Downregulation of Smac/DIABLO expression in renal cell carcinoma and its prognostic significance
Downregulation of Smac/DIABLO expression in renal cell carcinoma and its prognostic significance
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DOI：
10.1200/jco.2005.02.191
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发表时间：
2005-01-20
影响因子：
45.3
通讯作者：
Miki, T
中科院分区：
文献类型：
--
作者：
Mizutani, Y;Nakanishi, H;Miki, T
目的 第二个线粒体衍生的半胱天冬酶激活剂/低 pl 凋亡结合蛋白直接抑制剂 (Smac/DIABLO) 最近被鉴定为响应凋亡刺激从线粒体释放的蛋白质，并通过拮抗凋亡蛋白抑制剂促进凋亡。此外，Smac/DIABLO 在癌细胞对免疫和药物诱导的细胞凋亡的敏感性中发挥着重要的调节作用。然而，人们对 Smac/DIABLO 在包括肾细胞癌 (RCC) 在内的各种癌症中的临床意义知之甚少。本研究检测了 78 个健康肾脏和 78 个肾细胞癌中的 Smac/DIABLO 表达。 材料和方法 使用非固定的新鲜冷冻组织，通过蛋白质印迹分析来定量 Smac/DIABLO 表达水平。 结果 与自体正常肾脏相比，RCC 中 Smac/DIABLO 的表达较低。 78 例肾细胞癌中有 64 例（82%）表达 Smac/DIABLO，18% 呈阴性，而正常肾组织 100% 呈阳性。在 I/II 期 RCC 中，96% 表达 Smac/DIABLO，而在 III/IV 期仅 50% 表达 Smac/DIABLO。 Smac/DIABLO 表达与 RCC 分级呈负相关。在 5 年随访中，表达 Smac/DIABLO 的 RCC 患者比不表达 Smac/DIABLO 的患者术后疾病特异性生存期更长。 Smac/DIABLO cDNA 转染增强了 RCC 中肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 介导和顺铂介导的细胞毒性结论本研究首次证明 Smac/DIABLO 表达在 RCC 中下调，并且 RCC 中没有 Smac/DIABLO 表达预示着较差的预后。此外，Smac/DIABLO 转染使 RCC 对 TRAIL/顺铂诱导的细胞凋亡敏感。这些结果表明，RCC 中的 Smac/DIABLO 表达可用作预后参数，并且 RCC 中 Smac/DIABLO 表达的增强可能会增强免疫治疗和化疗。 (C) 2005 年，美国临床肿瘤学会。
Purpose Second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pl (Smac/DIABLO) was recently identified as a protein that is released from mitochondria in response to apoptotic stimuli and promotes apoptosis by antagonizing inhibitor of apoptosis proteins. Furthermore, Smac/DIABLO plays an important regulatory role in the sensitization of cancer cells to both immune- and drug-induced apoptosis. However, little is known about the clinical significance of Smac/DIABLO in various cancers, including renal cell carcinoma (RCC). This study examined Smac/DIABLO expression in 78 healthy kidneys and 78 RCCs.Materials and Methods The level of Smac/DIABLO expression was quantified by Western blot analysis using nonfixed fresh frozen tissues.Results The expression of Smac/DIABLO was lower in RCC compared with the autologous normal kidney. Sixty-four (82%) of 78 of RCC expressed Smac/DIABLO, and 18% were negative, whereas 100% of normal kidney tissues were positive. In stage I/II RCC, 96% expressed Smac/DIABLO, whereas only 50% expressed Smac/DIABLO in stage III/IV. Smac/DIABLO expression inversely correlated with the grade of RCC. Patients with RCC expressing Smac/DIABLO had a longer postoperative disease-specific survival than those without Smac/DIABLO expression in the 5-year follow-up. Transfection with Smac/DIABLO cDNA enhanced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) -mediated and cisplatin-mediated cytotoxicity in RCCConclusion The present study demonstrates for the first time that Smac/DIABLO expression was downregulated in RCC and that no Smac/DIABLO expression in RCC predicted a worse prognosis. In addition, transfection with Smac/DIABLO sensitized RCC to TRAIL/cisplatin-induced apoptosis. These results suggest that Smac/DIABLO expression in RCC may be used as a prognostic parameter, and that enhancement of Smac/DIABLO expression in RCC may potentiate immunotherapy and chemotherapy. (C) 2005 by American Society of Clinical Oncology.