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[Cancer Research 63, 4315-4321, August 1, 2003]
© 2003 American Association for Cancer Research

Advances in Brief

Insulin-like Growth Factor Binding Protein 2 Enhances Glioblastoma Invasion by Activating Invasion-enhancing Genes1

Hua Wang, Huamin Wang, Weiping Shen, Helen Huang, Limei Hu, Latha Ramdas, Yi-Hong Zhou, Warren S-L. Liao, Gregory N. Fuller and Wei Zhang2

Departments of Pathology [H. W., W. S., L. H., L. R., G. N. F., W. Z.], Biochemistry and Molecular Biology [W. L., H. H.], and Neuro-Oncology [Y. Z.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 and Department of Pathology, The University of Texas-Houston Medical School, Houston, Texas 77030 [H. W.]

Comparison of gene expressing profiles between gliomas with different grades revealed frequent overexpression of insulin-like growth factor binding protein 2 (IGFBP2) in glioblastoma (GBM), the most advanced stage of glioma. To determine whether IGFBP2 is involved in the proliferative and invasive nature of GBM, we established stable SNB19 GBM cell lines that overexpress IGFBP2. Although there was no marked difference in the cell growth between IGFBP2 overexpressing SNB19(BP2) lines when compared with the control cells, these clones showed significantly increased invasive rates when compared with the parental or vector transfected SNB19 cells. Total RNAs from controls and SNB19(BP2) clones were used for microarray analysis to detect IGFBP2-mediated alterations in gene expression. When compared with parental or vector-transfected control cells, SNB19(BP2) cells consistently showed 3–5-fold increase in the expression of matrix metalloproteinase-2 (MMP-2) as well as other invasion related genes. Increased MMP-2 expression in SNB19(BP2) cells was subsequently confirmed by real time reverse-transcription PCR, Western blotting, and gelatin zymography. Furthermore, consistent with increased MMP-2 expression in SNB19(BP2) cells, transient transfection of a MMP-2 promoter/luciferase reporter also resulted in 3–6-fold higher luciferase activity in SNB19(BP2) cells than in parental or vector-transfected control cells. Finally, tissue microarray analysis of 68 GBM tissue specimens showed a significant correlation between the overexpression of IGFBP2 and elevated MMP-2 expression. Taken together, our data provide evidence that IGFBP2 contributes to glioma progression in part by enhancing MMP-2 gene transcription and in turn tumor cell invasion.




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