Bmi-1 Promotes Glioma Angiogenesis by Activating NF-κB Signaling

Angiogenesis in glioma is associated with the poor prognosis of the disease and closely correlates with the highly invasive phenotype of glioma cells, which represents the most challenging impediment against the currently glioma treatments. Bmi-1, an onco-protein, has been implicated in the progression of various human cancers, including gliomas, whereas its role in glioma angiogenesis remains unclear. Our current study examined the effects of Bmi-1 on glioma angiogenesis in vitro as well as in vivo. We found that overexpression of Bmi-1 enhanced, whereas knockdown of Bmi-1 diminished, the capability of glioma cells to induce tubule formation and migration of endothelial cells and neovascularization in chicken chorioallantoic membrane. In vivo, Bmi-1 overexpression and knockdown, respectively, promoted and inhibited angiogenesis in orthotopically transplanted human gliomas. Furthermore, NF-κB activity and VEGF-C expression was induced by Bmi-1 overexpression, whereas Bmi-1 knockdown attenuated NF-κB signaling and decreased VEGF-C expression. Additionally suppression of NF-κB activity using a specific chemical inhibitor abrogated the NF-κB activation and the pro-angiogenic activities of glioma cells. Together, our data suggest that Bmi-1 plays an important role in glioma angiogenesis and therefore could represent a potential target for anti-angiogenic therapy against the disease.

[1]  L. Chin,et al.  Malignant astrocytic glioma: genetics, biology, and paths to treatment. , 2007, Genes & development.

[2]  Eric C. Holland,et al.  Gliomagenesis: genetic alterations and mouse models , 2001, Nature Reviews Genetics.

[3]  R. Mirimanoff,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[4]  Yi Jiang,et al.  A cell-based model exhibiting branching and anastomosis during tumor-induced angiogenesis. , 2007, Biophysical journal.

[5]  Napoleone Ferrara,et al.  VEGF and the quest for tumour angiogenesis factors , 2002, Nature Reviews Cancer.

[6]  Byung Hak Kim,et al.  Inhibitory action of novel aromatic diamine compound on lipopolysaccharide‐induced nuclear translocation of NF‐κB without affecting IκB degradation , 2004 .

[7]  A. Bikfalvi,et al.  Structure and Inhibitory Effects on Angiogenesis and Tumor Development of a New Vascular Endothelial Growth Inhibitor* , 2003, Journal of Biological Chemistry.

[8]  L. Parada,et al.  The Molecular and Genetic Basis of Neurological Tumours , 2002, Nature Reviews Cancer.

[9]  Peter Carmeliet,et al.  Angiogenesis in life, disease and medicine , 2005, Nature.

[10]  M. Ohtaki,et al.  Expression of Polycomb-group (PcG) protein BMI-1 predicts prognosis in patients with acute myeloid leukemia , 2007, Leukemia.

[11]  Shigeyoshi Itohara,et al.  Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis , 2000, Nature Cell Biology.

[12]  Libing Song,et al.  Bmi-1 promotes invasion and metastasis, and its elevated expression is correlated with an advanced stage of breast cancer , 2011, Molecular Cancer.

[13]  Y. Katayama,et al.  Angiogenesis of glioma: evaluation of ultrastructural characteristics of microvessels and tubular bodies (Weibel–Palade) in endothelial cells and immunohistochemical findings with VEGF and p53 protein , 2005, Medical Molecular Morphology.

[14]  Xinyu Zhao,et al.  shRNA-mediated knockdown of Bmi-1 inhibit lung adenocarcinoma cell migration and metastasis. , 2012, Lung cancer.

[15]  Jun Li,et al.  Biomarkers , Genomics , Proteomics , and Gene Regulation miR-182 as a Prognostic Marker for Glioma Progression and Patient Survival , 2010 .

[16]  R. DePinho,et al.  Malignant glioma: genetics and biology of a grave matter. , 2001, Genes & development.

[17]  A. Bhushan,et al.  Bmi-1 regulates the Ink4a/Arf locus to control pancreatic beta-cell proliferation. , 2009, Genes & development.

[18]  L. Taylor.  Diagnosis, treatment, and prognosis of glioma , 2010, Neurology.

[19]  Libing Song,et al.  Oncoprotein Bmi-1 renders apoptotic resistance to glioma cells through activation of the IKK-nuclear factor-kappaB Pathway. , 2010, The American journal of pathology.

[20]  Byung Hak Kim,et al.  Inhibitory action of novel aromatic diamine compound on lipopolysaccharide-induced nuclear translocation of NF-kappaB without affecting IkappaB degradation. , 2004, FEBS letters.

[21]  Xin Chen,et al.  Bmi1 Functions as an Oncogene Independent of Ink4A/Arf Repression in Hepatic Carcinogenesis , 2009, Molecular Cancer Research.

[22]  Libing Song,et al.  Bmi-1, stem cells and cancer. , 2009, Acta biochimica et biophysica Sinica.

[23]  M. Lindström,et al.  p14ARF homozygous deletion or MDM2 overexpression in Burkitt lymphoma lines carrying wild type p53 , 2001, Oncogene.

[24]  I. Stamenkovic,et al.  Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. , 2000, Genes & development.

[25]  Mitchel S Berger,et al.  Neural stem cells and the origin of gliomas. , 2005, The New England journal of medicine.

[26]  Hua-mei Tang,et al.  Expression level of Bmi-1 oncoprotein is associated with progression and prognosis in colon cancer , 2010, Journal of Cancer Research and Clinical Oncology.

[27]  B. Aggarwal,et al.  A novel homologous recombination system to study 92 kDa type IV collagenase transcription demonstrates that the NFκB motif drives the transition from a repressed to an activated state of gene expression , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[28]  A. Palotie,et al.  Genomic Organization of Human and Mouse Genes for Vascular Endothelial Growth Factor C* , 1997, The Journal of Biological Chemistry.

[29]  P. Salvén,et al.  Angiogenic and Lymphangiogenic Molecules in Hematological Malignancies , 2002, Leukemia & lymphoma.

[30]  Carlo Sala,et al.  Antiangiogenic Therapy for Glioma , 2012, Journal of signal transduction.

[31]  D. Ribatti,et al.  The role of microenvironment in tumor angiogenesis , 2008, Genes & Nutrition.

[32]  M. Lohuizen,et al.  The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression , 2001, British Journal of Cancer.

[33]  Anton Berns,et al.  Identification of cooperating oncogenes in Eμ-myc transgenic mice by provirus tagging , 1991, Cell.

[34]  Jun Li,et al.  MicroRNA-30e* promotes human glioma cell invasiveness in an orthotopic xenotransplantation model by disrupting the NF-κB/IκBα negative feedback loop. , 2012, The Journal of clinical investigation.

[35]  C. Shun,et al.  Induced interleukin-8 expression in gliomas by tumor-associated macrophages , 2009, Journal of Neuro-Oncology.

[36]  G. Dontu,et al.  Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. , 2006, Cancer research.

[37]  Wenlin Huang,et al.  The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells. , 2009, The Journal of clinical investigation.

[38]  Susan M. Chang,et al.  Recent advances in therapy for glioblastoma. , 2010, Archives of neurology.

[39]  R. DePinho,et al.  The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus , 1999, Nature.

[40]  Erwin G. Van Meir,et al.  The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. , 2005, Neuro-oncology.

[41]  P. Black,et al.  Microvessel density is a prognostic indicator for patients with astroglial brain tumors , 1996, Cancer.

[42]  J. Folkman.  Role of angiogenesis in tumor growth and metastasis. , 2002, Seminars in oncology.

[43]  L. Sui,et al.  Correlation of Bmi-1 expression and telomerase activity in human ovarian cancer , 2008, British journal of biomedical science.

[44]  Yun-Fei Xia,et al.  Bmi-1 is a novel molecular marker of nasopharyngeal carcinoma progression and immortalizes primary human nasopharyngeal epithelial cells. , 2006, Cancer research.

[45]  B. Birlik,et al.  Tumour vascularity is of prognostic significance in adult, but not paediatric astrocytomas , 2006, Neuropathology and applied neurobiology.