Expression of Id proteins in human hepatocellular carcinoma: relevance to tumor dedifferentiation.
Several studies reported that Id (Inhibitor of DNA binding or Differentiation) proteins, helix-loop-helix transcription factors, have important roles in differentiation, cell cycle and angiogenesis in various cells. However, the role of Id proteins in hepatocellular carcinoma (HCC) remains unclear. We examined the immunohistochemical expression of Id1, Id2 and Id3 proteins in 54 surgically resected HCCs with surrounding HCV or HBV-related chronic hepatitis (n=30) and liver cirrhosis (n=24). All non-cancerous livers exhibited immunoreactivity for Id proteins and the expression increased from chronic hepatitis to cirrhosis. In HCCs (n=45), well-differentiated tumors mostly exhibited strong or moderate immunostaining for all Id proteins, while proportion of the samples with weak or no expression increased with tumor dedifferentiation and frequently observed in poorly (66.7, 93.3 and 93.3% respectively for Id1, 2, 3) or undifferentiated (100% for all Ids) HCCs. Clinicopathological survey demonstrated a significant correlation between Id1, 2 and 3 expression and differentiation of carcinoma (p=0.0044, 0.0014 and 0.0014, respectively) although univariate analysis indicated that high expression of Id1 was significant predictive factor for longer disease-free survival of the patients (p=0.047). A similar tendency was also observed with Id2 and Id3. The present study demonstrate high expression of Id1, 2 and 3 in well-differentiated HCC and low expression in advanced dedifferentiated HCC, in contrast to its continuous expression during breast, prostate and colon carcinogenesis. These findings suggested that Id1, 2 and 3 might play a role in the early stages of hepatocarcinogenesis, but not in the development of advanced carcinoma, and might consequently be related to HCC dedifferentiation.
Damdinsuren
Bazarragchaa
B
Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, Osaka, Japan.
Nagano
Hiroaki
H
Kondo
Motoi
M
Yamamoto
Hirofumi
H
Hiraoka
Nobuaki
N
Yamamoto
Tameyoshi
T
Marubashi
Shigeru
S
Miyamoto
Atsushi
A
Umeshita
Koji
K
Dono
Keizo
K
Nakamori
Shoji
S
Wakasa
Ken-Ichi
K
Sakon
Masato
M
Monden
Morito
M
D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000401:mortality; D002453:Cell Cycle; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000502:physiology*; D018450:Disease Progression; D018572:Disease-Free Survival; D015972:Gene Expression Regulation, Neoplastic; D006505:Hepatitis; D006801:Humans; D007150:Immunohistochemistry; D051798:Inhibitor of Differentiation Protein 1; D051797:Inhibitor of Differentiation Protein 2; D051796:Inhibitor of Differentiation Proteins; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000401:mortality; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000502:physiology*; D009389:Neovascularization, Pathologic; D012097:Repressor Proteins / Q000096:biosynthesis / Q000502:physiology*; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology*
D004268:DNA-Binding Proteins; C497453:ID1 protein, human; C497450:ID2 protein, human; D051798:Inhibitor of Differentiation Protein 1; D051797:Inhibitor of Differentiation Protein 2; D051796:Inhibitor of Differentiation Proteins; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C075640:ID3 protein, human