title: Anti-angiogenic pathway associations of the 3p21.3 mapped BLU gene in nasopharyngeal carcinoma.
abstract: Zinc-finger, MYND-type containing 10 (ZMYND10), or more commonly called BLU, expression is frequently downregulated in nasopharyngeal carcinoma (NPC) and many other tumors due to promoter hypermethylation. Functional evidence shows that the BLU gene inhibits tumor growth in animal assays, but the detailed molecular mechanism responsible for this is still not well understood. In current studies, we find that 93.5% of early-stage primary NPC tumors show downregulated BLU expression. Using a PCR array, overexpression of the BLU gene was correlated to the angiogenesis network in NPC cells. Moreover, expression changes of the MMP family, VEGF and TSP1, were often detected in different stages of NPC, suggesting the possibility that BLU may be directly involved in the microenvironment and anti-angiogenic activity in NPC development. Compared with vector-alone control cells, BLU stable transfectants, derived from poorly-differentiated NPC HONE1 cells, suppress VEGF165, VEGF189 and TSP1 expression at both the RNA and protein levels, and significantly reduce the secreted VEGF protein in these cells, reflecting an unknown regulatory mechanism mediated by the BLU gene in NPC. Cells expressing BLU inhibited cellular invasion, migration and tube formation. These in vitro results were further confirmed by in vivo tumor suppression and a matrigel plug angiogenesis assay in nude mice. Tube-forming ability was clearly inhibited, when the BLU gene is expressed in these cells. Up to 70-90% of injected tumor cells expressing increased exogenous BLU underwent cell death in animal assays. Overexpressed BLU only inhibited VEGF165 expression in differentiated squamous NPC HK1 cells, but also showed an anti-angiogenic effect in the animal assay, revealing a complicated mechanism regulating angiogenesis and the microenvironment in different NPC cell lines. Results of these studies indicate that alteration of BLU gene expression influences anti-angiogenesis pathways and is important for the development of NPC.
authors.affiliation: Department of Clinical Oncology/Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong, SAR, Hong Kong.
authors.forename: Y
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Clinical Oncology/Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong, SAR, Hong Kong.
authors.forename: R L K Y
authors.initials: RL
authors.lastname: Ho
authors.affiliation: Department of Clinical Oncology/Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong, SAR, Hong Kong.
authors.forename: K C
authors.initials: KC
authors.lastname: Chan
authors.affiliation: Department of Clinical Oncology/Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong, SAR, Hong Kong.
authors.forename: R
authors.initials: R
authors.lastname: Kan
authors.affiliation: Department of Clinical Oncology/Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong, SAR, Hong Kong.
authors.forename: E
authors.initials: E
authors.lastname: Tung
authors.affiliation: Department of Clinical Oncology/Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong, SAR, Hong Kong.
authors.forename: H L
authors.initials: HL
authors.lastname: Lung
authors.affiliation: Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, SAR, Hong Kong.
authors.forename: W L
authors.initials: WL
authors.lastname: Yau
authors.affiliation: Department of Clinical Oncology/Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong, SAR, Hong Kong.
authors.forename: A K L
authors.initials: AK
authors.lastname: Cheung
authors.affiliation: Department of Clinical Oncology/Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong, SAR, Hong Kong.
authors.forename: J M Y
authors.initials: JM
authors.lastname: Ko
authors.affiliation: Department of Pathology, Guangxi Medical University, Guangxi, People's Republic of China.
authors.forename: Z F
authors.initials: ZF
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Guangxi Medical University, Guangxi, People's Republic of China.
authors.forename: D Z
authors.initials: DZ
authors.lastname: Luo
authors.affiliation: Department of Pathology, Guangxi Medical University, Guangxi, People's Republic of China.
authors.forename: Z B
authors.initials: ZB
authors.lastname: Feng
authors.affiliation: Department of Pathology, Guangxi Medical University, Guangxi, People's Republic of China.
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Clinical Oncology/Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong, SAR, Hong Kong.
authors.forename: X Y
authors.initials: XY
authors.lastname: Guan
authors.affiliation: Department of Clinical Oncology/Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong, SAR, Hong Kong.
authors.forename: D
authors.initials: D
authors.lastname: Kwong
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine, CA, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Stanbridge
authors.affiliation: Department of Clinical Oncology/Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong, SAR, Hong Kong.
authors.forename: M L
authors.initials: ML
authors.lastname: Lung
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002277:Carcinoma; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D003598:Cytoskeletal Proteins; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D003598:Cytoskeletal Proteins; D019700:Thrombospondin 1; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; C472720:ZMYND10 protein, human; D020782:Matrix Metalloproteinases