Abstract

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.

Highlights

  • Thyroid cancer is one of the most common cancers with 567,000 new cases worldwide in 2018 [1]

  • By combining integrated bioinformatics analysis with experimental validation, we found several novel transcription factors (TFs) that were tightly relevant to aggressiveness of Anaplastic thyroid carcinoma (ATC) and may be potential targets for ATC therapy

  • differentially expressed genes (DEGs) (FDR

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Summary

Introduction

Thyroid cancer is one of the most common cancers with 567,000 new cases worldwide in 2018 [1]. Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid cancer. It is responsible for more than half of all thyroid cancer deaths, despite only accounting for 2% of thyroid cancer incidence. The overall survival rate of this undifferentiated thyroid cancer is as low as 13% [2]. Certain novel treatment methods, including surgical resection, radioiodine ablation, chemotherapy, and molecular targeted therapy, provide possibilities for the treatment of ATC, there is limited survival improvement over the last decades. Identification of regulatory networks associated with ATC and investigation of emerging molecularly targeted therapies have been an ongoing interest

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