Keire Paul A, Bressler Steven L, Lemire Joan M, Edris Badreddin, Rubin Brian P, Rahmani Maziar, McManus Bruce M, van de Rijn Matt, Wight Thomas N
From the Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101, Department of Pathology, University of Washington, Seattle, Washington 98195.
From the Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington 98101.
J Biol Chem. 2014 Dec 5;289(49):34089-103. doi: 10.1074/jbc.M114.607168. Epub 2014 Oct 15.
Leiomyosarcoma (LMS) is a mesenchymal cancer that occurs throughout the body. Although LMS is easily recognized histopathologically, the cause of the disease remains unknown. Versican, an extracellular matrix proteoglycan, increases in LMS. Microarray analyses of 80 LMSs and 24 leiomyomas showed a significant elevated expression of versican in human LMS versus benign leiomyomas. To explore the importance of versican in this smooth muscle cell tumor, we used versican-directed siRNA to knock down versican expression in a LMS human cell line, SK-LMS-1. Decreased versican expression was accompanied by slower rates of LMS cell proliferation and migration, increased adhesion, and decreased accumulation of the extracellular matrix macromolecule hyaluronan. Addition of purified versican to cells expressing versican siRNA restored cell proliferation to the level of LMS controls, increased the pericellular coat and the retention of hyaluronan, and decreased cell adhesion in a dose-dependent manner. The presence of versican was not only synergistic with hyaluronan in increasing cell proliferation, but the depletion of versican decreased hyaluronan synthase expression and decreased the retention of hyaluronan. When LMS cells stably expressing versican siRNA were injected into nude mice, the resulting tumors displayed significantly less versican and hyaluronan staining, had lower volumes, and had reduced levels of mitosis as compared with controls. Collectively, these results suggest a role for using versican as a point of control in the management and treatment of LMS.
平滑肌肉瘤（LMS）是一种可发生于全身的间叶组织癌症。尽管LMS在组织病理学上易于识别，但其病因仍不明。多功能蛋白聚糖是一种细胞外基质蛋白聚糖，在LMS中含量增加。对80例LMS和24例平滑肌瘤进行的微阵列分析显示，与良性平滑肌瘤相比，人LMS中多功能蛋白聚糖的表达显著升高。为了探究多功能蛋白聚糖在这种平滑肌细胞肿瘤中的重要性，我们使用针对多功能蛋白聚糖的小干扰RNA（siRNA）来敲低人LMS细胞系SK-LMS-1中多功能蛋白聚糖的表达。多功能蛋白聚糖表达降低伴随着LMS细胞增殖和迁移速率减慢、黏附增加以及细胞外基质大分子透明质酸的积累减少。向表达多功能蛋白聚糖siRNA的细胞中添加纯化的多功能蛋白聚糖可将细胞增殖恢复至LMS对照水平，增加细胞周围被膜和透明质酸的潴留，并以剂量依赖方式降低细胞黏附。多功能蛋白聚糖的存在不仅在增加细胞增殖方面与透明质酸具有协同作用，而且多功能蛋白聚糖的缺失会降低透明质酸合酶的表达并减少透明质酸的潴留。当将稳定表达多功能蛋白聚糖siRNA的LMS细胞注射到裸鼠体内时，与对照相比，产生的肿瘤显示多功能蛋白聚糖和透明质酸染色显著减少、体积更小且有丝分裂水平降低。总体而言，这些结果表明多功能蛋白聚糖在LMS的管理和治疗中可作为一个控制靶点发挥作用。
