Sense-antisense gene-pairs in breast cancer and associated pathological pathways.
Sense-antisense gene-pairs in breast cancer and associated pathological pathways.
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DOI：
10.18632/oncotarget.6255
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发表时间：
2015-12-08
期刊：
影响因子：
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通讯作者：
Kuznetsov VA
中科院分区：
文献类型：
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作者：
Grinchuk OV;Motakis E;Yenamandra SP;Ow GS;Jenjaroenpun P;Tang Z;Yarmishyn AA;Ivshina AV;Kuznetsov VA
超过30%的人类蛋白质编码基因形成由正反义（SA）基因对（SAGPs）从给定位点的两条链转录其rna组成的遗传性复杂基因组结构。这些结构代表了基因组复杂性的重要新组成部分，有助于癌细胞中基因表达的放松。因此，这些结构可能与癌症途径有关，进而可用于发现新的药物靶点。然而，SAGPs在癌症通路中的全局作用尚未得到研究。在这里，我们使用系统生物学、预后生存和实验方法研究了SAGPs与乳腺癌（BC）相关的途径。基因表达分析鉴定出73个BC相关的SAGPs，这些SAGPs在BC中高度相关。1161例BC患者的生存建模和元数据分析使我们能够开发一种新的患者预后分组方法，选择12个生存显著的sagp。qrt - pcr验证的12-SAGP预后特征可重复地将BC患者分为低风险和高风险预后亚组。确定了三个研究队列中共有的1381个sagp定义的差异表达基因。这些基因的功能富集分析揭示了GABPA基因网络，包括bc相关SAGPs，参与细胞周期，剪接体和蛋白酶体途径的特定基因集。通过siRNA敲低研究，GABPA在BC细胞中的共调节功能得到了支持。因此，我们证明了SAGPs是与癌症相关途径相互关联的协同功能基因组结构，并与BC患者的临床结果相关。综上所述，SAGPs代表了基因组复杂性的一个重要组成部分，可用于识别癌症中协调病理基因网络的新方面。
More than 30% of human protein-coding genes form hereditary complex genome architectures composed of sense-antisense (SA) gene pairs (SAGPs) transcribing their RNAs from both strands of a given locus. Such architectures represent important novel components of genome complexity contributing to gene expression deregulation in cancer cells. Therefore, the architectures might be involved in cancer pathways and, in turn, be used for novel drug targets discovery. However, the global roles of SAGPs in cancer pathways has not been studied. Here we investigated SAGPs associated with breast cancer (BC)-related pathways using systems biology, prognostic survival and experimental methods. Gene expression analysis identified 73 BC-relevant SAGPs that are highly correlated in BC. Survival modelling and metadata analysis of the 1161 BC patients allowed us to develop a novel patient prognostic grouping method selecting the 12 survival-significant SAGPs. The qRT-PCR-validated 12-SAGP prognostic signature reproducibly stratified BC patients into low- and high-risk prognostic subgroups. The 1381 SAGP-defined differentially expressed genes common across three studied cohorts were identified. The functional enrichment analysis of these genes revealed the GABPA gene network, including BC-relevant SAGPs, specific gene sets involved in cell cycle, spliceosomal and proteasomal pathways. The co-regulatory function of GABPA in BC cells was supported using siRNA knockdown studies. Thus, we demonstrated SAGPs as the synergistically functional genome architectures interconnected with cancer-related pathways and associated with BC patient clinical outcomes. Taken together, SAGPs represent an important component of genome complexity which can be used to identify novel aspects of coordinated pathological gene networks in cancers.