Linoleic acid enhances angiogenesis through suppression of angiostatin induced by plasminogen activator inhibitor 1.
BACKGROUND
The intake of dietary fatty acids is highly correlated with the risk of various cancers. Linoleic acid (LA) is the most abundant polyunsaturated fat in the western diet, but the mechanism(s) by fatty acids such as LA modulate cancer cells is unclear. In this study, we examined the role of LA in various steps in gastric cancer progression.


METHODS
The difference in gene expression between LA-treated and untreated OCUM-2MD3 gastric carcinoma cells was examined by mRNA differential display. The involvement of candidate genes was examined by oligo- and plasmid-mediated RNA interference. Biological functions of several of these genes were examined using in vitro assays for invasion, angiogenesis, apoptosis, cell viability, and matrix digestion. Angiogenesis in vivo was measured by CD-31 immunohistochemistry and microvessel density scoring.


RESULTS
LA enhanced the plasminogen activator inhibitor 1 (PAI-1) mRNA and protein expression, which are controlled by PAI-1 mRNA-binding protein. LA-stimulated invasion depended on PAI-1. LA also enhanced angiogenesis by suppression of angiostatin, also through PAI-1. LA did not alter cell growth in culture, but increased dietary LA-enhanced tumour growth in an animal model.


CONCLUSIONS
Our findings suggest that dietary LA impacts multiple steps in cancer invasion and angiogenesis, and that reducing LA in the diet may help slow cancer progression.
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, NC 27709, USA. matsuoka@med.osaka-cu.ac.jp
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N
Nishioka
T
T
Matsuoka
M
M
Yashiro
K
K
Hirakawa
K
K
Olden
J D
JD
Roberts
D043168:Angiostatins / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019787:Linoleic Acid / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D046228:Microarray Analysis / Q000379:methods; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D043168:Angiostatins; D019787:Linoleic Acid