Nicotinamide N-methyltransferase induces cellular invasion through activating matrix metalloproteinase-2 expression in clear cell renal cell carcinoma cells
Journal
Carcinogenesis
Journal Volume
32
Journal Issue
2
Pages
138-145
Date Issued
2011
Author(s)
Abstract
Nicotinamide N-methyltransferase (NNMT) was recently identified as one clear cell renal cell carcinoma (ccRCC)-associated gene by analyzing full-length complementary DNA-enriched libraries of ccRCC tissues. The aim of this study is to investigate the potential role of NNMT in cellular invasion. A strong NNMT expression is accompanied with a high invasive activity in ccRCC cell lines, and small interfering RNA-mediated NNMT knockdown effectively suppressed the invasive capacity of ccRCC cells, whereas NNMT overexpression markedly enhanced that of human embryonic kidney 293 (HEK293) cells. A positive correlation between the expression of NNMT and matrix metallopeptidase (MMP)-2 was found in ccRCC cell lines and clinical tissues. The treatment of blocking antibody or inhibitor specific to MMP-2 significantly suppressed NNMT-dependent cellular invasion in HEK293 cells. Furthermore, SP-1-binding region of MMP-2 promoter was found to be essential in NNMT-induced MMP-2 expression. The specific inhibitors of PI3K/Akt signaling markedly decreased the binding of SP1 to MMP-2 promoter as shown by chromatin immunoprecipitation assay. We also demonstrated that PI3K/Akt pathway plays a role in NNMT-dependent cellular invasion and MMP-2 activation. Moreover, short hairpin RNA-mediated knockdown of NNMT expression efficiently inhibited the growth and metastasis of ccRCC cells in non-obese diabetic severe combined immunodeficiency mice. Taken together, the present study suggests that NNMT has a crucial role in cellular invasion via activating PI3K/Akt/SP1/MMP-2 pathway in ccRCC. ? The Author 2010. Published by Oxford University Press. All rights reserved.
SDGs
Other Subjects
gelatinase A; matrix metalloproteinase inhibitor; nicotinamide methyltransferase; phosphatidylinositol 3 kinase; protein antibody; protein kinase B; short hairpin RNA; small interfering RNA; transcription factor Sp1; animal experiment; animal model; animal tissue; article; binding site; cancer tissue; carcinoma cell; cell invasion; cell strain HEK293; clinical article; controlled study; enzyme activation; enzyme activity; female; gene overexpression; human; human cell; human tissue; kidney carcinoma; male; metastasis inhibition; mouse; nonhuman; priority journal; promoter region
Publisher
Oxford University Press
Type
journal article