Angiogenin promotes glioblastoma invasive growth through FOSL2-mediated upregulation of CD24 and MMP9.
Yang, Hailing.
2015
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Abstract: Glioblastoma (GBM) is the most aggressive brain tumor and patients suffer from neurological debilitation and die from rapid disease progression due to the lack of effective therapeutics. The current treatment includes surgery, radiation, and chemotherapy. More recently, anti-angiogenic therapy with bevacizumab, a humanized anti-VEGF antibody, has been added and shown to improve neurologi... read morecal conditions. However, bevacizumab fails to extend overall patient survival, and results in a more invasive recurrent disease characterized by a robust perivascular invasion phenotype. Angiogenin (ANG) is significantly upregulated in higher-grade gliomas, and is one of the two most upregulated genes in bevacizumab-resistant GBM. ANG expression is inversely correlated with GBM patient survival, particularly in the proneural subtype. However, the mechanism by which ANG contributes to GBM progression is unknown. I therefore established a PDGF-induced proneural GBM model under the ANG null background and investigated the function and mechanism of ANG in GBM tumorigenesis and progression. I showed that ANG deficiency is not sufficient to prevent PDGFB-induced mouse proneural GBM in the Ink4a/Arf null background. However, lack of ANG expression significantly extends animal survival as a result of decreased cancer cell proliferation, reduced extracellular matrix remodeling, and less perivascular tumor invasion. I found that ANG activates MMP-9 expression and consequently increases extracellular matrix remodeling and GBM invasion, which likely contributes to perivascular invasion in vivo. I also showed that ANG upregulates CD24 that mediates the interaction of GBM cells with endothelial cells thereby promoting perivascular invasion.Mechanistically, I found that ANG induces MMP-9 and CD24 expression through upregulation of FOSL2, a member of the Fos family proteins and a transcription factor for both CD24 and MMP-9. I found that ANG activates FOSL2 both transcriptionally through binding to its promoter region and post-translationally by stimulating its nuclear localization via the ERK pathway. Moreover, I found that expressions of FOSL2, MMP- 9, and CD24 are significantly correlated with ANG expression in GBM patients. Lastly, I showed that neomycin, an ANG inhibitor, significantly increased survival of GBM mice, accompanied with reduced expression of Mmp-9 and Fosl2, decreased extracellular matrix remodeling, and diminished perivascular invasion, resembling the phenotype observed in ANG knockout tumors. In summary, I present two key findings: 1) ANG promotes perivascular invasion of GBM through the FOSL2-CD24/MMP-9 pathway; 2) ANG inhibition effectively reduces perivascular invasion and extends survival of mice in a proneural GBM model. This thesis has revealed an unexpected role of ANG, an angiogenic protein, in regulating perivascular invasion of GBM. More importantly, these findings suggest a novel strategy for GBM therapy based on ANG inhibition.
Thesis (Ph.D.)--Tufts University, 2015.
Submitted to the Dept. of Cellular & Molecular Physiology.
Advisor: Guo-fu Hu.
Committee: Brent Cochran, Philip Hinds, Philip Tsichlis, Gary Sahagian, and Paul Anderson.
Keywords: Biology, Molecular biology, and Oncology.read less - ID:
- 3f462j51c
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