Unsaturated fatty acids promote hepatoma proliferation and progression through downregulation of the tumor suppressor PTEN.
OBJECTIVE
The impact of dietary fatty acids on the development of cancers is highly controversial. We recently demonstrated that unsaturated fatty acids trigger the downregulation of the tumor suppressor PTEN through an mTOR/NF-kappaB-dependent mechanism in hepatocytes. In this study, we investigated whether unsaturated fatty acids promote hepatoma progression by downregulating PTEN expression.


METHODS
The effects of fatty acids and PTEN-specific siRNAs on proliferation, invasiveness and gene expression were assessed using HepG2 hepatoma cells. The tumor promoting activity of unsaturated fatty acids was evaluated in vivo using HepG2 xenografts in nude mice.


RESULTS
Incubation of HepG2 cells with unsaturated fatty acids, or PTEN-specific siRNAs, increased cell proliferation, cell migration and invasiveness, and altered the expression of genes involved in inflammation, epithelial-to-mesenchymal transition and carcinogenesis. These effects were dependent on PTEN expression levels and were prevented by mTOR and NF-kappaB inhibitors. Consistent with these data, the development and size of subcutaneous HepG2-derived tumors in nude mice xenografts were dramatically increased when mice were fed with an oleic acid-enriched diet, even in the absence of weight gain.


CONCLUSIONS
These data demonstrate that dietary unsaturated fatty acids promote hepatoma progression by reducing the expression of the tumor suppressor PTEN.
Vinciguerra
Manlio
M
Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, CMU, 1 rue Michel-Servet, 1211 Geneva, Switzerland.
Carrozzino
Fabio
F
Peyrou
Marion
M
Carlone
Sebastiano
S
Montesano
Roberto
R
Benelli
Roberto
R
Foti
Michelangelo
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D005231:Fatty Acids, Unsaturated / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D014162:Transfection; D014183:Transplantation, Heterologous
D002273:Carcinogens; D017931:DNA Primers; D005231:Fatty Acids, Unsaturated; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human