Integrated Bioinformatics Analysis of Master Regulators in Anaplastic Thyroid Carcinoma
Integrated Bioinformatics Analysis of Master Regulators in Anaplastic Thyroid Carcinoma
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甲状腺未分化癌主调节因子的综合生物信息学分析
DOI：
10.1155/2019/9734576
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发表时间：
2019-01-01
影响因子：
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通讯作者：
Huang, Ping
中科院分区：
文献类型：
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作者：
Pan, Zongfu;Li, Lu;Huang, Ping
甲状腺间变性癌（ATC）是最具侵袭性和快速致死性的肿瘤之一。然而，近几十年来，在延长寿命和降低死亡率方面取得的进展有限。因此，迫切需要确定ATC进展的主要调控因子。本研究从Gene Expression Omnibus中检索了32个ATC样本和78个正常甲状腺组织的GSE33630、GSE29265和GSE65144三个数据集。从三个数据集中共鉴定出1804个一致变化的差异表达基因（deg）。KEGG通路富集提示上调的deg主要富集于ecm受体相互作用、细胞周期、PI3K-Akt信号通路、局灶黏附和p53信号通路。此外，通过Cytoscape插件MCODE鉴定出PPI网络中的关键基因模块，这些关键基因模块主要与DNA复制、细胞周期过程、胶原纤维组织和白细胞迁移调控有关。此外，TOP2A、CDK1、CCNB1、VEGFA、BIRC5、MAPK1、CCNA2、MAD2L1、CDC20和BUB1被鉴定为PPI网络的枢纽基因。有趣的是，模块分析显示，10个枢纽基因中有8个参与了模块1的网络，模块2中超过70%的基因由胶原蛋白家族成员组成。值得注意的是，转录因子调控网络分析表明，E2F7、FOXM1和NFYB是模块1的主调控因子，而CREB3L1是模块2的主调控因子。实验验证表明，与正常甲状腺组相比，ATC组织和细胞系中CREB3L1、E2F7和FOXM1的表达明显上调。总之，TFs调控网络提供了ATC发生和发展的更详细的分子机制。包括E2F7、FOXM1、CREB3L1和NFYB在内的tf可能是ATC进展的主要调节因子，这表明它们在ATC治疗中具有潜在的分子治疗靶点作用。
Anaplastic thyroid carcinoma (ATC) is one of the most aggressive and rapidly lethal tumors. However, limited advances have been made to prolong the survival and to reduce the mortality over the last decades. Therefore, identifying the master regulators underlying ATC progression is desperately needed. In our present study, three datasets including GSE33630, GSE29265, and GSE65144 were retrieved from Gene Expression Omnibus with a total of 32 ATC samples and 78 normal thyroid tissues. A total of 1804 consistently changed differentially expressed genes (DEGs) were identified from three datasets. KEGG pathways enrichment suggested that upregulated DEGs were mainly enriched in ECM-receptor interaction, cell cycle, PI3K-Akt signaling pathway, focal adhesion, and p53 signaling pathway. Furthermore, key gene modules in PPI network were identified by Cytoscape plugin MCODE and they were mainly associated with DNA replication, cell cycle process, collagen fibril organization, and regulation of leukocyte migration. Additionally, TOP2A, CDK1, CCNB1, VEGFA, BIRC5, MAPK1, CCNA2, MAD2L1, CDC20, and BUB1 were identified as hub genes of the PPI network. Interestingly, module analysis showed that 8 out of 10 hub genes participated in Module 1 network and more than 70% genes of Module 2 consisted of collagen family members. Notably, transcription factors (TFs) regulatory network analysis indicated that E2F7, FOXM1, and NFYB were master regulators of Module 1, while CREB3L1 was the master regulator of Module 2. Experimental validation showed that CREB3L1, E2F7, and FOXM1 were significantly upregulated in ATC tissue and cell line when compared with normal thyroid group. In conclusion, the TFs regulatory network provided a more detail molecular mechanism underlying ATC occurrence and progression. TFs including E2F7, FOXM1, CREB3L1, and NFYB were likely to be master regulators of ATC progression, suggesting their potential role as molecular therapeutic targets in ATC treatment.