The mRNA-destabilizing protein tristetraprolin is suppressed in many cancers, altering tumorigenic phenotypes and patient prognosis.
The mRNA-destabilizing protein tristetraprolin is suppressed in many cancers, altering tumorigenic phenotypes and patient prognosis.
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DOI：
10.1158/0008-5472.can-08-4238
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发表时间：
2009-06-15
期刊：
影响因子：
11.2
通讯作者：
Wilson GM
中科院分区：
文献类型：
--
作者：
Brennan SE;Kuwano Y;Alkharouf N;Blackshear PJ;Gorospe M;Wilson GM
富含AU的元件结合蛋白（ARE-BP）调节含有同源结合位点的mRNA的稳定性和/或翻译效率。许多靶向转录物编码控制细胞分裂、凋亡和血管生成等过程的因子，这表明ARE-BP表达失调可能会显著影响致癌表型。使用几种方法，我们评估了四个充分表征的ARE-BP在各种人类肿瘤综合征中的表达。AUF 1、TIA-1和HuR mRNA在癌症中没有系统性失调;然而，在许多肿瘤类型中，包括晚期乳腺癌和前列腺癌，tristetraprolin（TTP）mRNA水平显著降低。在侵袭性肿瘤细胞系中恢复TTP表达抑制了三种关键的致瘤表型：细胞增殖、对促凋亡刺激的抗性和VEGF mRNA的表达。然而，TTP表达的细胞后果在不同的细胞模型中不同。基因阵列数据集的分析显示，TTP表达的抑制是乳腺癌的一个负面预后指标，因为肿瘤TTP mRNA水平低的患者更有可能表现出增加的病理肿瘤分级、VEGF表达和复发性疾病的死亡率。总的来说，这些数据确定TTP表达在人类癌症中经常被抑制，这反过来可以改变影响患者结果的致瘤表型。
AU-rich element-binding proteins (ARE-BPs) regulate the stability and/or translational efficiency of mRNAs containing cognate binding sites. Many targeted transcripts encode factors that control processes like cell division, apoptosis, and angiogenesis, suggesting that disregulated ARE-BP expression could dramatically influence oncogenic phenotypes. Using several approaches, we evaluated the expression of four well characterized ARE-BPs across a variety of human neoplastic syndromes. AUF1, TIA-1, and HuR mRNAs were not systematically disregulated in cancers; however, tristetraprolin (TTP) mRNA levels were significantly decreased across many tumor types, including advanced cancers of the breast and prostate. Restoring TTP expression in an aggressive tumor cell line suppressed three key tumorgenic phenotypes: cell proliferation, resistance to pro-apoptotic stimuli, and expression of VEGF mRNA. However, the cellular consequences of TTP expression varied across different cell models. Analyses of gene array datasets revealed that suppression of TTP expression is a negative prognostic indicator in breast cancer, since patients with low tumor TTP mRNA levels were more likely to present increased pathological tumor grade, VEGF expression, and mortality from recurrent disease. Collectively, these data establish that TTP expression is frequently suppressed in human cancers, which in turn can alter tumorigenic phenotypes that influence patient outcomes.