The incidence of CESC patients tends to be younger. Although CESC screening and diagnosis methods have been gradually improved, and surgical treatment and radiotherapy and chemotherapy have made great progress, the long-term survival rate and quality of life of patients still need to be improved . Starting from the genetic level to study the mechanism of the occurrence and development of CESC is conducive to the discovery of new molecular targets, and provides research basis for the precise treatment and prognosis of CESC . Our research showed for the first time that DEFGs and prognostic risk signature based on DEFGs were good predictors of CESC. Moreover, DEFGs were also potential therapeutic targets of CESC, and at the same time affected the stromal components and immune components of the tumor microenvironment in CESC, indicating that DEFGs may be closely related to the occurrence, development, invasion and metastasis of CESC. At the same time, DEFGs may also be the biomarkers for predicting the efficacy of immunotherapy.
A large number of studies have shown that ferroptosis can kill tumor cells and inhibit tumor growth. On the contrary, tumor cells inhibit ferroptosis through self-protection mechanisms to reduce cell death . The main feature of ferroptosis is the accumulation of lipid-ROS (L-ROS) and fatal ROS from iron metabolism, which can be inhibited by iron chelators and lipid peroxidation inhibitors . Gluathione peroxidase 4, (GPX4), heat shock protein β1 (HSBP1) and nuclear factor-f2 (Nrf2) play a negative regulatory role on ferroptosis by limiting the production of ROS and reducing the uptake of iron by cells . NADPH oxidase and P53 play a positive regulatory role by promoting the production of ROS. The current research on the related mechanism of ferroptosis focuses on the direction of oxidative damage, the direction of iron metabolism regulation, and the relevant targets discovered in experiments . Studies have shown that the sensitivity of cells to ferroptosis can be changed by adjusting the content of intracellular iron. By increasing transferrin and TFRl, intracellular iron can be increased and the occurrence of ferroptosis can be promoted. Among them, heat shock protein has become a relevant target for initial results . However, research on the relationship between ferroptosis and tumors is still mainly limited to cell and animal experiments.
In our research, ACACA was reported for the first time in relation to ferroptosis in the role of CESC. PHKG2, SQLE and TRFC are also the first time that the potential role of ferroptosis-related pathways in the prognosis of CESC and the tumor microenvironment has been discovered. The full name of ACACA is acetyl-CoA carboxylase alpha. It is found to be highly expressed in prostate cancer. After ACACA is inhibited in in vivo experiments, the mitochondrial ATP production decreases significantly, and the ratio of NAD+/NADH to ROS levels increases. Therefore, targeting ACACA genes and mitochondria to induce ferroptosis may be a new therapy for prostate cancer . In invasive non-functional pituitary adenoma (NFPA), it was found that ACACA is one of the key regulators of phosphorylation-mediated changes in the signaling pathway network, and is a potential predictor/prognostic marker for patients with NFPA, as well as a potential therapeutic target .
Alectinib is an ALK inhibitor, which can be used to treat ALK-positive lung cancer, but it also targets PHKG2 (phosphorylase kinase gamma submit 2) for anti-tumor effects . In patients with metastatic colorectal cancer (mCRC) treated with cetuximab and irinotecan (CI), PHKG2 was significantly overexpressed, which can effectively predict the efficacy of CI for mCRC . PHKG2 has been verified to be differentially expressed in endometrial cancer tissues and is a potential marker for the diagnosis and identification of endometrial cancer .
The stable expression of SQLE leads to increased cholesterol synthesis and activates PI3K/Akt signaling, thereby regulating the stemness of breast cancer stem cells, which may overcome breast cancer chemotherapy resistance . Metformin can inhibit the stemness of mCRC by down-regulating SQLE and affecting lipid metabolism through the mevalonate pathway . SQLE is also a cholesterol metabolism molecule and a promising therapeutic target for tumors . Current research mainly shows that SQLE is a new type of lipid metabolism regulator, which will affect tumor development and metastasis. Abnormal lipid metabolism is the core mechanism of ferroptosis, so it may also play an important role in tumor development and metastasis.
YTHDF1 enhances the expression of TFRC in head and neck squamous cell carcinomas (HPSCC) through an m6A-dependent mechanism, so TFRC is a key target gene for YTHDF1-mediated increase in iron metabolism. In the future, it is possible to target YTHDF1 and TFRC-mediated iron metabolism may be a promising treatment strategy for HPSCC . We found that the high expression of ACACA, SQLE and TFRC in CESC was associated with a poor prognosis, while the high expression of PHKG2 was associated with a good prognosis. Therefore, ACACA, SQLE and TFRC can be inhibited, and the high expression of PHKG2 can effectively induce ferroptosis as a target for CSEC treatment and overcome chemotherapy resistance. At the same time, detecting their expression level and the ferroptosis-related signature constructed based on these DEFGs can predict the prognosis of CSEC.
Immune cells activated during immunotherapy can enhance the level of ferroptosis-specific lipid peroxidation in tumor cells, and the enhancement of ferroptosis contributes to the anti-tumor efficacy of immunotherapy . Through further research, it is found that the mechanism of interferon gamma (IFN gamma) released by CD8 + T cells down-regulates the expression of System Xc-, impairing the absorption of cystine by tumor cells, thereby promoting lipid peroxidation and ferroptosis in tumor cells. Through the analysis of clinical tumor samples, the expression of System Xc- in cancer patients is negatively correlated with the number of CD8 + T cells, the expression of IFNγ, and the prognosis of patients . Both immunotherapy and radiotherapy require immune cells. Immune cells can change the sensitivity of tumor cells to radiotherapy by promoting ferroptosis. Immune cell-derived IFNγ and radiation synergistically inhibit the expression of tumor SLC7A11 and induce tumor cell apoptosis, while radiotherapy activate ATM to inhibit the expression of SLC7A11, limit the uptake of tumor cystine, reduce glutathione, and increase lipid oxidative damage to mediate the iron vision of tumor cells. Biochemical and genetic suppression of ataxia telangiectasia mutant gene (ATM) can prevent the loss of SLC7A11 expression, reduce lipid oxidation, and rescue tumor cell ferroptosis caused by radiotherapy . This study shows that ferroptosis is a previously unknown mechanism of tumor cell death after in vivo and in vitro radiotherapy, and that radiotherapy can make tumor cells sensitive to ferroptosis agonists both in vitro and in vivo, highlighting a new strategy for radiosensitizing tumors. Radiotherapy is the main treatment of CESC, so increasing the activity of ferroptosis during radiotherapy of CESC will be an effective way to improve the sensitivity of radiotherapy.
Inducing the secretion of key factors such as ROS produced by ferroptosis into the tumor microenvironment to enhance the anti-tumor effect is an effective step for tumor treatment or improving the efficacy . We found that the low-risk group of ferroptosis-related signatures has a high TME score, and the TME score is also high when the expression of ACACA and SQLE is low, indicating that increasing the level of ferroptosis is indeed more conducive to enhancing the anti-tumor effect of CESC. At present, there are few studies on the relationship between the four key prognostic-related DEFGs and tumors. Therefore, the four key prognostic-related DEFGs are potential therapeutic targets of CESC and are also biomarkers for predicting efficacy and prognosis.
The limitations of this study are: (1) The sample is limited; (2) It lacks of the experiment verification in vivo or vitro. Therefore, we will further verify the results in the next research.