Department of Gynecology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China.
Department of Gynecology, Shanghai University of Medicine & Health Sciences, Shanghai, China.
Oncol Res. 2023 Dec 28;32(2):373-391. doi: 10.32604/or.2023.031404. eCollection 2023.
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 . 54) and more advanced histologic grade (78.19% . 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.
不同铁代谢过程（DIMP）对卵巢癌的影响尚不清楚。本研究采用多种基因芯片和数据库，探讨 DIMP 在卵巢癌发生发展中的作用。cBioPortal 用于确定卵巢癌中 DIMP 相关基因的突变。Kaplan-Meier plotter 用于研究 DIMP 对卵巢癌预后的影响。通过分析 1669 例浆液性卵巢癌病例，我们鉴定了一系列铁代谢基因的突变，特别是铁摄取过程中编码转铁蛋白受体（19%）、黑素转铁蛋白（19%）和铜蓝蛋白（10%）的基因，以及铁调节过程中编码葡萄糖-6-磷酸异构酶（9%）、抗菌肽 hepcidin（9%）、金属调节转录因子 1（8%）和骨形态发生蛋白 6（8%）的基因。与未改变的组相比，基因改变的组肿瘤突变负荷计数更高（43.54），组织学分级更高级（78.19%~87.90%）。与正常卵巢相比，铁利用过程中 14 个基因中的 9 个和铁输出过程中 5 个基因中的 4 个表达降低，而铁储存过程中 2 个基因和铁摄取过程中 14 个基因中的 13 个表达增加。此外，与顺铂敏感细胞相比，在顺铂耐药细胞中，铁储存过程中的所有基因和铁摄取过程中的 14 个基因中的 13 个基因表达降低，而铁利用过程中的 8 个基因表达增加。此外，生存曲线分析表明，铁摄取过程中大多数基因（12/21）表达升高或铁输出过程中大多数基因（4/5）表达降低与无进展生存期不良相关。此外，TGF-β可调节大多数铁代谢相关基因的表达；特别是，TGF-β1 或 TGF-β2 处理后，铁储存过程中基因的表达受到抑制（2/2）。总之，DIMP 在卵巢癌的发生、化疗耐药和预后中发挥多方面的作用。针对 DIMP 的治疗可能为卵巢癌的个体化治疗方法开辟道路。
