Lu Kan V, Jong Kimberly A, Kim Gloria Y, Singh Jatinder, Dia Ederlyn Q, Yoshimoto Koji, Wang Maria Y, Cloughesy Timothy F, Nelson Stanley F, Mischel Paul S
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
J Biol Chem. 2005 Jul 22;280(29):26953-64. doi: 10.1074/jbc.M502614200. Epub 2005 May 20.
Glioblastoma is the most common malignant brain tumor of adults and one of the most lethal cancers. The secreted growth factor pleiotrophin (PTN) promotes glioblastoma migration and proliferation, initiating its oncogenic activities through two cell surface receptors, the protein tyrosine phosphatase receptor zeta (PTPRZ1) and the anaplastic lymphoma kinase (ALK), respectively. Here, we report on the presence and purification of two naturally occurring forms of PTN (18 and 15 kDa) that differentially promote glioblastoma migration and proliferation. Using a panel of glioblastoma cell lines, including low passage patient-derived cultures, we demonstrate that PTN15 promotes glioblastoma proliferation in an ALK-dependent fashion, whereas immobilized PTN18 promotes haptotactic migration of glioblastoma cells in a PTPRZ1-dependent fashion. Mass spectrometric analysis indicated that PTN15 differs from PTN18 by processing of 12 C-terminal amino acids. To demonstrate clinical relevance, we show that PTN15, PTN18, and PTPRZ1 are significantly overexpressed in glioblastoma relative to normal brain at both mRNA and protein levels using microarray, Western blot, and tissue microarray analyses on human tumors. These results indicate that the PTN18-PTPRZ1 and the PTN15-ALK signaling pathways represent potentially important therapeutic targets for glioblastoma invasion and growth.
胶质母细胞瘤是成人中最常见的恶性脑肿瘤，也是最致命的癌症之一。分泌型生长因子多效蛋白（PTN）可促进胶质母细胞瘤的迁移和增殖，分别通过两种细胞表面受体——蛋白酪氨酸磷酸酶受体ζ（PTPRZ1）和间变性淋巴瘤激酶（ALK）启动其致癌活性。在此，我们报告了两种天然存在形式的PTN（18 kDa和15 kDa）的存在及纯化情况，它们对胶质母细胞瘤迁移和增殖的促进作用存在差异。利用一组胶质母细胞瘤细胞系，包括低传代患者来源的培养物，我们证明PTN15以ALK依赖的方式促进胶质母细胞瘤增殖，而固定化的PTN18以PTPRZ1依赖的方式促进胶质母细胞瘤细胞的趋触性迁移。质谱分析表明，PTN15与PTN18的区别在于其C末端12个氨基酸的加工方式。为了证明其临床相关性，我们通过对人类肿瘤进行微阵列、蛋白质印迹和组织微阵列分析表明，在mRNA和蛋白质水平上，相对于正常脑组织，PTN15、PTN18和PTPRZ1在胶质母细胞瘤中均显著过表达。这些结果表明，PTN18 - PTPRZ1和PTN15 - ALK信号通路代表了胶质母细胞瘤侵袭和生长潜在的重要治疗靶点。
