title: An expression signature of phenotypic resistance to hepatocellular carcinoma identified by cross-species gene expression analysis.
abstract: OBJECTIVE
  Hepatocarcinogenesis is under polygenic control. We analyzed gene expression patterns of dysplastic liver nodules (DNs) and hepatocellular carcinomas (HCCs) chemically-induced in F344 and BN rats, respectively susceptible and resistant to hepatocarcinogenesis.
  
  
  METHODS
  Expression profiles were performed by microarray and validated by quantitative RT-PCR and Western blot.
  
  
  RESULTS
  Cluster analysis revealed two distinctive gene expression patterns, the first of which included normal liver of both strains and BN nodules, and the second one F344 nodules and HCC of both strains. We identified a signature predicting DN and HCC progression, characterized by highest expression of oncosuppressors Csmd1, Dmbt1, Dusp1, and Gnmt, in DNs, and Bhmt, Dmbt1, Dusp1, Gadd45g, Gnmt, Napsa, Pp2ca, and Ptpn13 in HCCs of resistant rats. Integrated gene expression data revealed highest expression of proliferation-related CTGF, c-MYC, and PCNA, and lowest expression of BHMT, DMBT1, DUSP1, GADD45g, and GNMT, in more aggressive rat and human HCC. BHMT, DUSP1, and GADD45g expression predicted patients' survival.
  
  
  CONCLUSIONS
  Our results disclose, for the first time, a major role of oncosuppressor genes as effectors of genetic resistance to hepatocarcinogenesis. Comparative functional genomic analysis allowed discovering an evolutionarily conserved gene expression signature discriminating HCC with different propensity to progression in rat and human.
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, 07100, Sassari, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Frau
authors.forename: Maria M
authors.initials: MM
authors.lastname: Simile
authors.forename: Maria L
authors.initials: ML
authors.lastname: Tomasi
authors.forename: Maria I
authors.initials: MI
authors.lastname: Demartis
authors.forename: Lucia
authors.initials: L
authors.lastname: Daino
authors.forename: Maria A
authors.initials: MA
authors.lastname: Seddaiu
authors.forename: Stefania
authors.initials: S
authors.lastname: Brozzetti
authors.forename: Claudio F
authors.initials: CF
authors.lastname: Feo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Massarelli
authors.forename: Giuliana
authors.initials: G
authors.lastname: Solinas
authors.forename: Francesco
authors.initials: F
authors.lastname: Feo
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Pascale
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D016000:Cluster Analysis; D060467:Disease Resistance / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D013045:Species Specificity