Bassi D E, Mahloogi H, Al-Saleem L, Lopez De Cicco R, Ridge J A, Klein-Szanto A J
Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Mol Carcinog. 2001 Aug;31(4):224-32. doi: 10.1002/mc.1057.
Pro-protein convertases (PCs) are proteases that recognize and cleave precursor proteins. Furin, a well-studied PC, is ubiquitously expressed, and it has been implicated in many physiological and pathological processes. Some substrates for furin, such as membrane type 1 (MT1) matrix metalloproteinase (MMP), an MMP that activates gelatinase, a collagen-degrading enzyme, are associated with the advanced malignant phenotype. This report examines the expression of furin in carcinoma cell lines of different invasive ability. The levels of furin mRNA and protein correlated with the aggressiveness of tumor cell lines derived from head and neck and lung cancers. Furin expression also was investigated in primary head and neck squamous cell carcinomas (HNSCCs). Furin mRNA was not detected in nonmetastasizing carcinomas. In contrast, furin mRNA was expressed in metastasizing HNSCCs. Immunohistochemistry and Western blot analysis confirmed these results at the protein level. Furin activity was investigated indirectly by evaluating the expression of the pro-form and the processed form of MT1-MMP. Metastasizing HNSCCs showed increased expression of MT1-MMP. Furthermore, pro-MT1-MMP expression was noted in most of the nonmetastasizing HNSCCs analyzed by Western blot, and it was absent in the metastasizing HNSCCs. This finding suggests a lower level of furin-mediated MT1-MMP activation in the less aggressive cancers. These observations indicate that furin plays a role in tumor progression. Its overexpression in more aggressive or metastasizing cancers resulted in increased MMP processing.
前体蛋白转化酶（PCs）是一类能够识别并切割前体蛋白的蛋白酶。弗林蛋白酶（Furin）是一种研究较为深入的PC，它在全身广泛表达，并参与了许多生理和病理过程。弗林蛋白酶的一些底物，如膜型1（MT1）基质金属蛋白酶（MMP），一种可激活明胶酶（一种胶原蛋白降解酶）的MMP，与晚期恶性表型相关。本报告研究了弗林蛋白酶在不同侵袭能力的癌细胞系中的表达情况。弗林蛋白酶mRNA和蛋白水平与源自头颈部和肺癌的肿瘤细胞系的侵袭性相关。研究人员还对头颈部原发性鳞状细胞癌（HNSCCs）中的弗林蛋白酶表达进行了调查。在无转移的癌组织中未检测到弗林蛋白酶mRNA。相比之下，在有转移的HNSCCs中可检测到弗林蛋白酶mRNA。免疫组织化学和蛋白质印迹分析在蛋白质水平证实了这些结果。通过评估MT1-MMP的前体形式和加工形式的表达间接研究了弗林蛋白酶的活性。有转移的HNSCCs中MT1-MMP的表达增加。此外，在大多数通过蛋白质印迹分析的无转移HNSCCs中可检测到前体MT1-MMP的表达，而在有转移的HNSCCs中则未检测到。这一发现表明在侵袭性较低的癌症中弗林蛋白酶介导的MT1-MMP激活水平较低。这些观察结果表明弗林蛋白酶在肿瘤进展中发挥作用。其在侵袭性更强或有转移的癌症中的过表达导致MMP加工增加。
