In the present study, we built a novel IDR prediction model integrating 10 ferroptosis-related genes to stratify KIRC patients into two risk groups. The overall survival (OS) of KIRC patients with high-risk scores was significantly shorter than those with low-risk scores in both training set and validation set. Moreover, the risk score was confirmed as an independent prognostic predictor for OS. In addition, the positive and negative correlated genes with this model were significantly enriched in p53 signaling pathway, and cGMP-PKG signaling pathway. Immune infiltration analysis revealed that KIRC patients in the high-risk group had higher ratios of plasma cells, T cells CD8, and T cells regulatory Tregs. Furthermore, IgG, HCK, and LCK metagenes were significantly positively correlated with risk score, and Interferson metagenes was negatively correlated. By TIDE score analysis, patients in the high-risk group could benefit from immunotherapy. These findings present future KIRC research with more information.
Increasing evidence has confirmed that ferroptosis plays a crucial role in diverse kidney diseases, including KIRC (31) and has anticancer functions that are useful in cancer treatment (10). Investigating the role of ferroptosis and identifying the ferroptosis-related genes will facilitate to the development of effective treatment strategies for KIRC. Moreover, it is reported that multigene signatures could provide risk stratification and prognostic prediction in breast cancer, such as PAM50 signature (32). A multigene panel has exhibited the potent peformance to predict poor prognosis in patients with KIRC (33). In this present study, the IDR prediction model was built by 10 ferroptosis-related genes, and the risk score was confirmed as an independent prognostic predictor for OS. Therefore, we conduct that our identified multigene signature can predict clinical prognosis and brings insight to molecular biologic characteristics of KIRC.
The identified IDR prediction model included 6 OS-related risk factors (STEAP3, CD44, CHAC1, FANCD2, G6PD, and FADS2) and 4 potective factors (GOT1, NCOA4, PEBP1, and GLS2). STEAP3 is shown to have a ability to catalyse the reduction of free ferric iron (Fe3+) to divalent iron (Fe2+) in endosome and then release Fe2+ to the cellular labile iron pool, thus triggering ferropotsis (34). CD44 is widely implicated in various malignant processes such as tumor growth, and angiogenesis (35), which has been observed to be associated with a poor survival rate in many human tumors (36). The P-selectin and the CD44 receptor interactions is reveal to promote the cellular uptake of Fe3O4[email protected] nanoparticles, resulting in higher cytotoxicity by ferroptosis (37). Upregulated CHAC1 can degrade intracellular glutathione and then contribute to ferroptosis in human triple negative breast cancer cells (38). FANCD2 is a nuclear protein that can protect against bone marrow injury form ferroptosis-mediated injury and represent an amenable target for the development of novel anticancer therapies (39). G6PD is a key enzyme that generates NADPH to maintain reduced glutathione, whose high expression is correlated with poor prognosis and poor outcome in several types of carcinoma (40, 41). FADS2 is a key enzyme involved in the biosynthesis of polyunsaturated fatty acids, whose expression is correlated with multiple tumor processes in human cancers, such as tumor proliferation, angiogenesis, ferroptosis, and prognosis (42). NCOA4-mediated ferritinophagy is shown to be implicated in the initiation of ferroptosis (43). PEBP1 is required to form the 15LOX/PEBP1 complex, and suppression of this complex can mediate the Ferrostatin-1 prevention of ferroptosis (44). GOT1 and GLS2 is found to take part in glutaminolysis to regulate ferroptosis process (45). It is reported that miR-9 can suppress ferroptosis via downregulating GOT1 expression in melanoma (46). In cancer cells, GLS2 upregulation can induce an antiproliferative response with cell cycle arrest (47). Notably, high expression of risk genes, such as CD44, FANCD2 and CHAC1 as well as low expression of NCOA4 were found to be correlated with worse OS in KIRC (21, 22), in line with our results. Taken together, these genes may be involved in KIRC via involved in ferroptosis. Moreover, the positive and negative correlated genes with this model were significantly enriched in p53 signaling pathway, and cGMP-PKG signaling pathway. The p53 signaling pathway has been confirmed to exert tumor suppressive function via regulating cellular processes, like anti-oxidant defense and ferroptosis (48). The cGMP/PKG signaling pathway is revealed to play a significant role in regulating the proliferation and survival of human renal carcinoma cells (49). Therefore, we speculate that p53 signaling pathway, and cGMP-PKG signaling pathway may participate in KIRC via regulating ferroptosis.
Although great efforts have been made to investigate the mechanisms underlying tumor susceptibility to ferroptosis, it remains elusive in the potential modulation between ferroptosis and tumor immunity. The immune infiltration analysis revealed that KIRC patients in the high-risk group had higher proportion of plasma cells, T cells CD8, and T cells regulatory Tregs. Tumor-infiltrating plasma cells are shown to play a positive role in antitumor immunity, suggesting that the potential of enhanced these response in the design of cancer immunotherapy (50). Lee et al. demonstrated that increased Tumor-infiltrating plasma cells are associated with worse survival in lung adenocarcinomas (51). CD8 + T cells can enhance ferroptosis-specific lipid peroxidation and, in turn, affect the anti-tumor efficacy of immunotherapy (52). Treg frequency in peripheral blood and in tumour-infiltrating lymphocytes is revealed associated with poor prognosis in renal cell carcinoma (53). Moreover, we found that IgG, HCK, and LCK metagenes were significantly positively correlated with risk score, and Interferson metagenes was negatively correlated. By TIDE score analysis, most of immunotherapy biomarkers, such as CAF, TIDE, T Cell Exclusion, CD8, Merck18, MDSC, T Cell Dysfunction, CD274, MSI.Expr.Sig, and TAM.M2 were significantly different between high-risk and low-risk groups. These data prompted that patients in the high-risk group were in an immunoactive state and benefit from immunotherapy, which will provide a more comprehensive view of cancer immunotherapy efficacy
Limitations of our study are as follows: first, our IDR prediction model was constructed and validated with data from TCGA database, therefore, the use of this model in a real clinical setting remains controversial. Second, the relationships between the risk score and immune immunity are not experimentally confirmed. More studies are still required to confirm our observation.
In conclusion, a novel gene signature consisting of 10 ferroptosis-related genes shows reliable ability in predicting clinical prognosis and is correlated with immune immunity in patients with KIRC. The patients at higher risk might be more suitable to benefit from immunotherapy. With further validation, this model can be explored as a predictive biomarker to develop personalized therapies for patients with KIRC.