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AIM: To characterize the expression and genomic amplification of decoy receptor 3 (DcR3) in hepatocellular carcinoma (HCC) and to evaluate the role of DcR3 in apoptosis.METHODS: We examined 48 cases of HCC for DcR3 expression by RT-PCR and DcR3 gene amplification by quantitative genomic PCR. DcR3 protein was detected by immunohistochemistry. Terminal deoxynucleotidyl transferase-mediated dUTP digoxigenin nick and labeling (TUNEL) was used to identify the apoptosis cells in tissues.Primary hepatoma cell culture and MTr test were used to evaluate the protection against FasL- and chemicalinduced apoptosis by DcR3 expression.RESULTS: DcR3 mRNA overexpression was detected in 60% HCC (29/48) patients. The occurrence of HCC was not associated with amplification of the gene. One sample base substitution was found in three sites as a sequence in Genbank. The expression of DcR3 in HCC was associated with the apoptotic index (0.067±0.04 vs 0.209±0.12, P＜0.01), size of mass, stage, and infiltration or metastasis (41.2% vs 71.0%, 40% vs 75%, 51.8% vs 84.6%, P＜0.05). DcR3 expression could protect hepatoma cells against apoptosis induced by FasL, but not by chemicals.CONCLUSION: These data suggest that in addition to gene amplification there may be another mechanism underlying DcR3 overexpression. The effect of overexpression of DcR3 on the apoptosis of cancer cells may have direct therapeutic implications for the management of HCC.