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Clinical and biological significance of forkhead class box O 3a expression in glioma: mediation of glioma malignancy by transcriptional regulation of p27kip1

  • Clinical Study - Patient Study
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Abstract

Forkhead box class O 3a (FOXO3a) is an important direct target of the phosphatidylinositol 3-kinase (PI3K)/protein B(Akt) pathway, mediating signal transduction in regulating cell survival and cell-cycle progression. Recent reports have shown that FOXO3a inhibits cell-cycle progression at the G1/S transition by controlling transcription of the cyclin-dependent kinase inhibitor p27kip1, which is frequently down-regulated in human cancers, including human glioma. In this study we investigated the status of FOXO3a expression and related signaling in human glioma in order to test its potential value as a therapeutic target for this disease. Immunohistochemistry, western blot, RT-PCR, and immunofluorescence staining analysis were performed on specimens from 70 cases of human glioma and on U87MG and T98G glioma cells. Our data showed FOXO3a expression is directly correlated with the malignant grade of glioma. More importantly, low expression of FOXO3a was associated with poor patient outcome. In vitro, FOXO3a modulated the cell cycle by transcriptional regulation of p27kip1. Administration of the PI3K pharmacological inhibitor LY294002 abrogated this effect by regulating FOXO3a expression and subcellular localization. Our results suggested that FOXO3a may be a favorable independent prognostic indicator of glioma. Gene therapeutic approaches aimed at PI3K or at pharmacological inhibitors of PI3K to down-regulate P-FOXO3a expression could be developed for management of glioma.

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Abbreviations

FOXO3a:

Forkhead box class O 3a

PI3K:

Phosphatidylinositol 3-kinase

PTEN:

Phosphatase and tensin homolog deleted on chromosome 10

EGFR:

Epidermal growth factor receptor

CDK4:

Cyclin-dependent kinase 4

CDK6:

Cyclin-dependent kinase 6

PCNA:

Proliferating cell nuclear antigen

RT-PCR:

Reverse transcriptase polymerase chain reaction

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

PI:

Propidium iodide

FITC:

Fluorescein isothiocyanate

CML:

Myelogenous leukemia

DMSO:

Dimethyl sulfoxide

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Acknowledgments

This work was supported by the National Natural Scientific Foundation of China (grants 30300099 and 30770488), the Natural Scientific Foundation of Jiangsu Province (grants BK2003035 and BK2006547), the College and University Natural Scientific Research Program of Jiangsu Province (grants 03KJB180109 and 04KJB320114), the Technology Guidance Plan for Social Development of Jiangsu Province (grant BS2004526), and the Health Project of Jiangsu Province (grant H200632).

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Authors and Affiliations

  1. Department of Neurosurgery, Affiliated Huashan Hospital of Fudan University, Shanghai, Peoples’ Republic of China

    Jinlong Shi

  2. Department of Microbiology and Immunology, Medical College of Nantong University, 226001, Nantong, Peoples’ Republic of China

    Li Zhang, Aiguo Shen, Yuchan Wang, Yueming Zhao, Lin Zou, Qing Ke, Fei He, Ping Wang & Chun Cheng

  3. Department of Pathology, Affiliated Hospital of Nantong University, 226001, Nantong, Peoples’ Republic of China

    Jianguo Zhang & Gongshen Shi

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  1. Jinlong Shi
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  2. Li Zhang
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Correspondence to Chun Cheng or Gongshen Shi.

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Jinlong Shi and Li Zhang both contributed equally to this work.

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Shi, J., Zhang, L., Shen, A. et al. Clinical and biological significance of forkhead class box O 3a expression in glioma: mediation of glioma malignancy by transcriptional regulation of p27kip1 . J Neurooncol 98, 57–69 (2010). https://doi.org/10.1007/s11060-009-0045-8

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  • DOI: https://doi.org/10.1007/s11060-009-0045-8

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