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The therapeutic potential of soluble TRAIL (sTRAIL) in hepatocellular carcinoma(HCC) was studied. The expression of TRAIL receptors was detected in 60 HCC tissues, 20 normal liver samples and 2 HCC cell lines (HepG2 and SMMC-7721) by in situ hybridization. Before and after HepG2 and SMMC-7721 were treated with sTRAIL protein with various concentrations,the apoptosis rate was observed by using flow cytometry and in situ terminal deoxynucleotidyl tranferase (TdT) labeling. The results showed death receptor 4 (DR4) and DR5 were expressed in 60 HCC tissues and 20 normal liver samples, while the expression intensity of DR in HCC tissues was stronger than in normal liver samples. DcR1and DcR2 were not detectable in 54 (90 %) and 25 (41.7 %)HCC tissues, while in 20 normalliver samples, DcR was detectable. The high expressionof DR and low expression of DcR in HCC tissues were significantly differed from the low expression and high expression in normal liver samples. The expression of DR5, DR4 and DcR2 in both HCC cell lines was detectable, but the expression of DcR1 was not detectable. The expression of DR in HCC tissues was related to the differentiation and grades of HCC. In the poor differentiated HCC, the expression of DR was decreased (P＜0.01). The expression of DR in Ⅲ/Ⅳ grades was significantly lower than that in Ⅰ / Ⅱ grades (P＜0.05). The expression of DR was not related to gender, age, HBsAg, AFP, tumor sizeand metastasis. The expression of DR in the HCC drugresistant lines was decreased. After treatment with TRAIL (100 ng/ml) for 24 h, the apoptosis rate of HCC cells, Jurkat cells and human cholangiocarcinoma cell line QBC939 was 10 %, 70 %,50 % respectively. It was suggested that the TRAILR expression is prevalent in HCC with different expression patterns of different receptor types. HCC is resistant to TRAIL-mediated apoptosis.The treatment of TRAIL alone has a limited effect on inducing apoptosis of HepG2 and SMMC-7721.