Anticancer therapy against hepatocellular carcinoma by survivin targeting

生存素靶向治疗肝细胞癌

• 批准号: 13670531
• 负责人: NAKAO Kazuhiko
• 金额: $ 2.3万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670531/
• 关键词: Survivin; Interferon-α; Hepatoma; TRAIL; siRNA; 樹状細胞; survivin; DNAワクチン; 肝癌; TIAP遺伝子

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.

存活素在包括肝细胞癌在内的癌组织中表达，但在正常组织中不表达，其抑制半胱天冬酶的活性，导致癌细胞对Fas或化疗剂介导的细胞凋亡的抗性。此外，通过用反义寡核苷酸或显性负表达载体转导抑制存活素表达，使癌细胞对化疗剂介导的凋亡敏感。肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）是TNF超家族的一员，可诱导多种癌细胞凋亡，对正常细胞几乎没有影响。然而，人肝癌细胞对TRAIL诱导的凋亡具有抗性。最近，Griffith等报道了存活素的细胞水平与肾细胞癌细胞对TRAIL介导的凋亡的抵抗密切相关。在本研究中，我们已经表明，与1,000 IU的IFN-α预孵育明显增强TRAIL诱导的HuH-7，Hep 3B和PLC/PRF/5人肝癌细胞的凋亡。IFN-α可抑制Survivin及其mRNA的表达。我们还证实了Survivin的异位表达显著抑制了TRAIL/IFN-α诱导的HuH-7细胞凋亡。这些结果表明IFN-α下调Survivin表达可能是IFN-α增强TRAIL诱导的细胞凋亡的机制之一，TRAIL与IFN-α联合应用可能具有治疗人肝癌的潜力，我们还发现siRNA转染下调Survivin表达可使人肝癌细胞对TRAIL诱导的凋亡敏感。

项目成果

Masaya Shigeno, et al.: "Interferon-α sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-κB inactivation"Oncogene. (in press). (2003)

Masaya Shigeno 等人：“干扰素-α 通过 DR5 上调和 NF-κB 失活使人肝癌细胞对 TRAIL 诱导的细胞凋亡敏感”Oncogene（出版中）。

Masaya Shigeno, et al.: "Interferon-α sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-κB inactivation"Oncogene. 22. 1653-1662 (2003)

Masaya Shigeno 等人：“干扰素-α 通过 DR5 上调和 NF-κB 失活使人肝癌细胞对 TRAIL 诱导的细胞凋亡敏感”Oncogene。22. 1653-1662 (2003)

Yoko Tamada, et al.: "p48 overexpression enhances interferon-mediated expression and activity of double-stranded RNA-dependent protein kinase in human hepatoma cells"Journal of Hepatology. 37. 493-499 (2002)

Yoko Tamada 等人：“p48 过表达增强人肝癌细胞中干扰素介导的双链 RNA 依赖性蛋白激酶的表达和活性”《肝脏病学杂志》。

Hiroki Ishikawa, et al.: "Retrovirus-mediated gene therapy for hepatocellular carcinoma with reversely oriented therapeutic gene expression regulated by α-fetoprotein enhancer/promoter"Biochem Biophys Res Commun. 287・4. 1034-1040 (2001)

Hiroki Ishikawa 等人：“逆转录病毒介导的肝细胞癌基因治疗，通过 α-胎蛋白增强子/启动子调节反向治疗基因表达”Biochem Biophys Res Commun. 287·4 (2001)。

Hiroyuki Ishikawa, et al.: "Retrovirus-mediated gene therapy for hepatocellular carcinoma with reversely oriented therapeutic gene expression regulated by α-fetoprotein enhancer/promoter"Biochem.Biophys.Res.Commun.. 287. 1034-1040 (2001)

Hiroyuki Ishikawa 等人：“逆转录病毒介导的肝细胞癌基因治疗，通过甲胎蛋白增强子/启动子调节反向治疗基因表达”Biochem.Biophys.Res.Commun.. 287. 1034-1040 (2001)