Cellular Retinol–Binding Protein–1 in Hepatocellular Carcinoma Correlates With β–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 ≥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.