Forced expression of methionine adenosyltransferase 1A in human hepatoma cells suppresses in vivo tumorigenicity in mice.
Methionine adenosyltransferase (MAT) catalyzes the synthesis of S-adenosylmethionine, the principal methyl donor, and is encoded by MAT1A and MAT2A in mammals. Normal liver expresses MAT1A, which is silenced in hepatocellular carcinoma. We have shown that hepatoma cells overexpressing MAT1A grew slower, but whether this is also true in vivo remains unknown. To investigate the effect of overexpressing MAT1A on in vivo tumorigenesis, we generated stable transfectants of Huh7 cells overexpressing either MAT1A or empty vector. Real-time PCR and Western blotting were used to measure expression, and BALB/c nude mice were injected subcutaneously with untransfected or Huh7 cells transfected with empty or MAT1A expression vector to establish tumors. Tumor properties such as proliferation, angiogenesis, and apoptosis were compared, and microarray analysis was performed. Huh7 cells overexpressing MAT1A had higher S-adenosylmethionine levels but lower bromodeoxyuridine incorporation than control cells. Tumor growth rates and weights were lower in MAT1A transfected tumors. In addition, microvessel density and CD31 and Ki-67 staining were lower in MAT1A transfected tumors than control tumors, whereas the apoptosis index was higher in MAT1A-transfected tumors. Forced expression of MAT1A induced genes related to apoptosis and tumor suppression and lowered expression of cell growth and angiogenesis proteins. Our data demonstrate in vivo overexpression of MAT1A in liver cancer cells can suppress tumor growth. They also suggest inducing MAT1A expression might be a strategy to treat hepatocellular carcinoma.
Li
Jiaping
J
Division of Gastroenterology and Liver Diseases, University of Southern California Research Center for Liver Diseases, Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine University of Southern California, Los Angeles, CA 90033, USA.
Ramani
Komal
K
Sun
Zhanfeng
Z
Zee
Chishing
C
Grant
Edward G
EG
Yang
Heping
H
Xia
Meng
M
Oh
Pilsoo
P
Ko
Kwangsuk
K
Mato
José M
JM
Lu
Shelly C
SC
D000818:Animals; D001973:Bromodeoxyuridine / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism*; D008716:Methionine Adenosyltransferase / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019394:Ki-67 Antigen; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C490703:Mat1a protein, mouse; D008716:Methionine Adenosyltransferase; D001973:Bromodeoxyuridine