title: DNA methylation and gene expression profiles show novel regulatory pathways in hepatocellular carcinoma.
abstract: BACKGROUND
  Alcohol is a well-known risk factor for hepatocellular carcinoma (HCC), but the mechanisms underlying the alcohol-related hepatocarcinogenesis are still poorly understood. Alcohol alters the provision of methyl groups within the hepatic one-carbon metabolism, possibly inducing aberrant DNA methylation. Whether specific pathways are epigenetically regulated in alcohol-associated HCC is, however, unknown. The aim of the present study was to investigate the genome-wide promoter DNA methylation and gene expression profiles in non-viral, alcohol-associated HCC. From eight HCC patients undergoing curative surgery, array-based DNA methylation and gene expression data of all annotated genes were analyzed by comparing HCC tissue and homologous cancer-free liver tissue.
  
  
  RESULTS
  After merging the DNA methylation with gene expression data, we identified 159 hypermethylated-repressed, 30 hypomethylated-induced, 49 hypermethylated-induced, and 56 hypomethylated-repressed genes. Notably, promoter DNA methylation emerged as a novel regulatory mechanism for the transcriptional repression of genes controlling the retinol metabolism (ADH1A, ADH1B, ADH6, CYP3A43, CYP4A22, RDH16), iron homeostasis (HAMP), one-carbon metabolism (SHMT1), and genes with a putative, newly identified function as tumor suppressors (FAM107A, IGFALS, MT1G, MT1H, RNF180).
  
  
  CONCLUSIONS
  A genome-wide DNA methylation approach merged with array-based gene expression profiles allowed identifying a number of novel, epigenetically regulated candidate tumor-suppressor genes in alcohol-associated hepatocarcinogenesis. Retinol metabolism genes and SHMT1 are also epigenetically regulated through promoter DNA methylation in alcohol-associated HCC. Due to the reversibility of epigenetic mechanisms by environmental/nutritional factors, these findings may open up to novel interventional strategies for hepatocarcinogenesis prevention in HCC related to alcohol, a modifiable dietary component.
authors.affiliation: Department of Medicine, University of Verona School of Medicine, Policlinico 'G.B. Rossi', P.le L.A. Scuro, 10, 37134 Verona, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Udali
authors.affiliation: Department of Medicine, University of Verona School of Medicine, Policlinico 'G.B. Rossi', P.le L.A. Scuro, 10, 37134 Verona, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Guarini
authors.affiliation: Department of Surgery, University of Verona School of Medicine, Policlinico 'G.B. Rossi', P.le L.A. Scuro, 10, 37134 Verona, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ruzzenente
authors.affiliation: Department of Biotechnology, Genetics and Heredity Section, University of Verona School of Agroindustrial Biotechnology, Ca' Vignal 1, Strada Le Grazie 15, 37134 Verona, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ferrarini
authors.affiliation: Department of Surgery, University of Verona School of Medicine, Policlinico 'G.B. Rossi', P.le L.A. Scuro, 10, 37134 Verona, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Guglielmi
authors.affiliation: Department of Medicine, University of Verona School of Medicine, Policlinico 'G.B. Rossi', P.le L.A. Scuro, 10, 37134 Verona, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Lotto
authors.affiliation: Department of Biotechnology, Genetics and Heredity Section, University of Verona School of Agroindustrial Biotechnology, Ca' Vignal 1, Strada Le Grazie 15, 37134 Verona, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Tononi
authors.affiliation: Department of Medicine, University of Verona School of Medicine, Policlinico 'G.B. Rossi', P.le L.A. Scuro, 10, 37134 Verona, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pattini
authors.affiliation: Department of Medicine, University of Verona School of Medicine, Policlinico 'G.B. Rossi', P.le L.A. Scuro, 10, 37134 Verona, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Moruzzi
authors.affiliation: Department of Surgery, University of Verona School of Medicine, Policlinico 'G.B. Rossi', P.le L.A. Scuro, 10, 37134 Verona, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Campagnaro
authors.affiliation: Department of Surgery, University of Verona School of Medicine, Policlinico 'G.B. Rossi', P.le L.A. Scuro, 10, 37134 Verona, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Conci
authors.affiliation: Department of Medicine, University of Verona School of Medicine, Policlinico 'G.B. Rossi', P.le L.A. Scuro, 10, 37134 Verona, Italy.
authors.forename: Oliviero
authors.initials: O
authors.lastname: Olivieri
authors.affiliation: Department of Medicine, University of Verona School of Medicine, Policlinico 'G.B. Rossi', P.le L.A. Scuro, 10, 37134 Verona, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Corrocher
authors.affiliation: Department of Biotechnology, Genetics and Heredity Section, University of Verona School of Agroindustrial Biotechnology, Ca' Vignal 1, Strada Le Grazie 15, 37134 Verona, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Delledonne
authors.affiliation: Friedman School of Nutrition Science and Policy Tufts University, 150 Harrison Ave, Boston, MA 02111 USA ; Chaum Life Center, CHA University, 4-1, Cheongdam-dong, Gangnam-gu, 135-948 Seoul, Korea.
authors.forename: Sang-Woon
authors.initials: SW
authors.lastname: Choi
authors.affiliation: Department of Medicine, University of Verona School of Medicine, Policlinico 'G.B. Rossi', P.le L.A. Scuro, 10, 37134 Verona, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Friso
keywords: Alcohol; Candidate tumor-suppressor genes; DNA methylation; Epigenetics; Gene expression array; Hepatocellular carcinoma; MeDIP-chip; One-carbon metabolism; Retinol metabolism