Anticancer therapy against hepatocellular carcinoma by survivin targeting

Survivin在包括肝细胞癌在内的癌症组织中表达，但在正常组织中不表达，它抑制半胱天冬酶的活性，导致癌细胞对Fas或化疗药物介导的凋亡产生抗性。此外，通过反义寡核苷酸转导或显性阴性表达载体抑制survivin表达，使癌细胞对化疗药物介导的细胞凋亡敏感。肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）是TNF超家族的一员，在多种癌细胞中诱导细胞凋亡，对正常细胞影响很小或没有影响。然而，人肝癌细胞对trail诱导的细胞凋亡具有抗性。最近Griffith等人报道了survivin的细胞水平与肾细胞癌细胞抵抗trail介导的凋亡密切相关。在本研究中，我们发现1000 IU IFN-α预孵育明显增强了trail诱导的人肝癌细胞HuH-7、Hep3B和PLC/PRF/5的凋亡。IFN-α抑制survivin及其m-RNA的表达。我们还发现异位表达survivin显著抑制TRAIL/IFN-α -诱导的HuH-7细胞凋亡。这些发现提示，IFN-α下调survivin可能是IFN-α增强TRAIL介导的细胞凋亡的原因，并且TRAIL联合IFN-α可能在治疗人肝细胞癌中具有治疗潜力。我们还发现，转染siRNA下调存活表达可使人肝癌细胞对trail诱导的凋亡敏感。

Survivin, which is expressed in cancer tissues including hepatocellular carcinoma but not in normal tissues, represses the activities of caspases resulting in resistance of cancer cells to Fas- or chemotherapeutic agent-mediated apoptosis. In addition, inhibition of survivin expression, by transduction with anti-sense oligonucleotides or a dominant-negative expression vehicle, sensitized cancer cells to chemotherapeutic agent-mediated apoptosis. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, induces apoptosis in a variety of cancer cells with little or no effect on normal cells. Human hepatoma cells, however, are resistant to TRAIL-induced apoptosis. Recently, Griffith et al. reported that the cellular level of survivin is closely relevant to the resistance against TRAIL-mediated apoptosis of renal cell carcinoma cells. In the present study, we have shown that the preincubation with 1,000 IU of IFN-α apparently enhanced the TRAIL-induced apoptosis in HuH-7, Hep3B and PLC/PRF/5 human hepatoma cells. The expression of survivin as well as its m-RNA was repressed by IFN-α in these cells. We also demonstrated that ectopic expression of survivin significantly repressed the TRAIL/IFN-α -induced apoptosis of HuH-7 cells. These findings suggest that downregulation of survivin by IFN-α may account for the enhancement of TRAIL-mediated apoptosis by IFN-α, and that TRAIL in combination with IFN-α may have therapeutic potential in the treatment of human hepatocellular carcinoma.We also found that down regulation of surviving expression by siRNA transfection sensitized human hepatoma cells to TRAIL-induced apoptosis.