RNA processing as an alternative route to attack glioblastoma.
RNA processing as an alternative route to attack glioblastoma.
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DOI：
10.1007/s00439-017-1819-2
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发表时间：
2017-09
期刊：
影响因子：
5.3
通讯作者：
Penalva LO
中科院分区：
文献类型：
--
作者：
Marcelino Meliso F;Hubert CG;Favoretto Galante PA;Penalva LO
基因组分析已经成为确定新的治疗途径的重要工具。对于预后极差的癌症类型尤其如此，因为我们缺乏有效的治疗方法，没有具体的临床起点可供建立。高度恶性的脑肿瘤胶质母细胞瘤(GBM)就是这种难治性癌症的例证，患者的平均生存期只有15个月。对TCGA(癌症基因组图谱)编制的数百个GBM样本的分析已经产生了广泛的转录图谱，确定了普遍的染色体变化，并确定了重要的驱动突变。不幸的是，基于这些结果的临床试验还没有带来结果的改善。因此，有必要对已知在肿瘤复发和治疗反应中发挥作用的其他调节途径进行表征。选择性剪接影响人类90%以上的编码基因，是转录变异和基因调控的重要来源。剪接因子的突变和改变在多种癌症中非常普遍，表明剪接具有作为肿瘤驱动因素的潜力。因此，许多基因被表达为癌症特异性剪接异构体，在功能上与正常组织中发现的典型异构体不同。这些基因包括调控癌症关键途径的基因，如细胞凋亡、DNA修复、细胞增殖和迁移。剪接缺陷甚至会导致基因组不稳定，这是癌症的常见特征，也是肿瘤进化的驱动因素。重要的是，剪接机制的组件是有针对性的；多种药物可以抑制剪接因子或促进剪接的变化，这可以被利用来开始改善临床结果。在这里，我们回顾了当前的文献，并提出了一个探索RNA加工作为治疗GBM的治疗途径的案例。
Genomic analyses have become an important tool to identify new avenues for therapy. This is especially true for cancer types with extremely poor outcomes, since our lack of effective therapies offers no tangible clinical starting point to build upon. The highly malignant brain tumor glioblastoma (GBM) exemplifies such a refractory cancer, with only 15 month average patient survival. Analyses of several hundred GBM samples compiled by the TCGA (The Cancer Genome Atlas) have produced an extensive transcriptomic map, identified prevalent chromosomal alterations, and defined important driver mutations. Unfortunately, clinical trials based on these results have not yet delivered an improvement on outcome. It is, therefore, necessary to characterize other regulatory routes known for playing a role in tumor relapse and response to treatment. Alternative splicing affects more than 90% of the human coding genes and it is an important source for transcript variation and gene regulation. Mutations and alterations in splicing factors are highly prevalent in multiple cancers, demonstrating the potential for splicing to act as a tumor driver. As a result, numerous genes are expressed as cancer-specific splicing isoforms that are functionally distinct from the canonical isoforms found in normal tissue. These include genes that regulate cancer-critical pathways such as apoptosis, DNA repair, cell proliferation, and migration. Splicing defects can even induce genomic instability, a common characteristic of cancer, and a driver of tumor evolution. Importantly, components of the splicing machinery are targetable; multiple drugs can inhibit splicing factors or promote changes in splicing which could be exploited to begin improving clinical outcomes. Here, we review the current literature and present a case for exploring RNA processing as therapeutic route for the treatment of GBM.
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影响因子：
29
作者：
Babic I;Anderson ES;Tanaka K;Guo D;Masui K;Li B;Zhu S;Gu Y;Villa GR;Akhavan D;Nathanson D;Gini B;Mareninov S;Li R;Camacho CE;Kurdistani SK;Eskin A;Nelson SF;Yong WH;Cavenee WK;Cloughesy TF;Christofk HR;Black DL;Mischel PS
通讯作者：
Mischel PS
影响因子：
3.7
作者：
Cote GJ;Zhu W;Thomas A;Martin E;Murad F;Sharina IG
通讯作者：
Sharina IG
影响因子：
20.3
作者：
Cazzola, Mario;Rossi, Marianna;Malcovati, Luca
通讯作者：
Malcovati, Luca
影响因子：
8.8
作者：
Darman, Rachel B.;Seiler, Michael;Buonamici, Silvia
通讯作者：
Buonamici, Silvia
影响因子：
9.7
作者：
Fontana, L.;Rovina, D.;Larizza, L.
通讯作者：
Larizza, L.