Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, USA.
Am J Pathol. 2011 Jun;178(6):2866-78. doi: 10.1016/j.ajpath.2011.02.017.
Differential expression of secretory leukocyte protease inhibitor (SLPI) impacts on tumor progression. SLPI directly inhibits elastase and other serine proteases, and regulates matrix metalloproteinases, plasminogen activation, and plasmin downstream targets to influence invasion. We examined tissues from human oral squamous cell carcinoma (OSCC) for SLPI expression in parallel with proteases associated with tumor progression and evaluated their relationships using tumor cell lines. Significantly decreased SLPI was detected in OSCC compared to normal oral epithelium. Furthermore, an inverse correlation between SLPI and histological parameters associated with tumor progression, including stage of invasion, pattern of invasion, invasive cell grade, and composite histological tumor score was evident. Conversely, elevated plasmin and elastase were positively correlated with histological parameters of tumor invasion. In addition to its known inhibition of elastase, we identify SLPI as a novel inhibitor of plasminogen activation through its interaction with annexin A2 with concomitant reduced plasmin generation by macrophages and OSCC cell lines. In an in vitro assay measuring invasive activity, SLPI blocked protease-dependent tumor cell migration. Our data suggest that SLPI may possess antitumorigenic activity by virtue of its ability to interfere with multiple requisite proteolytic steps underlying tumor cell invasion and may provide insight into potential stratification of oral cancer according to risk of occult metastasis, guiding treatment strategies.
分泌白细胞蛋白酶抑制剂 (SLPI) 的差异表达影响肿瘤进展。SLPI 直接抑制弹性蛋白酶和其他丝氨酸蛋白酶，并调节基质金属蛋白酶、纤溶酶原激活和纤溶酶下游靶标，从而影响侵袭。我们检测了人口腔鳞状细胞癌 (OSCC) 组织中的 SLPI 表达情况，并与与肿瘤进展相关的蛋白酶进行平行检测，使用肿瘤细胞系评估它们之间的关系。与正常口腔上皮相比，OSCC 中明显检测到 SLPI 减少。此外，SLPI 与与肿瘤进展相关的组织学参数之间存在明显的负相关，包括浸润阶段、浸润模式、浸润细胞分级和综合组织学肿瘤评分。相反，纤溶酶和弹性蛋白酶的升高与肿瘤浸润的组织学参数呈正相关。除了其已知的弹性蛋白酶抑制作用外，我们还发现 SLPI 通过与膜联蛋白 A2 相互作用成为纤溶酶原激活的新型抑制剂，同时巨噬细胞和 OSCC 细胞系中纤溶酶的生成减少。在测量侵袭活性的体外测定中，SLPI 阻断了依赖蛋白酶的肿瘤细胞迁移。我们的数据表明，SLPI 可能通过干扰肿瘤细胞侵袭的多个必需的蛋白水解步骤而具有抗肿瘤活性，并可能为根据隐匿性转移的风险对口腔癌进行潜在分层提供依据，从而指导治疗策略。
