Anti-angiogenic pathway associations of the 3p21.3 mapped BLU gene in nasopharyngeal carcinoma

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 de...

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Bibliographic Details
Published in:Oncogene 2015-08, Vol.34 (32), p.4219-4228
Main Authors: Cheng, Y, Ho, R L K Y, Chan, K C, Kan, R, Tung, E, Lung, H L, Yau, W L, Cheung, A K L, Ko, J M Y, Zhang, Z F, Luo, D Z, Feng, Z B, Chen, S, Guan, X Y, Kwong, D, Stanbridge, E J, Lung, M L
Format: Article
Language:English
Subjects:
Angiogenesis
Animals
Blotting, Western
Carcinoma
Cell growth
Cell Line, Tumor
Cell Movement - genetics
Cells, Cultured
Chromosome Mapping
Chromosomes, Human, Pair 3 - genetics
Down-Regulation
Drug therapy
Female
Gene expression
Gene Expression Regulation, Neoplastic
Genetic aspects
Head & neck cancer
Humans
Immunohistochemistry
Male
Matrix Metalloproteinases - genetics
Matrix Metalloproteinases - metabolism
Mice, Nude
Nasopharyngeal cancer
Nasopharyngeal Carcinoma
Nasopharyngeal Neoplasms - genetics
Nasopharyngeal Neoplasms - metabolism
Nasopharyngeal Neoplasms - pathology
Neovascularization, Pathologic - genetics
Original
Physiological aspects
Reverse Transcriptase Polymerase Chain Reaction
Risk factors
Signal Transduction - genetics
Thrombospondin 1 - genetics
Thrombospondin 1 - metabolism
Transplantation, Heterologous
Tumor Microenvironment - genetics
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
Vascular endothelial growth factor
Vascular Endothelial Growth Factor A - genetics
Vascular Endothelial Growth Factor A - metabolism
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Summary: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.
ISSN:0950-9232
1476-5594
DOI:10.1038/onc.2014.353