Cellular retinol-binding protein-1 in hepatocellular carcinoma correlates with beta-catenin, Ki-67 index, and patient survival.
The cellular retinol-binding protein-1 (CRBP-1) plays a key role in the esterification and intercellular transfer of retinol. By in situ hybridization, immunohistochemistry, and confocal laser scanning microscopy (CLSM), we show that, in normal liver, CRBP-1 is strongly expressed in the cytoplasm of hepatic stellate cells (HSCs) and myofibroblasts (MFs) with only low CRBP-1 levels in hepatocytes. By contrast, in 196 hepatocellular carcinoma (HCC) specimens CRBP-1 expression in MFs was down-regulated in 83%. Patients with high CRBP-1 expression in MFs had a significantly higher 2-year survival as compared with patients with low CRBP-1 expression (52% vs. 29%, respectively; P =.034). An aberrant nuclear CRBP-1 accumulation resulting from cytoplasmic invagination was found in 29% of HCCs. Nuclear CRBP-1 staining correlated positively with a favorable tumor stage (Okuda stage I; P =.01) and negatively with the Ki-67(+) proliferation fraction (PF). A Ki-67(+) PF of > or =10% was associated with a lower 2-year survival probability as compared with patients with a Ki-67(+) PF of <10% (12% vs. 40%, respectively; P =.015). Prognosis did not correlate with the nuclear beta-catenin expression. There was, however, a close correlation between nuclear CRBP-1 inclusions and nuclear beta-catenin staining in HCCs (P =.008), suggesting a cross talk between CRBP-1 and the Wnt/wingless signal transduction pathway. In conclusion, our findings demonstrate that CRBP-1 detection may be useful for the discrimination between nonneoplastic and neoplastic liver cells and suggest that modulation of CRBP-1 expression in HCCs contributes to tumor growth and progression via retinoid-mediated signaling and disruption of cellular vitamin A homeostasis.
Schmitt-Gräff
Annette
A
Institute of Pathology, University of Freiburg, Freiburg, Germany. ahsg@ukl.uni-freiburg.de
Ertelt
Viktoria
V
Allgaier
Hans-P
HP
Koelble
Konrad
K
Olschewski
Manfred
M
Nitschke
Roland
R
Bochaton-Piallat
Marie-L
ML
Gabbiani
Giulio
G
Blum
Hubert E
HE
D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000401:mortality / Q000503:physiopathology*; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000032:analysis*; D004951:Esterification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis*; D008099:Liver / Q000737:chemistry / Q000502:physiology; D008103:Liver Cirrhosis / Q000503:physiopathology; D008113:Liver Neoplasms / Q000737:chemistry / Q000401:mortality / Q000503:physiopathology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D012176:Retinoids / Q000502:physiology; D012177:Retinol-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D054840:Retinol-Binding Proteins, Cellular; D015398:Signal Transduction / Q000502:physiology; D015996:Survival Rate; D015534:Trans-Activators / Q000032:analysis*; D014801:Vitamin A / Q000378:metabolism; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D019394:Ki-67 Antigen; D011518:Proto-Oncogene Proteins; C518456:RBP1 protein, human; D012176:Retinoids; D012177:Retinol-Binding Proteins; D054840:Retinol-Binding Proteins, Cellular; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D014801:Vitamin A