J Cancer 2020; 11(14):4181-4192. doi:10.7150/jca.42736

Research Paper

TOP2A Promotes Tumorigenesis of High-grade Serous Ovarian Cancer by Regulating the TGF-β/Smad Pathway

Yan Gao1*, Hongyu Zhao1*, Meng Ren1, Qi Chen1, Jie Li1, Zhefeng Li1, Chenghong Yin2✉, Wentao Yue1✉

1. Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China
2. Departments of Internal Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China
*Yan Gao and Hong-Yu Zhao contributed equally to the work.

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Citation:
Gao Y, Zhao H, Ren M, Chen Q, Li J, Li Z, Yin C, Yue W. TOP2A Promotes Tumorigenesis of High-grade Serous Ovarian Cancer by Regulating the TGF-β/Smad Pathway. J Cancer 2020; 11(14):4181-4192. doi:10.7150/jca.42736. Available from http://www.jcancer.org/v11p4181.htm

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Abstract

Background: High-grade serous ovarian cancer (HGS) is the most aggressive form of ovarian cancer due to its rapid spread, insidious onset, and early dissemination throughout the abdominal cavity. However, the molecular pathogenesis of HGS remains unclear. This study aimed to identify key pathogenic genes and explore the underlying molecular mechanisms of HGS using bioinformatics analysis and biological experiments.

Methods: Two datasets were downloaded from the Gene Expression Omnibus databases to find differentially expressed genes (DEGs) between HGS and normal tissue samples. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were applied to investigate the primary functions of the DEGs. The protein-protein interaction network of the DEGs was constructed, and the interactions of various genes were ranked.

Results: Topoisomerase IIα (TOP2A) was identified as the hub gene associated with survival and mutation. Gene Set Enrichment Analysis and Gene Set Variation Analysis were conducted to predict the potential biological functions of TOP2A. Furthermore, the TOP2A expression level was significantly up-regulated in HGS cell lines, SKOV3 and HEY. Moreover, the proliferation, migration, and invasion capacities of SKOV3 and HEY cells were strongly suppressed after TOP2A knockdown. In addition, the levels of phosphorylated Smad2 and Smad3, the key members of the transforming growth factor-β (TGF-β)/Smad pathway that regulate HGS tumorigenesis, strongly decreased after knockdown of TOP2A.

Conclusions: This study identified that TOP2A was up-regulated in HGS, and it accelerated HGS progression via the TGF-β/Smad pathway. The findings provided a blueprint for TOP2A serving as a therapeutic target and a treatment response prediction biomarker for HGS.

Keywords: high-grade serous ovarian cancer, topoisomerase IIα, TGF-β/Smad, DEGs