Golembieski William A, Thomas Stacey L, Schultz Chad R, Yunker Christopher K, McClung Heather M, Lemke Nancy, Cazacu Simona, Barker Thomas, Sage E Helene, Brodie Chaya, Rempel Sandra A
Barbara Jane Levy Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan 48202, USA.
Glia. 2008 Aug 1;56(10):1061-75. doi: 10.1002/glia.20679.
Secreted protein acidic and rich in cysteine (SPARC) regulates cell-extracellular matrix interactions that influence cell adhesion and migration. We have demonstrated that SPARC is highly expressed in human gliomas, and it promotes brain tumor invasion in vitro and in vivo. To further our understanding regarding SPARC function in glioma migration, we transfected SPARC-green fluorescent protein (GFP) and control GFP vectors into U87MG cells, and assessed the effects of SPARC on cell morphology, migration, and invasion after 24 h. The expression of SPARC was associated with elongated cell morphology, and increased migration and invasion. The effects of SPARC on downstream signaling were assessed from 0 to 6 h and 24 h. SPARC increased the levels of total and phosphorylated HSP27; the latter was preceded by activation of p38 MAPK and inhibited by the p38 MAPK inhibitor SB203580. Augmented expression of SPARC was correlated with increased levels of HSP27 mRNA. In a panel of glioma cell lines, increasing levels of SPARC correlated with increasing total and phosphorylated HSP27. SPARC and HSP27 were colocalized to invading cells in vivo. Inhibition of HSP27 mRNA reversed the SPARC-induced changes in cell morphology, migration, and invasion in vitro. These data indicate that HSP27, a protein that regulates actin polymerization, cell contraction, and migration, is a novel downstream effector of SPARC-regulated cell morphology and migration. As such, it is a potential therapeutic target to inhibit SPARC-induced glioma invasion.
富含半胱氨酸的酸性分泌蛋白（SPARC）调节细胞与细胞外基质的相互作用，这种相互作用会影响细胞黏附和迁移。我们已经证明，SPARC在人类胶质瘤中高度表达，并且在体外和体内均可促进脑肿瘤侵袭。为了进一步了解SPARC在胶质瘤迁移中的功能，我们将SPARC-绿色荧光蛋白（GFP）和对照GFP载体转染到U87MG细胞中，并在24小时后评估SPARC对细胞形态、迁移和侵袭的影响。SPARC的表达与细胞形态拉长、迁移和侵袭增加有关。在0至6小时和24小时评估了SPARC对下游信号传导的影响。SPARC增加了总HSP27和磷酸化HSP27的水平；后者在p38 MAPK激活之后出现，并被p38 MAPK抑制剂SB203580抑制。SPARC表达增强与HSP27 mRNA水平升高相关。在一组胶质瘤细胞系中，SPARC水平升高与总HSP27和磷酸化HSP27水平升高相关。在体内，SPARC和HSP27共定位于侵袭细胞。抑制HSP27 mRNA可逆转SPARC诱导的体外细胞形态、迁移和侵袭变化。这些数据表明，HSP27作为一种调节肌动蛋白聚合、细胞收缩和迁移的蛋白质，是SPARC调节细胞形态和迁移的新型下游效应物。因此，它是抑制SPARC诱导的胶质瘤侵袭的潜在治疗靶点。
