title: Expression of Smad7 in hepatocellular carcinoma and dysplastic nodules: resistance mechanism to transforming growth factor-beta.
abstract: OBJECTIVE
  Smad7 is an inhibitory Smad of the transforming growth factor (TGF)-beta signaling pathway. To study resistance mechanisms to antiproliferating effect of TGF-beta in human multistep hepatocarcinogenesis, Smad7, Smad4, TGF-beta1 and TGF-beta receptor II were investigated.
  
  
  METHODS
  Smad7 and Smad4 were evaluated in 15 low-grade dysplastic nodules (DNs), 9 high-grade DNs, 6 early hepatocellular carcinomas (eHCCs) and 41 advanced HCCs by immunohistochemistry and in 37 HCCs and corresponding non-HCCs with fresh tissue, the mRNAs of TGF-beta1 and TGF-beta receptor II were analyzed by RT-PCR.
  
  
  RESULTS
  Smad7 immunoreactivity in tumor cells was found in 25 (61%) advanced HCCs, in contrast to none of DNs and eHCCs. Smad7 expression was significantly higher in advanced HCCs with increased TGF-beta1 or no decrease of TGF-beta receptor II compared to those of corresponding non-HCCs (p=0.044, p=0.027). Smad4 expression in stellate cells was present in 28 (68%) advanced HCCs, which was higher in smaller sized and better differentiated HCCs.
  
  
  CONCLUSIONS
  Smad7, expressed in tumor cells, is considered to be one of resistance mechanisms to increased TGF-beta1 in late stage hepatocarcinogenesis, especially in advanced HCCs without reduced TGF-beta receptor II. Smad4, in stellate cells of HCCs, might be involved in the host resistance to hepatocarcinogenesis.
authors.affiliation: Department of Pathology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Young Nyun
authors.initials: YN
authors.lastname: Park
authors.forename: Kwang Jo
authors.initials: KJ
authors.lastname: Chae
authors.forename: Bong-Kyeong
authors.initials: BK
authors.lastname: Oh
authors.forename: Jinsub
authors.initials: J
authors.lastname: Choi
authors.forename: Kyeong Sook
authors.initials: KS
authors.lastname: Choi
authors.forename: Chanil
authors.initials: C
authors.lastname: Park
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051901:Smad4 Protein; D051906:Smad7 Protein; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; C497796:SMAD4 protein, human; C497806:SMAD7 protein, human; D051901:Smad4 Protein; D051906:Smad7 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta