Cellular retinol-binding protein-1 in hepatocellular carcinoma correlates with β-catenin, Ki-67 index, and patient survival

Abstract

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 ≥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 β-catenin expression. There was, however, a close correlation between nuclear CRBP-1 inclusions and nuclear β-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. (H epatology 2003;38:470-480.)