associated with major human pathological complications, including but not limited to tumor progress and angiogenesis. Several lines of literature have shown that overexpression of HPSE leads to enhanced tumor growth and metastatic transmission, as well as poor prognosis. Gene silencing of HPSE or treatment of tumor with compounds that block HPSE activity are shown to remarkably attenuate tumor progression. Therefore, targeting HPSE is considered as a potential therapeutical strategy for the treatment of cancer. Intriguingly, recent findings disclose that heparanase-2 (HPSE-2), a close homolog of HPSE but lacking enzymatic activity, can also regulate antitumor mechanisms. Given the pleiotropic roles of HPSE, further investigation is in demand to determine the precise mechanism of regulating action of HPSE in different cancer settings. In this review, we first summarize the current understanding of HPSE, such as its structure, subcellular localization, and tissue distribution. Furthermore, we systematically review the pro- and antitumorigenic roles and mechanisms of HPSE in cancer progress. In addition, we delineate HPSE inhibitors that have entered clinical trials and their therapeutic potential.
乙酰肝素酶（HPSE；乙酰肝素酶-1）是一种内切-β-葡萄糖醛酸酶，能够降解硫酸乙酰肝素蛋白聚糖的碳水化合物部分，从而调节并促进细胞外基质和基底膜的重塑。HPSE活性与主要的人类病理并发症密切相关，包括但不限于肿瘤进展和血管生成。多篇文献表明，HPSE的过表达会导致肿瘤生长增强、转移扩散以及预后不良。HPSE的基因沉默或用阻断HPSE活性的化合物治疗肿瘤可显著减弱肿瘤进展。因此，靶向HPSE被认为是一种潜在的癌症治疗策略。有趣的是，最近的研究发现揭示，乙酰肝素酶-2（HPSE-2）是HPSE的紧密同源物，但缺乏酶活性，也能调节抗肿瘤机制。鉴于HPSE的多效性作用，需要进一步研究以确定HPSE在不同癌症环境中的精确调节作用机制。在这篇综述中，我们首先总结了目前对HPSE的认识，如其结构、亚细胞定位和组织分布。此外，我们系统地综述了HPSE在癌症进展中的促肿瘤和抗肿瘤作用及机制。此外，我们还描述了已进入临床试验的HPSE抑制剂及其治疗潜力。
