目的：通过分析识别前列腺癌功能基因模块并挖掘影响这些模块的核心转录因子与关键基因，探讨前列腺癌的发病 机制。方法：通过加权基因共表达网络分析（weighted gene co-expressed network analysis, WGCNA）识别与前列腺癌病理分期、 Gleason分级等重要临床特征相关的枢纽基因模块，利用OPOSSUM在线工具分析富集调控这些基因的转录因子，应用通路富集 分析和蛋白质相互作用网络分析识别前列腺癌的关键基因及其对前列腺癌患者重要临床特征和无病生存率（disease free survival, DFS）的影响。结果：识别出3个枢纽模块，分别与前列腺癌病理T分期、病理N分期、Gleason分级高度相关。进一步筛选得到 13个前列腺癌核心转录因子参与调控这3个枢纽模块。这些转录因子调控的差异表达基因显著富集于Calcium、cGMP-PKG、 cAMP 前列腺癌相关信号通路, 其组成的基因网络中 14 个关键基因（PRKG1、PRKG2、CYSLTR2、GRPR、CHRM3、ADCY5、 ADRA1D、EDNRA、EDNRB、CYSLTR2、AGTR1、GRPR、GRIA1和OXT）处于重要节点位置，其中ADRA1A、PRKG2、CHRM3、 ADRA1D和EDN3高表达显著延长了前列腺癌患者的DFS（均P<0.01）。结论：ADRA1A、PRKG2、CHRM3、ADRA1D和EDN3 受前列腺癌核心转录因子调控，与前列腺癌重要临床特征高度相关，且高表达会显著增加前列腺癌的DFS，对前列腺癌机制的后 续研究具有重要的参考价值。

Objective: To investigate the pathogenesis of prostate cancer by analyzing the associated hub gene modules of prostate cancer and identifying key transcription factors and genes that affect these modules. Methods: WGCNA (weighted gene co-expressed network analysis) was used to identify hub gene modules associated with important clinicopathological features of prostate cancer, such as pathological staging, Gleason grading etc. The OPOSSUM online tool was used to analyze the transcription factors enriching and regulating those genes. Pathway enrichment analysis and protein-protein interaction network analysis were used to identify key genes in prostate cancer. Finally, the effects of these genes on clinical features and disease-free survival (DFS) of prostate cancer patients were analyzed. Results: Three hub modules were identified, and they were highly associated with pathologic T stage, pathologic N stage and Gleason grading of prostate cancer, respectively. Further screening revealed 13 key dysregulated transcription factors that participated in the regulation of these three hub modules. The differentially expressed genes regulated by the 13 key transcription factors were significantly enriched in Calcium signaling pathway, cGMP-PKG signaling pathway and cAMP signaling pathway. 14 key genes (PRKG1, PRKG2, CYSLTR2, GRPR, CHRM3, ADCY5, ADRA1D, EDNRA, EDNRB, CYSLTR2, AGTR1, GRPR, GRIA1 and OXT) were at important nodes in the gene network. Among them, the high expression of ADRA1A, PRKG2, CHRM3, ADRA1D and EDN3 significantly extended the DFS of patients with prostate cancer (all P<0.01). Conclusion: ADRA1A, PRKG2, CHRM3, ADRA1D and EDN3 are regulated by key dysregulated transcription factors and highly associated with clinical features of prostate cancer. Their high expressions will significantly prolong the DFS of prostate cancer patients, which may shed light to the discovery of mechanism in prostate adenocarcinoma.

传染病防治科技重大专项资助（No. 2018ZX10101-003-001-008）