Forced Expression of Methionine Adenosyltransferase 1A in Human Hepatoma Cells Suppresses in Vivo Tumorigenicity in Mice

Abstract

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.

MicroRNAs regulate methionine adenosyltransferase 1A expression in hepatocellular carcinoma

“…A better strategy to maintain increased SAMe level in liver cancer cells is to induce the expression of MAT1A. Consistent with this, liver cancer cells with forced expression of MAT1A doubled-cellular SAMe levels grew slower in vitro and in vivo and exhibited reduced angiogenesis, ERK, and AKT activation and increased apoptosis in vivo (12). This proof of concept prompted the current work to investigate whether MAT1A expression is regulated by microRNAs (miRNAs) that are dysregulated in HCC, as miRNAs are potentially much better therapeutic targets.…”

5-Aza-2'-deoxycytidine Induces Hepatoma Cell Apoptosis via Enhancing Methionine Adenosyltransferase 1A Expression and Inducing S-Adenosylmethionine Production

“…It has been found that Mat1A:Mat2A switch and low SAM levels, associated with CpG hypermethylation of Mat1A promoter, and prevalent CpG hypomethylation in Mat2A promoter of fast growing HCC (Frau et al, 2012). Forced MAT1A overexpression in HepG2 and Huh7 cells led to rise in SAMe level, decreased cell proliferation, increased apoptosis (Li et al, 2010;Frau et al, 2012).…”

Effect of As2O3 and Ginsenoside Rg3 on Inhibiting Angiogenesis in Rabbit Liver VX2 Tumor

“…CD31, immunohistochemical marker, was used to estimate microvessel proliferation in the tumor [3]. In the present study, we investigated the levels of CD31 following the effect of As 2 O 3 and GRg3 on the inhibiting angiogenesis in hepatic VX2 carcinoma.…”

“…Meanwhile, various immunohistochemical markers were used to estimate microvessel proliferation in tumors, such as pan-endothelial markers CD31 [3] and antibodies against angiogenic proteins like vascular endothelial growth factor (VEGF) [4]. In this study, we investigated the roles of As 2 O 3 and GRg3 in VX2 carcinoma model of rabbits through CD31 and VEGF.…”