Expression of Smad7 in hepatocellular carcinoma and dysplastic nodules: resistance mechanism to transforming growth factor-beta.
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.
Park
Young Nyun
YN
Department of Pathology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Chae
Kwang Jo
KJ
Oh
Bong-Kyeong
BK
Choi
Jinsub
J
Choi
Kyeong Sook
KS
Park
Chanil
C
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*
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