{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:39:21Z","timestamp":1790858361949,"version":"4.1.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":1157,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"name":"Associazione Italiana Ricerche sul Cancro","award":["IG8952"],"award-info":[{"award-number":["IG8952"]}]},{"name":"Ministero Universit\u00e0 e Ricerca","award":["PRIN 2009"],"award-info":[{"award-number":["PRIN 2009"]}]},{"name":"Regione Autonoma della Sardegna, Fondazione Banco di Sardegna"},{"name":"Third-term Comprehensive Cancer Control Strategy from the Ministry of Health, Labour, and Welfare, Japan"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,7]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>Down-regulation of the liver-specific <jats:italic toggle=\"yes\">MAT1A<\/jats:italic> gene, encoding S-adenosylmethionine (SAM) synthesizing isozymes MATI\/III, and up-regulation of widely expressed <jats:italic toggle=\"yes\">MAT2A<\/jats:italic>, encoding MATII isozyme, known as <jats:italic toggle=\"yes\">MAT1A:MAT2A<\/jats:italic> switch, occurs in hepatocellular carcinoma (HCC). Here we found <jats:italic toggle=\"yes\">Mat1A:Mat2A<\/jats:italic> switch and low SAM levels, associated with CpG hypermethylation and histone H4 deacetylation of <jats:italic toggle=\"yes\">Mat1A<\/jats:italic> promoter, and prevalent CpG hypomethylation and histone H4 acetylation in <jats:italic toggle=\"yes\">Mat2A<\/jats:italic> promoter of fast-growing HCC of F344 rats, genetically susceptible to hepatocarcinogenesis. In HCC of genetically resistant BN rats, very low changes in the <jats:italic toggle=\"yes\">Mat1A:Mat2A<\/jats:italic> ratio, CpG methylation, and histone H4 acetylation occurred. The highest <jats:italic toggle=\"yes\">MAT1A<\/jats:italic> promoter hypermethylation and <jats:italic toggle=\"yes\">MAT2A<\/jats:italic> promoter hypomethylation occurred in human HCC with poorer prognosis. Furthermore, levels of AUF1 protein, which destabilizes <jats:italic toggle=\"yes\">MAT1A<\/jats:italic> messenger RNA (mRNA), Mat1A-AUF1 ribonucleoprotein, HuR protein, which stabilizes <jats:italic toggle=\"yes\">MAT2A<\/jats:italic> mRNA, and Mat2A-HuR ribonucleoprotein sharply increased in F344 and human HCC, and underwent low\/no increase in BN HCC. In human HCC, <jats:italic toggle=\"yes\">Mat1A:MAT2A<\/jats:italic> expression and MATI\/III:MATII activity ratios correlated negatively with cell proliferation and genomic instability, and positively with apoptosis and DNA methylation. Noticeably, the MATI\/III:MATII ratio strongly predicted patient survival length. Forced <jats:italic toggle=\"yes\">MAT1A<\/jats:italic> overexpression in HepG2 and HuH7 cells led to a rise in the SAM level, decreased cell proliferation, increased apoptosis, down-regulation of <jats:italic toggle=\"yes\">Cyclin D1, E2F1, IKK, NF-\u03baB<\/jats:italic>, and antiapoptotic <jats:italic toggle=\"yes\">BCL2<\/jats:italic> and <jats:italic toggle=\"yes\">XIAP<\/jats:italic> genes, and up-regulation of <jats:italic toggle=\"yes\">BAX<\/jats:italic> and <jats:italic toggle=\"yes\">BAK<\/jats:italic> proapoptotic genes. In conclusion, we found for the first time a post-transcriptional regulation of <jats:italic toggle=\"yes\">MAT1A<\/jats:italic> and <jats:italic toggle=\"yes\">MAT2A<\/jats:italic> by AUF1 and HuR in HCC. Low MATI\/III:MATII ratio is a prognostic marker that contributes to determine a phenotype susceptible to HCC and patients' survival. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Interference with cell cycle progression and I-kappa B kinase (IKK)\/nuclear factor kappa B (NF-\u03baB) signaling contributes to the antiproliferative and proapoptotic effect of high SAM levels in HCC. (HEPATOLOGY 2012;56:165\u2013175)<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.25643","type":"journal-article","created":{"date-parts":[[2012,2,9]],"date-time":"2012-02-09T05:27:47Z","timestamp":1328765267000},"page":"165-175","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":82,"title":["Role of transcriptional and posttranscriptional regulation of methionine adenosyltransferases in liver cancer progression"],"prefix":"10.1097","volume":"56","author":[{"given":"Maddalena","family":"Frau","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria L.","family":"Tomasi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria M.","family":"Simile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria 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