Phosphorylated FADD induces NF-κB, perturbs cell cycle, and is associated with poor outcome in lung adenocarcinomas
Phosphorylated FADD induces NF-κB, perturbs cell cycle, and is associated with poor outcome in lung adenocarcinomas
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DOI：
10.1073/pnas.0500397102
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发表时间：
2005-08-30
影响因子：
11.1
通讯作者：
Rehemtulla, A
中科院分区：
文献类型：
--
作者：
Chen, GA;Bhojani, MS;Rehemtulla, A
为了确定肺癌的临床生物标志物，我们使用 cDNA 微阵列和 2D 蛋白质分析来证明 Fas 相关死亡结构域 (FADD) mRNA 和蛋白质的增加与较差的生存率显着相关。对 24 个独立肿瘤中 FADD 基因的拷贝数和序列的分析排除了侵袭性肺癌中存在扩增和/或突变的 FADD 基因。基于免疫组织化学的组织微阵列分析表明，FADD 的核定位和 FADD 磷酸化形式 (p-FADD) 的升高与不良预后相关 (P = 0.003)。 p-FADD 表达增加的肿瘤显示 NF-kappa B (P = 0.004) 激活升高，这是一种与多种癌症的肿瘤发生和转移相关的常见分子改变。为了提供 p-FADD 和 NF-kappa B 之间的联系，细胞培养研究表明，与表达非磷酸化形式 FADD 或载体对照的细胞相比，p-FADD 的过度表达会导致 NF-kappa B 活性增加，并导致细胞周期 G2 期细胞数量减少。此外，肺肿瘤样本的 cDNA 微阵列分析表明，FADD 转录本水平的升高与细胞周期蛋白 D1 (P < 0.01) 和 B1 (P < 0.01) 的过表达显着相关，这两个基因参与细胞周期进展的调节，并且可由 NF-κ B 诱导。这些研究表明，NF-κ B 活性的诱导及其对细胞周期进展的影响可能代表了与升高相关的侵袭性肿瘤行为的分子基础。 p-FADD 在肺腺癌中的表达。
In an effort to identify a clinical biomarker for lung cancer, we used cDNA microarray and 2D protein analyses to demonstrate that increased Fas-associated death domain (FADD) mRNA and protein were significantly associated with poor survival. Analyses of copy number and sequence of the FADD gene in 24 independent tumors ruled out the existence of an amplified and/or mutated FADD gene in aggressive lung cancers. Immunohistochemistry-based tissue microarray analysis showed that nuclear localization of FADD and elevation of the phosphorylated form of FADD (p-FADD) correlated with poor outcome (P = 0.003). Tumors with increased p-FADD expression showed elevated NF-kappa B (P = 0.004) activation, a frequent molecular alteration associated with tumorigenesis and metastasis in a variety of cancers. To provide a link between p-FADD and NF-kappa B, cell culture studies demonstrated that overexpression of p-FADD leads to an increase in NF-kappa B activity and a decrease in the number of cells in the G2 phase of the cell cycle, compared with cells expressing the nonphosphorylatable form of FADD or the vector control. Furthermore, cDNA microarray analyses of lung tumor samples showed that increased levels of FADD transcripts were significantly correlated with overexpression of cyclins D1 (P < 0.01) and B1 (P < 0.01), genes that are involved in the regulation of cell cycle progression and are inducible by NF-kappa B. These studies demonstrate that induction of NF-kappa B activity and its effects on cell-cycle progression may represent a molecular basis underlying the aggressive tumor behavior associated with elevated p-FADD expression in lung adenocarcinoma.