N-Myc and Bcl-2 coexpression induces MMP-2 secretion and activation in human neuroblastoma cells.
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.
Noujaim
Daniel
D
Department of Neurology, University of Michigan, Ann Arbor 48109, USA.
van Golen
Cynthia M
CM
van Golen
Kenneth L
KL
Grauman
Alyssa
A
Feldman
Eva L
EL
D015153:Blotting, Western; D002455:Cell Division; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009447:Neuroblastoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2