Cervical cancer, as the fourth most common tumor type in women, is a major threat to women's health worldwide. However, the molecular mechanisms underlying the development of cervical cancer are not yet fully understood. Emerging evidence has shown the potential of inducing ferroptosis as a cancer therapy, particularly for eliminating tumors that are tolerant to traditional radiotherapy and chemotherapy. Increasing numbers of studies have shown that lncRNAs are related to a variety of diseases(25–27), such as diabetic cardiomyopathy, liver cancer, CC, and atherosclerosis. Interestingly, some lncRNAs and microRNAs are largely considered key mediators that modulate ferroptosis. Therefore, we developed a model of ferroptosis-related lncRNAs that can be used as a novel biomarker in the treatment of CC patients.
In this study, the FRLS, comprising 10 lncRNAs (MIR100HG, WDR86-AS1, AC131159.1, AC092171.2, AL021707.6, AC007998.3, AC024270.4, AC004847.1, AC243829.4, MIAT), was constructed to predict OS in CC patients. For MIR100HG, we found that MIR100HG sponged miR-5590-3p to promote the progression of TNBC, thereby upregulating OTX1, which may be a novel biomarker of TNBC(28). A recent study showed that in gastric cancer, CXXC finger protein 4 (CXXC4) is involved in the ELK1/MIR100HG pathway to inhibit the immune evasion of tumors by restraining the CDK18-ERK1/2 axis(29). One study showed that the expression of MIR100HG and miR-204-5p had a marked relationship and that MIR100HG promoted tumor cell progression by downregulating miR-204-5p in laryngeal squamous cell carcinoma(30). MIAT, as a competing endogenous RNA that sponges miR-22-3p, upregulated DAPK2, which resulted in cardiomyocyte apoptosis(26). Research has demonstrated that MIAT can sponge miR-214 to facilitate migration and invasiveness of hepatocellular carcinoma cells and that MIAT can be a novel marker used in the treatment of HCC patients(31). As reported previously, a ceRNA network exists between MIAT and miR-186, and MIAT sponged miR-186-3p to regulate VEGFC, which facilitated the proliferation, invasiveness, and migration of osteosarcoma cells(32). Another study reported AL021707.6 as a prospective crucial moderator of apoptosis in polymorphonuclear leukocytes(33). Other lncRNAs have not yet been studied and will be further explored in future studies.
Furthermore, the KEGG analysis showed that the differentially expressed genes were mainly involved in the ferroptosis pathway, HIF-1 signaling pathway, PD-L1 expression, autophagy pathway, and the PD-1 checkpoint pathway in cancer and had a relationship with immunotherapy and ferroptosis. According to the risk score, CC patients were classified into two groups; of these groups, the low-risk group had better clinical outcomes. The multifactor ROC curve showed that the risk score can be an independent factor and superior to other traditional clinical characteristics in predicting OS. A nomogram was constructed to show the predictors of the 1-, 3-, and 5-year OS. Overall, the risk model of ferroptosis-related lncRNAs was effective and accurate for predicting the prognosis of patients. In this study, we also found that the risk score could increase with tumor progression. Moreover, during the treatment process, the pathological stage of cancer was the critical factor related to the OS of CC patients. However, the prognosis of patients at the same pathological stage was quite distinctive, which indicates that the current staging system is not comprehensive enough to reflect the heterogeneity of patients. Therefore, we established the FRLS to complement the staging system and to explore a novel biomarker to predict the prognosis of CC patients. Additionally, we validated the FRLS through several methods, and thus, this signature is an effective prognostic model.
Some genes have been confirmed to influence CC due to their abilities to modulate disease occurrence and development as well as immune response, even immunotherapy. WGCNA was used to analyze the immune-related genes, and subsequent selections eventually identified TLR4. Nanosystems activated by TLR4 have been shown to trigger the production of high levels of proinflammatory cytokines and chemokines by macrophages and DCs during immunotherapy(34). Moreover, TLR4 was also shown to be associated with ferroptosis; for example, suppression of TLR4 alleviates oxidative stress-induced injury and reduces ferroptosis activation in hippocampal neurons(35).
The TME of CC comprises various immune and stromal cells and likely modulates several hallmarks of tumors, including proliferation, invasion, and chemotherapy resistance(36). Some studies have shown that ferroptosis can occur in immune cells in the TME and as a result of the interaction between immune cells and tumor cells, which offers the possibility of targeting ferroptosis in immunotherapy(10). Our study demonstrated that the proportions of Macrophages M0, T cells CD8, B cells memory were related to the risk model, which exhibited a notable correlation with the risk score. A previous study showed that the role of CD8 + T cells was strengthened by cancer immunotherapy(37, 38). An interaction was observed between immunotherapy-activated CD8 + T cells and ferroptosis in which CD8 + T cells could increase ROS and ferroptosis, which is conducive to antitumor efficiency of immunotherapy(8). Furthermore, the effectiveness of radiation treatment in vivo depends on the existence of CD8 + T cells(39, 40), which regulate cancer ferroptosis via IFNγ. One study showed that ferroptosis inducers or blockers can affect the antineoplastic immunity mediated by T cells; examples are the ferroptosis blocker ferrostatin-1, which prevents T cell-mediated specific killing, and GPX4 blockers, which selectively kill CD8 + T cells to promote tumor cell growth(41).
In our study, we explored the relationship between ICIs and the FRLS. Over the past several years, substantial progress has been made in the development of ICIs for tumor immunotherapy. Moreover, ferroptosis coupled with ICIs can improve anticancer efficacy(42), and TIDE scores have revealed the enormous potential of ICI treatment. A recent study found that TYRO3 can restrain cancer cells, induce ferroptosis stimulated by anti-PD-1/PD-L1 treatment, and remodel the TME, leading to resistance to anti-PD-1/PD-L1 treatment(43). This might be an effective way to combine ferroptosis and immunotherapy based on ICIs (PD-1, CTLA-4) to treat CC patients.
However, this study still has some limitations. First, the number of CC samples in the TCGA database was comparatively small. Second, because of the lack of clinical samples, the clinical reliability and prognostic stability of the FRLS cannot be completely ensured. The mechanism of ferroptosis-related lncRNAs will be validated in later studies, which will provide more convincing data for clinical treatment.