Noujaim Daniel, van Golen Cynthia M, van Golen Kenneth L, Grauman Alyssa, Feldman Eva L
Department of Neurology, University of Michigan, Ann Arbor 48109, USA.
Oncogene. 2002 Jul 4;21(29):4549-57. doi: 10.1038/sj.onc.1205552.
Neuroblastoma is a peripheral nervous system tumor that accounts for 8-10% of all solid childhood tumors. N-Myc is the most reliable prognostic indicator for neuroblastoma. Bcl-2 is detected in 40-60% of primary neuroblastoma tumors and demonstrates anti-apoptotic action by conferring resistance to chemotherapy and radiation treatment. In neuroblastoma cell lines, the coexpression of N-Myc and Bcl-2 leads to increased tumorigenic properties. Matrix metalloproteinases (MMPs) are endopeptidases that degrade a wide range of basement membrane components, a process important for tumor invasion. This study investigates the effect of N-Myc and Bcl-2 on MMP expression and activation. MMP-2 expression and secretion are increased in SHEP neuroblastoma cells expressing Bcl-2 alone (SHEP/Bcl-2 cells) or both N-Myc and Bcl-2 (SHEP/N-Myc/Bcl-2 cells). MMP-2 activity is increased in the SHEP/N-Myc/Bcl-2 cells yet remains unchanged in SHEP/Bcl-2 cells. TIMP-2 expression is high in SHEP/Bcl-2 cells, which likely inhibits MMP-2 activity, and absent in SHEP/N-Myc/Bcl-2 cells, allowing MMP-2 activity. Invasion is increased in SHEP/N-Myc/Bcl-2 cells and prevented by the use of a pharmacologic MMP-2 inhibitor. These data imply that N-Myc and Bcl-2 cooperate to increase the expression, secretion, and activation of MMP-2, which likely leads to a more tumorigenic phenotype due to increased MMP-2 mediated invasion.
神经母细胞瘤是一种外周神经系统肿瘤，占儿童实体瘤的8-10%。N-Myc是神经母细胞瘤最可靠的预后指标。在40-60%的原发性神经母细胞瘤肿瘤中可检测到Bcl-2，它通过赋予对化疗和放疗的抗性来发挥抗凋亡作用。在神经母细胞瘤细胞系中，N-Myc和Bcl-2的共表达导致致瘤特性增加。基质金属蛋白酶（MMPs）是一类能降解多种基底膜成分的内肽酶，这一过程对肿瘤侵袭很重要。本研究调查了N-Myc和Bcl-2对MMP表达和激活的影响。单独表达Bcl-2的SHEP神经母细胞瘤细胞（SHEP/Bcl-2细胞）或同时表达N-Myc和Bcl-2的细胞（SHEP/N-Myc/Bcl-2细胞）中，MMP-2的表达和分泌均增加。SHEP/N-Myc/Bcl-2细胞中MMP-2活性增加，而SHEP/Bcl-2细胞中MMP-2活性保持不变。TIMP-2在SHEP/Bcl-2细胞中高表达，这可能抑制MMP-2活性，而在SHEP/N-Myc/Bcl-2细胞中不存在，从而使MMP-2具有活性。SHEP/N-Myc/Bcl-2细胞的侵袭能力增强，使用MMP-2药理抑制剂可阻止这种侵袭。这些数据表明，N-Myc和Bcl-2协同作用增加MMP-2的表达、分泌和激活，这可能由于MMP-2介导的侵袭增加而导致更具致瘤性的表型。
