Gene networks and microRNAs implicated in aggressive prostate cancer.
Gene networks and microRNAs implicated in aggressive prostate cancer.
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DOI：
10.1158/0008-5472.can-09-2183
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发表时间：
2009-12-15
期刊：
影响因子：
11.2
通讯作者：
Thibodeau SN
中科院分区：
文献类型：
--
作者：
Wang L;Tang H;Thayanithy V;Subramanian S;Oberg AL;Cunningham JM;Cerhan JR;Steer CJ;Thibodeau SN
前列腺癌(PC)是一种复杂的疾病，可能相对无害，也可能极具侵袭性。为了寻找侵袭性PC发病途径中的候选基因，我们采用差异表达分析和共表达网络分析相结合的系统生物学方法，对62例侵袭性PC患者(Gleason分级≥8级)和63例非侵袭性PC患者(Gleason分级≤5级)的淋巴母细胞系进行了转录谱分析。从检测的13935个基因和273个microRNA中，我们发现1100mRNAs和7个microRNAs存在显著差异，错误发现率为0.01%。我们还发现了一个与PC侵袭性表型显著相关的共表达模块(p=3.67×10−11)。感兴趣的模块的特征是细胞周期相关基因的过度表达(假发现率=3.5×10−50)。在这个模块中，我们进一步定义了20个与其他基因高度关联的HUB基因。有趣的是，在7个差异表达的microRNAs中，有5个与细胞周期调控有关，两个(miR-145和miR-331-3p)被预测针对20个Hub基因中的3个。这两个microRNAs的异位表达降低了目的HUB基因的表达，从而导致细胞生长抑制和细胞凋亡。这些结果表明，细胞周期可能是导致PC侵袭性表型的分子途径。进一步研究细胞周期相关基因(特别是HUB基因)和调节这些HUB基因的miRNAs有助于识别与侵袭性表型有关的候选基因，并有助于更好地理解PC的病因和进展。
Prostate cancer (PC), a complex disease, can be relatively harmless or extremely aggressive. To identify candidate genes involved in causal pathways of aggressive PC, we implemented a systems biology approach by combining differential expression analysis and co-expression network analysis to evaluate transcriptional profiles using lymphoblastoid cell lines from 62 PC patients with aggressive phenotype (Gleason grade ≥ 8) and 63 PC patients with nonaggressive phenotype (Gleason grade ≤ 5). From 13935 mRNA genes and 273 microRNAs tested, we identified significant differences in 1100 mRNAs and 7 microRNAs with false discovery rate < 0.01. We also identified a co-expression module demonstrating significant association with the aggressive phenotype of PC (p=3.67×10−11). The module of interest was characterized by over-representation of cell cycle-related genes (false discovery rate = 3.50×10−50). From this module, we further defined 20 hub genes that were highly connected to other genes. Interestingly, five of the 7 differentially expressed microRNAs have been implicated in cell cycle regulation and two (miR-145 and miR-331-3p) are predicted to target three of the 20 hub genes. Ectopic expression of these two microRNAs reduced expression of target hub genes and subsequently resulted in cell growth inhibition and apoptosis. These results suggest that cell cycle is likely to be a molecular pathway causing aggressive phenotype of PC. Further characterization of cell cycle-related genes (particularly, the hub genes) and miRNAs that regulate these hub genes could facilitate identification of candidate genes responsible for the aggressive phenotype and lead to a better understanding of PC etiology and progression.