Survival times for OC patients vary widely, spanning from less than 5 months to more than 10 years [17]. Nonetheless, due to a lack of choice in treatment approaches, all patients are treated relatively similarly. Prognostic features may help to accurately identify patients with different survival times and to individualize treatment. Over the past decades, clinical characteristics such as age and a range of serum markers have been used to determine tumour progression and predict the prognosis of OC patients. However, these clinical characteristics factors are often not sufficiently accurate prognostic predictors to help improve treatment options. In this study, we developed and validated a four lncRNA-based prognostic risk score using data from the TCGA cohort for which both clinical and gene expression data are available.
With the intensive study of various common cancers, there is growing evidence that ferroptosis contributes to cancer development [18,19,20]. Ferroptosis acts as a double-edged sword [21]: it can cause immunosuppression by triggering a cellular inflammatory response, which in turn accelerates tumour growth [22]; on the other hand, pharmacological induction of ferroptosis can inhibit tumour growth [23]. Ferroptosis has therefore shown great promise in cancer treatment, particularly in cancers that are resistant to conventional therapies [24]. Ferroptosis-associated drugs such as artesunate, FIN56, FINO2, erastin, and sorafenib have been successively discovered to exert antitumor effects. For instance, artesunate, a herbal medicine originally used for malaria control, has been found to inhibit the growth of OC cells via induction of reactive oxygen species-related (ROS) ferroptosis [25,26]. With increasing research, more ferroptosis-associated genes are being identified. Due to a lack of systematic reports, previous studies have tended to identify ferroptosis-related genes only based on existing literature, which may have resulted in some ferroptosis-related genes being overlooked [27]. The FerrDb database includes 259 regulators derived from ferroptosis articles in the PubMed database [28]. In this study, we used the FerrDb database to identify a comprehensive list of ferroptosis-related genes.
Our study identified four ferroptosis-related lncRNAs (FOXP4-AS1, USP30-AS1, DNM3OS, AC138904.1) with a prognostic role in OC. Among these four lncRNAs, three lncRNAs (FOXP4-AS1, USP30-AS1, DNM3OS) have been previously studied either in OC or other cancers. Among these, FOXP4-AS1 and USP30-AS1 were associated with a good prognosis for OC, while DNM3OS was associated with a poor prognosis for OC. For instance, FOXP4-AS1 has been proposed an emerging cancer-related biomarker. While a study by Huang et al. identified inconsistent effects of FOXP4-AS1 in different types of cancers [29], Yang et al. found that FOXP4-AS1 promoted osteosarcoma development by binding to LSD1 and EZH2 to downregulate LATS1 [30], and similar effects have been reported in prostate, cervical, and nasopharyngeal cancers [31,32,33]. Interestingly, the role of FOXP4-AS1 in OC may be different from other cancers. Liao et al. suggested that FOXP4-AS1 improves OC prognosis by participation in the CTLA4 pathway [34]. The authors found that FOXP4-AS1 was highly expressed in the low-risk group of OC patients. Based on these results and our own study, we infer that FOXP4-AS1 may be associated with a favourable OC prognosis. USP30-AS1 is transcribed from the antisense strand of the autophagy-related USP30 gene located on chromosome 12 [35]. In our study, elevated levels of USP30-AS1 was associated with an improved prognosis. This is again consistent with reports from previous studies which found abnormal expression of USP30-AS1 in ovarian, bladder, and cervical cancers as well as melanoma, where it acted as a good prognostic feature [36,37,38,39]. Wang et al. showed that the lncRNA DNM3OS may promote cell proliferation, invasion, and metastasis of hepatocellular carcinoma [40]. Similarly, DNM3OS has been shown to positively regulate SMAD6 in retinoblastoma via competitive interaction with miR-134-5p, where high SMAD6 expression promotes tumour cell proliferation, migration, and epithelial-mesenchymal transition [41]. Another previous study reported that DNM3OS knockdown resulted in altered EMT-related genes/pathways, mesenchymal to epithelial transformation, and reduced cell migration and invasion, which suggested that high DNM3OS expression may lead to a reduced survival rate in OC patients [42]. He et al. found that DNM3OS promoted OC progression via regulation of the miR-193a-3p/MAP3K3 axis [43], which again suggested that DNM3OS may represent a poor prognostic factor in OC, and DNM3OS has also been reported as a molecular marker for cancer progression in a variety of different cancer types [44,45,46]. In conclusion, the abovementioned three lncRNAs are thought to be involved in the development of OC or other cancers, and may represent therapeutic targets in OC. The other ferroptosis-related lncRNA in our prognostic risk score, AC138904.1, has been rarely reported, and the present study may provide a new perspective on its functional pathways and involvement in ovarian carcinogenesis and progression.
To further explore how the lncRNAs may be involved in OC development, we performed a functional enrichment analysis and found that the risk score-associated genes were highly associated with the immune response. GO analysis identified a significant enrichment in pathways linked to the activation and regulation of T cells, which suggested that T-cell activation may be closely linked to OC development. Yeung et al. previously showed that ISG15 can inhibit OC progression via activation of CD8+ T cells [47]. CD8+ T cells have been reported to inhibit cysteine uptake by tumor cells and may promote ferroptosis in cancer cells by releasing IFNγ, which may represent a novel anti-tumour mechanism [48,49]. Akyol et al. found that HSP10 produced by ovarian tumour cells suppressed the expression of CD3-zeta, , a key component of T cell activation, in T cells [50], and OC patients with lower T cell CD3-zeta expression have been found to exhibit shorter survival times [51]. In addition, IL4I1 has been found to impair T-cell activation, block T cell proliferation and differentiation, and thus promote OC proliferation, migration, and invasion [52]. From this, we hypothesized that T cell activation may prolong OC patient survival, while T cell suppression may be closely associated with low survival in OC patients. In addition, the negative regulation of immune system processes was significantly enriched in ferroptosis-associated lncRNAs. The immune system is known to play a significant role in cancer progression, and a previous study reported progressive impairment of the immune response in patients with advanced OC [53,54]. The most significant cellular component enrichment in GO analysis was the external side of the plasma membrane, including proteins which are attached, immobilised or embedded in the plasma membrane. LAG-3 is a cell surface molecule with diverse biological effects on T cell function. A study by Matsuzaki et al. found that LAG-3 indirectly inhibited T cell proliferation, which the authors proposed to be associated with a reduction in T cell receptor-induced calcium flux [55]. In conclusion, we may speculate that proteins attached to the external side of the plasma membrane are intimately involved in the development of OC.
KEGG results revealed that Human T-lymphotropic virus 1 infection, Epstein-Barr virus infection, and antigen handling and presentation pathways were significantly enriched. Human T-lymphotropic virus 1 (HTLV-1) is a retrovirus that can induce adult T cell leukaemia [56]. So far, there have been no studies reporting an association between HTLV-1 and OC. However, HTLV-1 infection can promote T cell proliferation by tampering with several core signalling pathways of T cell function [57], and the relationship between T cell function and OC has been demonstrated in several studies [49,50,52]. From this, we speculate that HTLV-1 may regulate OC via T cell function and offers a new direction for the treatment of OC. Epstein-Barr virus (EBV) is a double-stranded DNA virus [58]. In two different studies, the EBV positivity rate has been reported to be lower in the normal group than in OC patient groups [59,60]. It has moreover been reported that the miR-BART7 of EBV was more highly expressed in the OC patients than in cancer-free controls, and miR-BART7 may be related to poor OC prognosis [61]. Littman et al. showed that elevated EBV antibody titers may lead to increased risk of OC [62]. Although the potential role of EBV in OC has not been extensively researched, its role in other cancers has been clearly demonstrated [63,64]. In addition to HTLV-1 and EBV, pathways involved in processing and presentation of antigens were significantly enriched in KEGG analysis. A previous study showed that CCL22, expressed by macrophages in the tumour microenvironment of OC patients, helped to attract regulatory T cells to the tumour environment [65]. Interestingly, regulatory T cells have been shown to be related to a higher risk of death in OC patients [66]. Macrophage-expressed B7-H4 has also been found to suppress tumor-associated antigen-specific T cell immunity, and B7-H4 expression levels were negatively associated with patient survival [67,68]. Plasmacytoid dendritic cells (pDCs) are innate immune cells that appear in peripheral lymphoid organs and the circulation. A review reported that OC-related pDCs induce the activation of CD8+ Treg cells and promote tumour angiogenesis [68,69]. Therefore, we speculated that macrophages, plasmacytoid dendritic cells, and other antigen-presenting cells, may indirectly influence OC prognosis. In short, the four prognostic ferroptosis-related lncRNAs identified in this study are thought to be involved in OC development and prognosis.
We developed a prognostic profile of four lncRNAs associated with iron toxicity, and found it could effectively identify patients with high-risk OC. As OC has been studied closely, many prognostic markers have been identified. However, some studies screened prognostic markers with criteria that ignored the clinical significance by limiting their focus to the statistical performance [70]. Age has been reported as a survival and prognostic factor for OC patients in a recent study [71]. In this study, we analysed the prognostic value of clinical risk factors and prognostic features. Finally, we constructed a nomogram based on the prognostic risk score and age for easy clinical implementation [72].
The current study has several limitations. Firstly, some clinical data (e.g., stage) were not collected by TCGA, so we were unable to conduct a full survival analysis for these factors. Second, the prognostic features we established need to be validated in other independent cohorts for further confirmation and to ensure their robustness. Third, further experiments are needed to explore how ferroptosis-related lncRNAs are involved in OC development.