Expression profiles and prognostic values of BolA family members in ovarian cancer

Abstract

Background: The BOLA gene family, comprising three members, is mainly involved in regulating intracellular iron homeostasis. Emerging evidence suggests that BolA family member 2 plays a vital role in tumorigenesis and hepatic cellular carcinoma progression. However, there was less known about its role in ovarian cancer.

Methods: In the present study, we investigated the expression profiles, prognostic roles, and genetic alterations of three BolA family members in patients with ovarian cancer through several public databases, containing Oncomine and Gene Expression Profiling Interactive Analysis, Human Protein Atlas, Kaplan-Meier plotter and cBioPortal. Then, we constructed the protein-protein interaction networks of BOLA proteins and their interactors by using the String database and Cytoscape software. In addition, we performed the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment by the Annotation, Visualization, and Integrated Discovery database. Finally, we explored the mechanisms underlying BolA family members' involvement in OC by using gene set enrichment analysis.

Results: The mRNA and protein expression levels of BOLA2 and BOLA3 were heavily higher in ovarian cancer tissues than in normal ovarian tissues. Dysregulated mRNA expressions of three BolA family members were significantly associated with prognosis in overall or subgroup analysis. Moreover, genetic alterations also occurred in three BolA family members in ovarian cancer. GO analysis indicated that BolA family members might regulate the function of metal ion binding and protein disulfide oxidoreductase activity. Gene set enrichment analysis indicated that BolA family members were mainly associated with oxidative phosphorylation, proteasome, protein export, and glutathione metabolism in ovarian cancer.

Conclusion: In brief, our finding may contribute to increasing currently limited prognostic biomarkers and treatment options for ovarian cancer.

Keywords: Bioinformatics analysis; BolA family members; Database; Ovarian cancer; Prognosis.

Fig. 1

Expression levels of BOLA family members in different types of cancers (Oncomine). Each cell’s number represents the number of analyses conformed to the following threshold: P < 0.05, the absolute value of fold change > 2, and gene rank, 10%. The numbers in colored cells show the quantities of datasets with statistically significant mRNA higher expression (red) or lower expression (blue) of BOLA family members

Fig. 2

Dysregulated mRNA expression levels of BOLA family and the association with tumor stage in OC. a Box plots of dysregulated mRNA expression BOLA family members in OC based on GEPIA database. b The relationship between mRNA expression of BOLA family members and tumor stages in OC patients

Fig. 3

The protein expression profile of BOLA family members in regular ovarian compared with cancer tissues. Representative immunohistochemistry images (a) and expression status (b) of BOLA family members in normal ovarian tissues and ovarian cancer tissues based on HPA database (http://www.proteinatlas.org/)

Fig. 4

Prognostic values of mRNA level of BOLA family members in OC patients. Kaplan-Meier curves show the correlation between mRNA expression of BOLA family members and progression-free survival (a–c) and overall survival (d–f) of OC patients. * P < 0.05

Fig. 5

Genomic analysis of BOLA family members in OC based on cBioPortal databases. a Summary of genomic alteration of BOLA family members in OC. b Oncoprint visual summary of alteration on a query of BOLA family members in OC. c The mutations of BOLA1 were plotted. Kaplan–Meier plots comparing d overall survival (OS) and e progression-free survival (PFS) in cases with/without BOLA family members’ gene alterations

Fig. 6

Protein-protein interaction (PPI) and function enrichment of BOLA family members. a The network of 3 BOLA family members and 20 proteins significantly interacted with BOLA family members (String). b Gene Ontology (GO) enrichment analysis of BOLA family members and their interactors (DAVID). c The Pearson correlation coefficients between BOLA family members based on GEPIA and cBioPortal databases

Fig. 7

Gene set enrichment analysis (GSEA) analysis of BOLA family members. a GSEA showed that BOLA1 expression was positively correlated with oxidative phosphorylation. b GSEA showed that BOLA1 expression was negatively correlated with the focal adhesion. GSEA showed that BOLA3 expression was positively correlated with oxidative phosphorylation (c), proteasome (d), proteins export (e), and glutathione metabolism (f) in OC