A microarray study to characterize the molecular mechanism of TIMP-3-mediated tumor rejection.
Glial cell invasion is a multistep cellular process that involves a complex system of tightly regulated proteases (matrix metalloproteinases; MMPs) and their endogenous inhibitors (tissue inhibitors of metalloproteinases; TIMPs) to mediate the degradation of the basement membrane and extracellular matrix. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a matrix-bound inhibitor of MMPs. In the present study, we have overexpressed the TIMP3 gene in human glioma cells with a herpes simplex virus type 1 amplicon-based vector. Oligonucleotide DNA arrays were employed to identify genes that were differentially modulated by the overexpression of TIMP-3. Consistent with the function of TIMP-3, genes associated with angiogenesis, growth factors, cytokines, death receptors, and substrates of the various MMPs were found to be up-regulated. Furthermore, caspases are important in the signaling pathway of cellular apoptosis, and the overexpression of TIMP-3 in glioma cells is tightly associated with the activation of caspases, including caspase-1, at both the mRNA level (P=0.0371) and the protein level. Moreover, the activation of an apoptotic pathway via the overexpression of TIMP-3 induced apoptosis of transduced human glioma cells in vitro and the growth inhibition of human glioma tumor xenografts in immunodeficient mice.
Lam
Paula
P
Gene Vector Laboratory, Division of Cellular and Molecular Research, National Cancer Centre, 11 Hospital Drive, Singapore 169610.
Sian Lim
Kar
K
Mei Wang
Suk
S
Hui
Kam M
KM
D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D020869:Gene Expression Profiling; D005822:Genetic Vectors; D005910:Glioma / Q000276:immunology / Q000378:metabolism*; D018259:Herpesvirus 1, Human; D006801:Humans; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000276:immunology / Q000378:metabolism*; D014183:Transplantation, Heterologous; D015854:Up-Regulation
D019717:Tissue Inhibitor of Metalloproteinase-3; D020169:Caspases; D051722:ADAM Proteins; D000072198:ADAM17 Protein