Correlation of repressed transcription of alpha-tocopherol transfer protein with serum alpha-tocopherol during hepatocarcinogenesis.
Using a subtraction-enhanced display technique, we identified a rodent alpha-tocopherol transfer protein (alpha-TTP) cDNA which exhibited markedly lower messenger RNA (mRNA) amounts in rat hepatocellular carcinoma (HCC) than in healthy controls. Several lines of evidence have substantiated that abnormal alpha-TTP results in isolated vitamin E deficiency. In this study, we investigated the hepatic mRNA amounts of alpha-TTP during rat hepatic carcinogenesis and liver regeneration on Northern blot, localization of alpha-TTP mRNA in HCC of rats and humans by in situ hybridization, and we analyzed the correlation between alpha-TTP mRNA and alpha-tocopherol. alpha-TTP mRNA concentrations of the rats were decreased at the early stage of hepatic carcinogenesis, and remained 3-5-fold reduced as the tumor progressed. In parallel, serum alpha-tocopherol concentrations were significantly decreased to 40% of those in the controls at the early stages of rat hepatic carcinogenesis (p < 0.01). The 2 data sets were strongly correlated (r = 0.834, p < 0.001). In situ hybridization revealed that a decrease of alpha-TTP mRNA was preferentially localized in the tumor nodules of rats and humans with HCC. Our data suggest that repressed transcription of alpha-TTP is associated with a decrease of serum alpha-tocopherol and with hepatic carcinogenesis.
Wu
C G
CG
Department of Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, The Netherlands. c.wu@amc.uva.nl
Hoek
F J
FJ
Groenink
M
M
Reitsma
P H
PH
van Deventer
S J
SJ
Chamuleau
R A
RA
D000368:Aged; D000818:Animals; D002273:Carcinogens; D006528:Carcinoma, Hepatocellular / Q000737:chemistry* / Q000150:complications; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D004052:Diethylnitrosamine; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006965:Hyperplasia; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000737:chemistry* / Q000150:complications; D008114:Liver Neoplasms, Experimental / Q000097:blood / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D014158:Transcription, Genetic; D014801:Vitamin A / Q000097:blood; D014810:Vitamin E / Q000097:blood*; D014811:Vitamin E Deficiency / Q000209:etiology
D002273:Carcinogens; D002352:Carrier Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C017763:alpha-tocopherol transfer protein; D014801:Vitamin A; D014810:Vitamin E; D004052:Diethylnitrosamine; D002784:Cholesterol