title: COX-2 overexpression increases malignant potential of human glioma cells through Id1.
abstract: Increased COX-2 expression directly correlates with glioma grade and is associated with shorter survival in glioblastoma (GBM) patients. COX-2 is also regulated by epidermal growth factor receptor signaling which is important in the pathogenesis of GBMs. However, COX-2 expression has not been previously shown to directly alter malignancy of GBMs. Id1 is a member of the helix-loop-helix (HLH) family of transcriptional repressors that act as dominant-negative inhibitors of basic-HLH factors. This factor has been shown to be regulated by COX-2 in breast carcinoma cells and recent studies suggest that Id1 may also be involved in the genesis/progression of gliomas. We now show that COX-2 increases the aggressiveness of GBM cells. GBM cells with COX-2 overexpression show increased growth of colonies in soft agar. Tumorigenesis in vivo is also increased in both subcutaneous flank and orthotopic intracranial tumor models. COX-2 overexpression induces Id1 expression in two GBM cell lines suggesting a role for Id1 in glioma transformation/tumorigenesis. Furthermore, we find direct evidence of a role for Id1 with significant suppression of in vitro transformation and in vivo tumorigenesis in COX-2-overexpressing GBM cells where Id1 has been knocked down. In fact, Id1 is even more efficient at enhancing transformation/tumorigenesis of GBM cells than COX-2. Finally, GBM cells with COX-2 or Id1 overexpression show greater migration/invasive potential and tumors that arise from these cells also display increased microvessel density, results in line with the increased malignant potential seen in these cells. Thus, COX-2 enhances the malignancy of GBM cells through induction of Id1.
authors.affiliation: Department of Radiation Oncology and the Winship Cancer Institute, Emory University, Atlanta, GA.
authors.forename: Kaiming
authors.initials: K
authors.lastname: Xu
authors.forename: Lanfang
authors.initials: L
authors.lastname: Wang
authors.forename: Hui-Kuo G
authors.initials: HK
authors.lastname: Shu
mesh_terms: D000818:Animals; D000068579:Celecoxib; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005910:Glioma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008940:Mitotic Index; D009361:Neoplasm Invasiveness / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D018874:Spheroids, Cellular; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone