HuR Regulates β-Tubulin Isotype Expression in Ovarian Cancer
HuR Regulates β-Tubulin Isotype Expression in Ovarian Cancer
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DOI：
10.1158/0008-5472.can-09-4656
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发表时间：
2010-07-15
期刊：
影响因子：
11.2
通讯作者：
Ferlini, Cristiano
中科院分区：
文献类型：
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作者：
Raspaglio, Giuseppina;De Maria, Ilaria;Ferlini, Cristiano
向实体肿瘤供应氧气和营养物是低效的，因为癌组织具有数量不足的微血管，从而诱导最具侵袭性的癌细胞的选择性生长。这就解释了为什么许多导致预后不良的因素是在缺氧/低血糖条件下诱导的。在这些因素中，III类β-微管蛋白基因（TUBB 3）在几种实体瘤中起着重要作用。本文描述的研究表明，葡萄糖剥夺增强了A2780卵巢癌细胞中TUBB 3在基因和蛋白水平上的表达。TUBB 3 mRNA序列的计算机分析预测了3'侧翼非翻译区中RNA结合蛋白Hu抗原（HuR）的推定结合位点。使用RNA下拉和核糖核免疫沉淀技术显示该位点的低血糖依赖性参与。此后，HuR基因沉默揭示TUBB 3翻译在低血糖中是HuR依赖性的，因为HuR沉默抑制TUBB 3 mRNA进入细胞骨架和游离多聚核糖体。最后，在46名卵巢癌患者的临床队列中评估了这一发现的临床价值，在这些患者中发现HuR细胞质染色与高水平的TUBB 3和较差的生存率相关。Cancer Res; 70（14）; 5891-900.（C）2010年AACR。
The supply of oxygen and nutrients to solid tumors is inefficient because cancer tissues have an inadequate number of microvessels, thus inducing the selective growth of the most aggressive cancer cells. This explains why many of the factors underlying a poor prognosis are induced in hypoxic/hypoglycemic conditions. Among these factors, a prominent role in several solid tumors is played by the class III beta-tubulin gene (TUBB3). The study described here reveals that glucose deprivation enhances TUBB3 expression at both the gene and protein levels in A2780 ovarian cancer cells. In silico analysis of TUBB3 mRNA sequence predicted a putative binding site for the RNA-binding protein Hu antigen (HuR) in the 3' flanking untranslated region. A hypoglycemic-dependent engagement of this site was shown using RNA pull-down and ribonucleoimmunoprecipitation techniques. Thereafter, HuR gene silencing revealed that TUBB3 translation is HuR dependent in hypoglycemia because HuR silencing inhibited the entry of TUBB3 mRNA into cytoskeletal and free polysomes. Finally, the clinical value of this finding was assessed in a clinical cohort of 46 ovarian cancer patients in whom it was found that HuR cytoplasmic staining was associated with high levels of TUBB3 and poor survival. Cancer Res; 70(14); 5891-900. (C)2010 AACR.