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Alterations of ubiquitin ligases in human cancer and their association with the natural history of the tumor

机译：人类癌症中泛素连接酶的改变及其与肿瘤自然史的关系

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Protein ubiquitination is critical for many cellular processes, through its ability to regulate protein degradation and various signaling mechanisms. In the ubiquitin (Ub) system, substrate specificity is achieved through the E3 family of Ub ligases. Because alterations of the ubiquitination machinery have been reported in human cancers, the selective interference with Ub ligases might represent a powerful therapeutic tool. Here, we report the first wide survey of misregulation of Ub ligases in cancer. We analysed 82 Ub ligases in nine types of cancer by in situ hybridization on tissue microarrays. We found 27 instances in which an Ub ligase was altered in a given type of tumor, when compared with normal tissues: 21 cases of overexpression and 6 cases of underexpression. We further analysed selected Ub ligases in large cohorts of breast and non-small-cell lung carcinomas. In five, of six, of these extended analyses (HUWE1, CCNB1IP1, SIAH1 and SIAH2 in breast cancer and CCNB1IP1 in lung cancer), we found that the levels of Ub ligases correlated significantly with relevant prognostic factors, and with clinical outcome. Our findings show that the alteration of Ub ligases is a frequent event in cancer and identify candidate targets for molecular therapies.
机译：蛋白质泛素化通过调节蛋白质降解和各种信号传导机制的能力，对于许多细胞过程至关重要。在泛素（Ub）系统中，底物特异性是通过E3家族的Ub连接酶实现的。因为在人类癌症中已经报道了泛素化机制的改变，所以对Ub连接酶的选择性干扰可能代表了一种强大的治疗工具。在这里，我们报告了癌症中Ub连接酶失调的首次广泛调查。我们通过在组织芯片上原位杂交分析了9种类型的癌症中的82个Ub连接酶。我们发现，与正常组织相比，在给定类型的肿瘤中，有27例Ub连接酶发生了改变：21例过表达和6例表达不足。我们进一步分析了乳腺癌和非小细胞肺癌大样本人群中选定的Ub连接酶。在这些扩展分析的六分之五中（乳腺癌中的HUWE1，CCNB1IP1，SIAH1和SIAH2和肺癌中的CCNB1IP1），我们发现Ub连接酶的水平与相关的预后因素和临床结局显着相关。我们的发现表明，Ub连接酶的改变是癌症中的常见事件，并确定了分子疗法的候选靶标。

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