Abstract
BackgroundIn the quest for novel molecular mediators of glioma progression, we studied the regulation of FBXW7 (hCDC4/hAGO/SEL10), its association with survival of patients with glioblastoma and its potential role as a tumor suppressor gene in glioma cells. The F-box protein Fbxw7 is a component of SCFFbxw7, a Skp1-Cul1-F-box E3 ubiquitin ligase complex that tags specific proteins for proteasome degradation. FBXW7 is mutated in several human cancers and functions as a haploinsufficient tumor suppressor in mice. Any of the identified targets, Cyclin E, c-Myc, c-Jun, Notch1/4 and Aurora-A may have oncogenic properties when accumulated in tumors with FBXW7 loss.ResultsWe tested the expression of FBXW7 in human glioma biopsies by quantitative PCR and compared the transcript levels of grade IV glioma (glioblastoma, G-IV) with those of grade II tumors (G-II). In more than 80% G-IV, expression of FBXW7 was significantly reduced. In addition, levels of FBXW7 were correlated with survival indicating a possible implication in tumor aggressiveness. Locus 4q31.3 which carries FBXW7 was investigated by in situ hybridization on biopsy touchprints. This excluded allelic loss as the principal cause for low expression of FBXW7 in G-IV tumors. Two targets of Fbxw7, Aurora-A and Notch4 were preferentially immunodetected in G-IV biopsies. Next, we investigated the effects of FBXW7 misregulation in glioma cells. U87 cells overexpressing nuclear isoforms of Fbxw7 lose the expression of the proliferation markers PCNA and Ki-67, and get counterselected in vitro. This observation fits well with the hypothesis that Fbxw7 functions as a tumor suppressor in astroglial cells. Finally, FBXW7 knockdown in U87 cells leads to defects in mitosis that may promote aneuploidy in progressing glioma.ConclusionOur results show that FBXW7 expression is a prognostic marker for patients with glioblastoma. We suggest that loss of FBXW7 plays an important role in glioma malignancy by allowing the accumulation of multiple oncoproteins and that interfering with Fbxw7 or its downstream targets would constitute a new therapeutic advance.
Highlights
In the quest for novel molecular mediators of glioma progression, we studied the regulation of FBXW7, its association with survival of patients with glioblastoma and its potential role as a tumor suppressor gene in glioma cells
Expression of FBXW7 in glioma patients and correlation with survival FBXW7 expression was evaluated by quantitative RT-PCR in 56 G-IV and 5 grade II tumors (G-II) gliomas
G-IV tumors were classified according to the normalized expression levels of FBXW7 compared to the mean of expression levels in G-II tumors
Summary
In the quest for novel molecular mediators of glioma progression, we studied the regulation of FBXW7 (hCDC4/hAGO/SEL10), its association with survival of patients with glioblastoma and its potential role as a tumor suppressor gene in glioma cells. In contrast to other SCF complexes such as SCFFbxl which target both positive and negative regulators of the cell cycle [3], all known targets of SCFFbxw7 – namely Cyclin E [4,5,6], c-Myc [7], c-Jun [8], Notch 1 and 4 [9,10,11] and Aurora-A [12] – are cell growth promoters and potential oncoproteins Their turn-over can be seen as an ultimate process in tumor suppression control. Given the number of its targets and the fact that FBXW7 is translated into three different isoforms with distinct subcellular localization, possible mechanisms of tumor suppression are bound to be complex and variable depending upon the cell type in which downregulation occurs
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