title: Identification of the collagen type 1 α 1 gene (COL1A1) as a candidate survival-related factor associated with hepatocellular carcinoma.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death especially among Asian and African populations. It is urgent that we identify carcinogenesis-related genes to establish an innovative treatment strategy for this disease.
  
  
  METHODS
  Triple-combination array analysis was performed using one pair each of HCC and noncancerous liver samples from a 68-year-old woman. This analysis consists of expression array, single nucleotide polymorphism array and methylation array. The gene encoding collagen type 1 alpha 1 (COL1A1) was identified and verified using HCC cell lines and 48 tissues from patients with primary HCC.
  
  
  RESULTS
  Expression array revealed that COL1A1 gene expression was markedly decreased in tumor tissues (log2 ratio -1.1). The single nucleotide polymorphism array showed no chromosomal deletion in the locus of COL1A1. Importantly, the methylation value in the tumor tissue was higher (0.557) than that of the adjacent liver tissue (0.008). We verified that expression of this gene was suppressed by promoter methylation. Reactivation of COL1A1 expression by 5-aza-2'-deoxycytidine treatment was seen in HCC cell lines, and sequence analysis identified methylated CpG sites in the COL1A1 promoter region. Among 48 pairs of surgical specimens, 13 (27.1%) showed decreased COL1A1 mRNA expression in tumor sites. Among these 13 cases, 10 had promoter methylation at the tumor site. The log-rank test indicated that mRNA down-regulated tumors were significantly correlated with a poor overall survival rate (P = 0.013).
  
  
  CONCLUSIONS
  Triple-combination array analysis successfully identified COL1A1 as a candidate survival-related gene in HCCs. Epigenetic down-regulation of COL1A1 mRNA expression might have a role as a prognostic biomarker of HCC.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Gastroenterological Surgery (Department of Surgery II), Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. snomoto@med.nagoya-u.ac.jp.
authors.forename: Shuji
authors.initials: S
authors.lastname: Nomoto
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Hishida
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Inokawa
authors.forename: Mitsuro
authors.initials: M
authors.lastname: Kanda
authors.forename: Yukiyasu
authors.initials: Y
authors.lastname: Okamura
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nishikawa
authors.forename: Chie
authors.initials: C
authors.lastname: Tanaka
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kobayashi
authors.forename: Suguru
authors.initials: S
authors.lastname: Yamada
authors.forename: Goro
authors.initials: G
authors.lastname: Nakayama
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Fujii
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Masahiko
authors.initials: M
authors.lastname: Koike
authors.forename: Michitaka
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Shin
authors.initials: S
authors.lastname: Takeda
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kodera
mesh_terms: D000368:Aged; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000235:genetics*; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D008969:Molecular Sequence Data; D015996:Survival Rate / Q000639:trends
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain