Institute of Clinical Biochemistry and Pathobiochemistry, University of Wuerzburg, Wuerzburg, Germany.
Cancer Res. 2010 Oct 15;70(20):8003-14. doi: 10.1158/0008-5472.CAN-10-0592. Epub 2010 Oct 5.
Medulloblastoma is the most common malignant pediatric brain tumor and is one of the leading causes of cancer-related mortality in children. Treatment failure mainly occurs in children harboring metastatic tumors, which typically carry an isochromosome 17 or gain of 17q, a common hallmark of intermediate and high-risk medulloblastoma. Through mRNA expression profiling, we identified LIM and SH3 protein 1 (LASP1) as one of the most upregulated genes on chromosome 17q in tumors with 17q gain. In an independent validation cohort of 101 medulloblastoma samples, the abundance of LASP1 mRNA was significantly associated with 17q gain, metastatic dissemination, and unfavorable outcome. LASP1 protein expression was analyzed by immunohistochemistry in a large cohort of patients (n = 207), and high protein expression levels were found to be strongly correlated with 17q gain, metastatic dissemination, and inferior overall and progression-free survival. In vitro experiments in medulloblastoma cell lines showed a strong reduction of cell migration, increased adhesion, and decreased proliferation upon LASP1 knockdown by small interfering RNA-mediated silencing, further indicating a functional role for LASP1 in the progression and metastatic dissemination of medulloblastoma.
髓母细胞瘤是最常见的小儿脑恶性肿瘤，也是儿童癌症相关死亡的主要原因之一。治疗失败主要发生在患有转移性肿瘤的儿童中，这些肿瘤通常携带等臂染色体 17 或 17q 获得，这是中高危髓母细胞瘤的一个常见特征。通过 mRNA 表达谱分析，我们发现 LIM 和 SH3 蛋白 1（LASP1）是 17q 获得肿瘤中 17q 上上调最明显的基因之一。在 101 例髓母细胞瘤样本的独立验证队列中，LASP1 mRNA 的丰度与 17q 获得、转移扩散和不良预后显著相关。通过免疫组织化学分析了大量患者（n=207）的 LASP1 蛋白表达水平，发现高蛋白表达水平与 17q 获得、转移扩散以及总生存期和无进展生存期不良密切相关。在髓母细胞瘤细胞系中的体外实验表明，通过小干扰 RNA 介导的沉默抑制 LASP1 的表达可显著降低细胞迁移、增加细胞黏附和降低细胞增殖，进一步表明 LASP1 在髓母细胞瘤的进展和转移扩散中具有功能作用。
