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P14ARF inhibits human glioblastoma–induced angiogenesis by upregulating the expression of TIMP3
Abdessamad Zerrouqi, … , Daniel J. Brat, Erwin G. Van Meir
Abdessamad Zerrouqi, … , Daniel J. Brat, Erwin G. Van Meir
Published March 1, 2012
Citation Information: J Clin Invest. 2012;122(4):1283-1295. https://doi.org/10.1172/JCI38596.
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Research Article Oncology Article has an altmetric score of 2

P14ARF inhibits human glioblastoma–induced angiogenesis by upregulating the expression of TIMP3

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Abstract

Malignant gliomas are the most common and the most lethal primary brain tumors in adults. Among malignant gliomas, 60%–80% show loss of P14ARF tumor suppressor activity due to somatic alterations of the INK4A/ARF genetic locus. The tumor suppressor activity of P14ARF is in part a result of its ability to prevent the degradation of P53 by binding to and sequestering HDM2. However, the subsequent finding of P14ARF loss in conjunction with TP53 gene loss in some tumors suggests the protein may have other P53-independent tumor suppressor functions. Here, we report what we believe to be a novel tumor suppressor function for P14ARF as an inhibitor of tumor-induced angiogenesis. We found that P14ARF mediates antiangiogenic effects by upregulating expression of tissue inhibitor of metalloproteinase–3 (TIMP3) in a P53-independent fashion. Mechanistically, this regulation occurred at the gene transcription level and was controlled by HDM2-SP1 interplay, where P14ARF relieved a dominant negative interaction of HDM2 with SP1. P14ARF-induced expression of TIMP3 inhibited endothelial cell migration and vessel formation in response to angiogenic stimuli produced by cancer cells. The discovery of this angiogenesis regulatory pathway may provide new insights into P53-independent P14ARF tumor-suppressive mechanisms that have implications for the development of novel therapies directed at tumors and other diseases characterized by vascular pathology.

Authors

Abdessamad Zerrouqi, Beata Pyrzynska, Maria Febbraio, Daniel J. Brat, Erwin G. Van Meir

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Figure 1

P14ARF expression in tumor cells inhibits angiogenesis in vivo and EC migration in vitro.

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P14ARF expression in tumor cells inhibits angiogenesis in vivo and EC mi...
(A) Northern blots showing dox-inducible expression of P14ARF mRNA in LN229-L16 (L16) derived clones A5 and A18 (upper panel) and LNZ308-C16 derived clone C19 (lower panel) glioma cells. (B) Western blots showing induction of P14ARF in cells from A. P14ARF stabilizes P53 and induces p21 expression in A5 and A18 cells (WT for P53) but not in TP53-null C19 cells, as expected (data not shown). (C) Mouse cornea angiogenesis assays showing that CM from P14ARF-expressing A5 cells inhibits vessel formation. The neovascularized areas (mm2) in the corneas were quantified (error bars indicate SEM; *P < 0.05, ANOVA). The experiments were repeated twice independently (n = 2) with 6 mice/group. (D) Matrigel plug angiogenesis assay showing the antiangiogenic activity of P14ARF-expressing cells. The total length of vessels per surface area (left panel), the relative plug diameter (middle panel), and the number of dividing cells (right panel) were measured and compared in groups with or without dox. Unpaired 2-tailed Student’s t test, *P < 0.05; 4 mice/group, n = 2). (E) CM from P14ARF-induced cells inhibits EC migration in a modified Boyden chamber assay. The number of HDMECs migrated to the lower side of the filter were counted in 3 randomly-selected fields and the results expressed as mean ± SD per field (right panel). *P < 0.05, unpaired 2-tailed Student’s t test; n = 3. Scale bar: 200 μm. (F) CM of P14ARF-expressing cells does not alter HDMEC proliferation expressed as percentage of untreated cells (mean ± SD; n = 4).

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