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Increased COX2 expression directly correlates with glioma grade and is also associated with shorter survival in malignant glioma patients. Id1 is similarly overexpressed in higher grade gliomas. Id1 is a member of the helix-loop-helix (HLH) family of transcriptional repressors that act as dominant-negative inhibitors of basic-HLH factors. Recent studies indicate that Id1 may be involved in the genesis/progression of gliomas. Here, we find that COX2 overexpression in human glioma cells correlates with increased Id1 protein levels. We further find that forced expression of COX2 and Id1 enhances soft agar colony formation. In cell invasion assay, both COX2 and Id1 expression in LN229 human glioma cells (LN/COX2 and LN/Id1) increase migration through matrigel. These cells also showed more tumorigenic potential with development of significantly larger subcutaneous tumors compared with controls. Of note, tumors expressing COX2 or Id1 had higher microvessel density than control tumors. Next, the effect of COX2 and Id1 overexpression was assessed in an orthotopic intracranial model. Here, nude mice injected with LN/COX2 or LN/Id1 cells had significantly decreased survival times compared with corresponding controls (Table 1). To assess the role of Id1 induction on the malignant potential of COX2-expressing glioma cells, LN/COX2 cells with shRNA against Id1 were intracranially injected and found to have a statistically significant increase in survival compared to those injected with control shRNA LN/COX2 cells (Table 1). Finally, to test a COX2-targeting therapy, we used the COX2 inhibitor celecoxib in our xenograft model and found inhibition of growth of flank tumors derived from glioma cells overexpressing COX2. In conclusion, COX2 overexpression in human glioma cells results in elevated Id1 protein level, which, in turn, enhances the transformation and invasiveness of human glioma cells, promotes microvessel formation and enhances xenograft tumor growth subcutaneously and intracranially.

Table 1.

Survival of nude mice injected intracranially with the indicated glioma cells.

Expt. 1Expt. 2Expt. 3
Cell typeNMedian Survival (days)NMedian Survival (days)NMedian Survival (days)
LN/Ctrl 10 71 78   
LN/COX2 10 40 53   
LN/Id1 22 11 21   
LN/COX2 shCtrl     10 75 
LN/COX2 shId1     10 56 
p-value by logrank  <0.001  <0.001  0.011 
Expt. 1Expt. 2Expt. 3
Cell typeNMedian Survival (days)NMedian Survival (days)NMedian Survival (days)
LN/Ctrl 10 71 78   
LN/COX2 10 40 53   
LN/Id1 22 11 21   
LN/COX2 shCtrl     10 75 
LN/COX2 shId1     10 56 
p-value by logrank  <0.001  <0.001  0.011 

Citation Format: Kaiming Xu, Hui-Kuo G. Shu. COX2 overexpression increases malignant potential of human glioma cells through Id1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3129. doi:10.1158/1538-7445.AM2013-3129

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