Methylthioadenosine phosphorylase gene expression is impaired in human liver cirrhosis and hepatocarcinoma.
Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine and adenine salvage pathways. In mammals, the liver plays a central role in methionine metabolism, and this essential function is lost in the progression from liver cirrhosis to hepatocarcinoma. Deficient MTAP gene expression has been recognized in many transformed cell lines and tissues. In the present work, we have studied the expression of MTAP in human and experimental liver cirrhosis and hepatocarcinoma. We observe that MTAP gene expression is significantly reduced in human hepatocarcinoma tissues and cell lines. Interestingly, MTAP gene expression was also impaired in the liver of CCl4-cirrhotic rats and cirrhotic patients. We provide evidence indicating that epigenetic mechanisms, involving DNA methylation and histone deacetylation, may play a role in the silencing of MTAP gene expression in hepatocarcinoma. Given the recently proposed tumor suppressor activity of MTAP, our observations can be relevant to the elucidation of the molecular mechanisms of multistep hepatocarcinogenesis.
Berasain
Carmen
C
Division of Hepatology and Gene Therapy, CIMA, Facultad de Medicina, Universidad de Navarra. 31008 Pamplona, Spain.
Hevia
Henar
H
Fernández-Irigoyen
Jokin
J
Larrea
Esther
E
Caballería
Juan
J
Mato
José M
JM
Prieto
Jesús
J
Corrales
Fernando J
FJ
García-Trevijano
Elena R
ER
Avila
Matías A
MA
D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015536:Down-Regulation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006262:Health; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D012333:RNA, Messenger; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase