Grinchuk Oleg V, Motakis Efthymios, Yenamandra Surya Pavan, Ow Ghim Siong, Jenjaroenpun Piroon, Tang Zhiqun, Yarmishyn Aliaksandr A, Ivshina Anna V, Kuznetsov Vladimir A
Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore.
Current address: RIKEN, Japan.
Oncotarget. 2015 Dec 8;6(39):42197-221. doi: 10.18632/oncotarget.6255.
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.
超过30%的人类蛋白质编码基因形成了遗传性复杂基因组结构，其由正义-反义（SA）基因对（SAGP）组成，这些基因对从给定基因座的两条链转录其RNA。这种结构代表了基因组复杂性的重要新组成部分，促成了癌细胞中的基因表达失调。因此，这些结构可能参与癌症通路，进而可用于发现新的药物靶点。然而，SAGP在癌症通路中的整体作用尚未得到研究。在此，我们使用系统生物学、预后生存和实验方法研究了与乳腺癌（BC）相关通路相关的SAGP。基因表达分析确定了73个与BC相关的SAGP，它们在BC中高度相关。对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个具有生存意义的SAGP。经qRT-PCR验证的12-SAGP预后特征可重复性地将BC患者分为低风险和高风险预后亚组。确定了在三个研究队列中共同的1381个由SAGP定义的差异表达基因。对这些基因的功能富集分析揭示了GABPA基因网络，包括与BC相关的SAGP、参与细胞周期、剪接体和蛋白酶体途径的特定基因集。使用siRNA敲低研究支持了GABPA在BC细胞中的共调节功能。因此，我们证明了SAGP是与癌症相关通路相互连接并与BC患者临床结果相关的协同功能基因组结构。综上所述，SAGP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的病理基因网络的新方面。
