Abstract
Simple SummaryIn this review, public datasets were mined in an attempt to identify genes that code for proteins of the ubiquitin proteasome system that can be used as therapeutic targets in high-grade serous ovarian cancer. In this study, we found that more than 50 genes coding for ubiquitin ligases and more than 100 for ubiquitin ligase adaptors were differentially expressed between the low malignant potential tumors and the malignant invasive ovarian tumors. We conclude that several genes coding for the ubiquitin ligases and their adaptors have a potential to serve as therapeutic targets in high-grade serous ovarian cancer.In this article, we reviewed the transcription of genes coding for components of the ubiquitin proteasome pathway in publicly available datasets of epithelial ovarian cancer (EOC). KEGG analysis was used to identify the major pathways distinguishing EOC of low malignant potential (LMP) from invasive high-grade serous ovarian carcinomas (HGSOC), and to identify the components of the ubiquitin proteasome system that contributed to these pathways. We identified elevated transcription of several genes encoding ubiquitin conjugases associated with HGSOC. Fifty-eight genes coding for ubiquitin ligases and more than 100 genes encoding ubiquitin ligase adaptors that were differentially expressed between LMP and HGSOC were also identified. Many differentially expressed genes encoding E3 ligase adaptors were Cullin Ring Ligase (CRL) adaptors, and 64 of them belonged to the Cullin 4 DCX/DWD family of CRLs. The data suggest that CRLs play a role in HGSOC and that some of these proteins may be novel therapeutic targets. Differential expression of genes encoding deubiquitinases and proteasome subunits was also noted.
Highlights
Gene expression of epithelial ovarian cancers (EOCs) has been studied in terms of the major histological subgroups as well as classifications based on clinical outcome
KEGG analysis of the top differentially expressed genes of the Anglesio dataset between the low malignant potential (LMP) and high-grade serous ovarian cancer (HGSOC) groups shows that the pathways most over-represented were: cell cycle (49 genes), DNA replication (19 genes), p53 signaling (28 genes), Huntington’s disease (54 genes), and the Fanconi anemia pathway (17 genes), in order of statistical significance (Table 1)
While we found no association of UBE2L6 with EOC in the literature, the association with cisplatin sensitivity makes it relevant to the treatment of chemoresistant HGSOC
Summary
Gene expression of epithelial ovarian cancers (EOCs) has been studied in terms of the major histological subgroups as well as classifications based on clinical outcome. These studies generated large datasets which included gene expression data that went well beyond the objectives of the original studies. In the original Tothill manuscript, six molecular subtypes of ovarian cancer (C1–C6) were described based on gene expression [1], four of which were high-grade serous ovarian cancer (HGSOC) tumors. The Anglesio dataset reports gene expression in low malignant potential (LMP) vs a HGSOC invasive (INV) group of tumors; the Bowtell dataset reports gene expression in LMP serous tumors
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