Decoy receptor-2 small interfering RNA (siRNA) strategy employing three different siRNA constructs in combination defeats adenovirus-transferred tumor necrosis factor-related apoptosis-inducing ligand resistance in lung cancer cells
Decoy receptor-2 small interfering RNA (siRNA) strategy employing three different siRNA constructs in combination defeats adenovirus-transferred tumor necrosis factor-related apoptosis-inducing ligand resistance in lung cancer cells
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DOI：
10.1089/hum.2006.111
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发表时间：
2007-01-01
影响因子：
4.2
通讯作者：
Sanlioglu, Salih
中科院分区：
文献类型：
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作者：
Aydin, Cigdem;Sanlioglu, Ahter D.;Sanlioglu, Salih
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）选择性诱导癌细胞凋亡，而非正常细胞凋亡。然而，研究表明，超过一半的人类肿瘤表现出TRAIL耐药性。虽然TRAIL耐药的机制尚不清楚，但它代表了任何TRAIL介导的基因治疗方法的障碍。此外，在癌细胞中，TRAIL受体（TRAIL- r）表达谱与TRAIL耐药之间没有相关性。在这项研究中，筛选了三种不同的肺癌细胞系和三种不同的原代培养的肺癌患者（两名鳞状细胞肺癌患者和一名腺癌患者）对腺病毒递送TRAIL的敏感性。尽管trail耐药的原代肺细胞培养和A549肺癌细胞系表现出高水平的表面诱饵受体-2 （DcR2/TRAIL-R4）表达，但trail敏感的肺癌细胞系（HBE和H411）未能表达它。一种包含三种不同siRNA结构的DcR2短干扰RNA （siRNA）方法联合下调DcR2/TRAILR4的表达，并使肺癌细胞对trail诱导的凋亡敏感。10例肺癌患者的免疫组化染色表明，DcR2/TRAIL-R4高水平表达是非小细胞肺癌患者常见的表型。
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells but not in normal cells. However, studies have indicated that more than half of human tumors exhibit TRAIL resistance. Although the mechanism of TRAIL resistance is not understood, it represents a barrier to any TRAIL-mediated gene therapy approach. In addition, no correlation between TRAIL receptor (TRAIL-R) expression profile and TRAIL resistance has been demonstrated in cancer cells. In this study, three different lung cancer cell lines and three different primary cell cultures established from patients with lung cancer (two patients with squamous cell lung carcinoma and one with adenocarcinoma) were screened for sensitivity to adenoviral delivery of TRAIL. Whereas TRAIL-resistant primary lung cell cultures and the A549 lung cancer cell line exhibited high levels of surface decoy receptor-2 (DcR2/TRAIL-R4) expression, TRAIL-sensitive lung cancer cell lines (HBE and H411) failed to express it. A DcR2 short interfering RNA (siRNA) approach involving three different siRNA constructs in combination downregulated DcR2/TRAILR4 expression and sensitized lung cancer cells to TRAIL-induced apoptosis. Immunohistochemical staining of samples from 10 patients with lung carcinoma suggested that high-level DcR2/TRAIL-R4 expression is a common phenotype observed in patients with non-small cell lung carcinoma.