Osteoactivin expressed during cirrhosis development in rats fed a choline-deficient, L-amino acid-defined diet, accelerates motility of hepatoma cells.
OBJECTIVE
Hepatocellular carcinoma (HCC) is closely associated with chronic liver diseases, particularly cirrhosis. However, the genes involved in hepatocarcinogenesis in the context of developing cirrhosis remain unknown. This study aims to identify genes associated with early cirrhosis-associated hepatocarcinogenesis.


METHODS
We examined genes differentially expressed between the livers of normal rats and rats fed a choline-deficient, L-amino acid-defined (CDAA) diet using suppression subtractive hybridization. We examined both the expression in the liver and HCC tissues of osteoactivin (OA), isolated in this screen, and its effect on invasiveness and metastasis.


RESULTS
OA mRNA was strongly expressed in the livers of rats fed the CDAA diet for 1-3 months. Moderate expression was sustained for 18 months. OA overexpression increased the invasiveness and metastasis of rat hepatoma cells in vitro and in vivo. In humans, OA expression was not detectable in normal liver tissues. While OA transcripts were detectable in cirrhotic nontumorous liver tissues surrounding HCCs, the majority of HCC tissue samples exhibited higher levels of OA expression than the surrounding normal tissue.


CONCLUSIONS
These results indicate that OA is a novel factor involved in the progression of HCC via stimulation of tumor invasiveness and metastatic potential.
Onaga
Masaaki
M
Department of Internal Medicine II, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
Ido
Akio
A
Hasuike
Satoru
S
Uto
Hirofumi
H
Moriuchi
Akihiro
A
Nagata
Kenji
K
Hori
Takeshi
T
Hayash
Katsuhiro
K
Tsubouchi
Hirohito
H
D000368:Aged; D000596:Amino Acids / Q000008:administration & dosage*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000503:physiopathology*; D002455:Cell Division; D002465:Cell Movement; D002794:Choline / Q000008:administration & dosage*; D003001:Cloning, Molecular; D004032:Diet / Q000009:adverse effects*; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology* / Q000378:metabolism*; D008113:Liver Neoplasms / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008562:Membrane Glycoproteins; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D000596:Amino Acids; C503042:GPNMB protein, human; C503043:Gpnmb protein, rat; D008562:Membrane Glycoproteins; D011506:Proteins; D002794:Choline