title: Peretinoin, an acyclic retinoid, improves the hepatic gene signature of chronic hepatitis C following curative therapy of hepatocellular carcinoma.
abstract: BACKGROUND
  The acyclic retinoid, peretinoin, has been shown to be effective for suppressing hepatocellular carcinoma (HCC) recurrence after definitive treatment in a small-scale randomized clinical trial. However, little has been documented about the mechanism by which peretinoin exerts its inhibitory effects against recurrent HCC in humans in vivo.
  
  
  METHODS
  Twelve hepatitis C virus-positive patients whose HCC had been eradicated through curative resection or ablation underwent liver biopsy at baseline and week 8 of treatment with either a daily dose of 300 or 600 mg peretinoin. RNA isolated from biopsy samples was subjected to gene expression profile analysis.
  
  
  RESULTS
  Peretinoin treatment elevated the expression levels of IGFBP6, RBP1, PRB4, CEBPA, G0S2, TGM2, GPRC5A, CYP26B1, and many other retinoid target genes. Elevated expression was also observed for interferon-, Wnt-, and tumor suppressor-related genes. By contrast, decreased expression levels were found for mTOR- and tumor progression-related genes. Interestingly, gene expression profiles for week 8 of peretinoin treatment could be classified into two groups of recurrence and non-recurrence with a prediction accuracy rate of 79.6% (P<0.05). In the liver of patients with non-recurrence, expression of PDGFC and other angiogenesis genes, cancer stem cell marker genes, and genes related to tumor progression was down-regulated, while expression of genes related to hepatocyte differentiation, tumor suppression genes, and other genes related to apoptosis induction was up-regulated.
  
  
  CONCLUSIONS
  Gene expression profiling at week 8 of peretinoin treatment could successfully predict HCC recurrence within 2 years. This study is the first to show the effect of peretinoin in suppressing HCC recurrence in vivo based on gene expression profiles and provides a molecular basis for understanding the efficacy of peretinoin.
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, 13-1Takara-machi, Kanazawa 920-0934, Japan. mhonda@m-kanazawa.jp
authors.forename: Masao
authors.initials: M
authors.lastname: Honda
authors.forename: Taro
authors.initials: T
authors.lastname: Yamashita
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamashita
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Arai
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Sakai
authors.forename: Akito
authors.initials: A
authors.lastname: Sakai
authors.forename: Mikiko
authors.initials: M
authors.lastname: Nakamura
authors.forename: Eishiro
authors.initials: E
authors.lastname: Mizukoshi
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000601:surgery; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D019698:Hepatitis C, Chronic / Q000150:complications; D006801:Humans; D008113:Liver Neoplasms / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000517:prevention & control; D020411:Oligonucleotide Array Sequence Analysis; D012176:Retinoids / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D012176:Retinoids; C487689:(2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid