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

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.

Integrated Bioinformatics Analysis for Identification of the Hub Genes Linked with Prognosis of Ovarian Cancer Patients

“…A lot of studies also suggest that involvement of carcinogenesis in various cancers (lung, liver, and breast cancer) is due to highly expressed TOP2A thereby causing slow prognosis in patients [ 31 – 33 ]. TOP2A also promotes tumorigenesis in ovarian cancer which regulates the TGF- β /Smad pathway; the expression of TOP2A was also found to correlate with poor survival of ovarian cancer patients and platinum resistance [ 34 , 35 ]. Our results have shown that upregulation of TOP2A in tissues of ovarian cancer is linked with poor prognosis.…”

Identification of the Hub Genes Associated with the Prognosis of Ovarian Cancer Patients via Integrated Bioinformatics Analysis and Experimental Validation

“… 49 In ovarian cancer, TOP2A promotes tumorigenesis of high-grade serous ovarian cancer by regulating the TGF-β/Smad pathway. 50 The clinical data suggested that TOP2A status might predict activity of pegylated liposomal doxorubicin in patients with epithelial ovarian cancers. 25 A study by Gulec et al showed that TOP2A expression was found to be related to poor OS of ovarian cancer patients, and was associated with platinum resistance.…”

FAST1 Predicts Poor Survival of Renal Carcinoma and Promotes Its Progression Through the TGF-β/Smad Pathway

“…For instance, Zhang et al showed that overexpressed SALT4 promotes the metastasis of gastric cancer by activating the TGF-β/Smad signaling pathway. 32 Also, Gao et al claimed that Topoisomerase II (TOP2A) aggravates the progression of advanced ovarian cancer by activating TGF-β/Smad, 33 suggesting that inhibiting the TGF-β/Smad signaling pathway may be a novel method for cancer treatment. Some scholars have found that the activation of down-regulated miR-542-3p on the TGF-β/Smad signaling pathway mediates hepatocellular carcinoma progression.…”