Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Department of Gynecology and Obstetrics, Münster University Hospital, Münster, Germany.
Adv Exp Med Biol. 2020;1221:97-135. doi: 10.1007/978-3-030-34521-1_4.
The cell surface heparan sulfate proteoglycan Syndecan-1 acts as an important co-receptor for receptor tyrosine kinases and chemokine receptors, and as an adhesion receptor for structural glycoproteins of the extracellular matrix. It serves as a substrate for heparanase, an endo-β-glucuronidase that degrades specific domains of heparan sulfate carbohydrate chains and thereby alters the functional status of the proteoglycan and of Syndecan-1-bound ligands. Syndecan-1 and heparanase show multiple levels of functional interactions, resulting in mutual regulation of their expression, processing, and activity. These interactions are of particular relevance in the context of inflammation and malignant disease. Studies in animal models have revealed a mechanistic role of Syndecan-1 and heparanase in the regulation of contact allergies, kidney inflammation, multiple sclerosis, inflammatory bowel disease, and inflammation-associated tumorigenesis. Moreover, functional interactions between Syndecan-1 and heparanase modulate virtually all steps of tumor progression as defined in the Hallmarks of Cancer. Due to their prognostic value in cancer, and their mechanistic involvement in tumor progression, Syndecan-1 and heparanase have emerged as important drug targets. Data in preclinical models and preclinical phase I/II studies have already yielded promising results that provide a translational perspective.
细胞表面硫酸乙酰肝素蛋白聚糖连接蛋白-1 作为受体酪氨酸激酶和趋化因子受体的重要共受体，以及细胞外基质结构糖蛋白的黏附受体发挥作用。它可作为内切-β-葡糖醛酸酶（heparanase）的底物，后者可降解硫酸乙酰肝素碳水化合物链的特定结构域，从而改变蛋白聚糖和连接蛋白-1 结合配体的功能状态。连接蛋白-1 和肝素酶之间存在多种功能相互作用，导致它们的表达、加工和活性相互调节。这些相互作用在炎症和恶性疾病的背景下具有特殊的意义。动物模型研究揭示了连接蛋白-1 和肝素酶在调节接触过敏、肾脏炎症、多发性硬化、炎症性肠病和炎症相关肿瘤发生中的机制作用。此外，连接蛋白-1 和肝素酶之间的功能相互作用调节了癌症定义的几乎所有肿瘤进展步骤。由于它们在癌症中的预后价值及其在肿瘤进展中的机制参与，连接蛋白-1 和肝素酶已成为重要的药物靶点。临床前模型和临床 I/II 期研究的数据已经产生了有前景的结果，提供了转化的视角。
