TGF-β-regulated different iron metabolism processes in the development and cisplatin resistance of ovarian cancer.

Abstract

The impact of different iron metabolism processes (DIMP) on ovarian cancer remains unclear. In this study, we employed various gene chips and databases to investigate the role of DIMP in the initiation and development of ovarian cancer. cBioPortal was used to determine mutations in DIMP-associated genes in ovarian cancer. Kaplan-Meier plotter was used to examine the influence of DIMP on the prognosis of ovarian cancer. By analyzing 1669 serous ovarian cancer cases, we identified a range of mutations in iron metabolism genes, notably in those coding for the transferrin receptor (19%), melanotransferrin (19%), and ceruloplasmin (10%) in the iron import process, and glucose-6-phosphate isomerase (9%), hepcidin antimicrobial peptide (9%), metal regulatory transcription factor 1 (8%), and bone morphogenetic protein 6 (8%) in the iron regulation process. Compared to the unaltered group, the group with gene alterations exhibited a higher tumor mutation burden count (43 vs. 54) and more advanced histologic grade (78.19% vs. 87.90%). Compared to the normal ovarian counterparts, a reduction in expression was observed in 9 out of the 14 genes involved in iron utilization and 4 out of the 5 genes involved in iron export in ovarian cancer; in contrast, an increase in expression was observed in 2 out of the 3 genes involved in iron storage in ovarian cancer. Furthermore, in cisplatin-resistant cells compared to cisplatin-sensitive ones, the expression of all genes in iron storage and 13 out of 14 genes in iron import was decreased, while that of 8 out of the 10 genes in iron utilization was increased. In addition, survival curve analysis indicated that a higher expression in the majority of genes in the iron import process (12/21), or a reduced expression in most genes in the iron export process (4/5) correlated with poor progression-free survival. Additionally, TGF-β could regulate the expression of most iron metabolism-associated genes; particularly, expression of genes involved in the iron storage process (2/2) was inhibited after TGF-β1 or TGF-β2 treatment. In conclusion, DIMP plays multifaceted roles in the initiation, chemo-resistance, and prognosis of ovarian cancer. Therapeutically targeting DIMP may pave the way for more tailored treatment approaches for ovarian cancer.