Identification of a 6-gene signature associated with ferroptosis for predicting the prognosis in prostate cancer

Ferroptosis is intimately correlated with the development of cancers. We aimed to identify ferroptosis-related prognostic signatures for prognosis prediction of prostate adenocarcinoma (PRAD). The expression profile and clinical data of patients were from The Cancer Genome Atlas Program (TCGA) database. The Cox regression and Lasso analyses were utilized to construct a multigene signature, and the Kaplan-Meier (K-M), receiver operating characteristic (ROC), and decision curve analysis (DCA) curves were used to validate the predictive effect. Additionally, pathway enrichment analyses were performed to explore the potential mechanism associated with biomarkers. In this study, 41 ferroptosis-related genes (FRGs) were differentially expressed between PRAD and normal tissues. Then, we finally constructed a risk model consisting of 6 signatures (Transferrin Receptor (TFRC), Ferritin Heavy Chain 1 (FTH1), Poly (RC) Binding Protein 2 (PCBP2), Acyl-CoA Synthetase Long Chain Family Member 3 (ACSL3), Prion Protein (PRNP), and Lysophosphatidylcholine Acyltransferase 3 (LPCAT3)) among 41 biomarkers. The K-M, ROC, and DCA curves all validated the fine predictive performance of our prognostic signature. We also revealed the significant clinical value of each signature in PRAD. The enrichment analysis suggested the correlation of these genes with the calcium signaling pathway, Transforming Growth Factor Beta 1 (TGF-β), and Wingless-Type MMTV Integration Site Family (WNT) pathways, implying that these genes might be involved in the migration of PRAD. In conclusion, the 6-gene ferroptosis-related signature could serve as a novel biomarker for predicting the prognosis in PRAD. Their function in cancer migration needs further investigation.

Prostate cancer; Ferroptosis; Risk model; Prognosis

[1] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2021; 71: 209–249.

[2] Brockman JA, Alanee S, Vickers AJ, Scardino PT, Wood DP, Kibel AS, et al. Nomogram predicting prostate cancer-specific mortality for men with biochemical recurrence after radical prostatectomy. European Urology. 2015; 67: 1160–1167.

[3] Van den Broeck T, van den Bergh RCN, Arfi N, Gross T, Moris L, Briers E, et al. Prognostic value of biochemical recurrence following treatment with curative intent for prostate cancer: a systematic review. European Urology. 2019; 75: 967–987.

[4] Venclovas Z, Jievaltas M, Milonas D. Significance of time until PSA recurrence after radical prostatectomy without neo- or adjuvant treatment to clinical progression and cancer-related death in high-risk prostate cancer patients. Frontiers in Oncology. 2019; 9: 1286.

[5] Nunes SBR, de Matos Oliveira F, Neves AF, Araujo GR, Marangoni K, Goulart LR, et al. Association of vitamin D receptor variants with clinical parameters in prostate cancer. SpringerPlus. 2016; 5: 364.

[6] Liu Z, Zhong J, Cai C, Lu J, Wu W, Zeng G. Immune-related biomarker risk score predicts prognosis in prostate cancer. Aging. 2020; 12: 22776–22793.

[7] Wang Y, Wei Z, Pan K, Li J, Chen Q. The function and mechanism of ferroptosis in cancer. Apoptosis. 2020; 25: 786–798.

[8] Lv Z, Wang J, Wang X, Mo M, Tang G, Xu H, et al. Identifying a ferroptosis-related gene signature for predicting biochemical recurrence of prostate cancer. Frontiers in Cell and Developmental Biology. 2021; 9: 666025.

[9] Ghoochani A, Hsu E, Aslan M, Rice MA, Nguyen HM, Brooks JD, et al. Ferroptosis inducers are a novel therapeutic approach for advanced prostate cancer. Cancer Research. 2021; 81: 1583–1594.

[10] Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017; 171: 273–285.

[11] Hangauer MJ, Viswanathan VS, Ryan MJ, Bole D, Eaton JK, Matov A, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature. 2017; 551: 247–250.

[12] Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature. 2017; 547: 453–457.

[13] Bordini J, Morisi F, Elia AR, Santambrogio P, Pagani A, Cucchiara V, et al. Iron induces cell death and strengthens the efficacy of antiandrogen therapy in prostate cancer models. Clinical Cancer Research. 2020; 26: 6387–6398.

[14] Nassar ZD, Mah CY, Dehairs J, Burvenich IJ, Irani S, Centenera MM, et al. Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis. Elife. 2020; 9: e54166.

[15] Liang JY, Wang DS, Lin HC, Chen XX, Yang H, Zheng Y, et al. A novel ferroptosis-related gene signature for overall survival prediction in patients with hepatocellular carcinoma. International Journal of Biological Sciences. 2020; 16: 2430–2441.

[16] Lu T, Xu R, Li Q, Zhao J, Peng B, Zhang H, et al. Systematic profiling of ferroptosis gene signatures predicts prognostic factors in esophageal squamous cell carcinoma. Molecular Therapy Oncolytics. 2021; 21: 134–143.

[17] Wang D, Wei G, Ma J, Cheng S, Jia L, Song X, et al. Identification of the prognostic value of ferroptosis-related gene signature in breast cancer patients. BMC Cancer. 2021; 21: 645.

[18] Li S, Shi L, Li F, Yao B, Chang L, Lu H, et al. Establishment of a novel combined nomogram for predicting the risk of progression related to castration resistance in patients with prostate cancer. Frontiers in Genetics. 2022; 13: 823716.

[19] Lei G, Zhuang L, Gan B. Targeting ferroptosis as a vulnerability in cancer. Nature Reviews Cancer. 2022; 22: 381–396.

[20] Yang C, Li J, Guo Y, Gan D, Zhang C, Wang R, et al. Role of TFRC as a novel prognostic biomarker and in immunotherapy for pancreatic carcinoma. Frontiers in Molecular Biosciences. 2022; 9: 756895.

[21] Zhu G, Murshed A, Li H, Ma J, Zhen N, Ding M, et al. O-GlcNAcylation enhances sensitivity to RSL3-induced ferroptosis via the YAP/TFRC pathway in liver cancer. Cell Death Discovery. 2021; 7: 83.

[22] Huang Y, Huang J, Huang Y, Gan L, Long L, Pu A, et al. TFRC promotes epithelial ovarian cancer cell proliferation and metastasis via up-regulation of AXIN2 expression. American Journal of Cancer Research. 2020; 10: 131–147.

[23] Kong N, Chen X, Feng J, Duan T, Liu S, Sun X, et al. Baicalin induces ferroptosis in bladder cancer cells by downregulating FTH1. Acta Pharmaceutica Sinica B. 2021; 11: 4045–4054.

[24] Ali A, Shafarin J, Abu Jabal R, Aljabi N, Hamad M, Sualeh Muhammad J, et al. Ferritin heavy chain (FTH1) exerts significant antigrowth effects in breast cancer cells by inhibiting the expression of c-MYC. FEBS Open Bio. 2021; 11: 3101–3114.

[25] Choi M, Moon S, Eom HJ, Lim SM, Kim YH, Nam S. High expression of PRNP predicts poor prognosis in korean patients with gastric cancer. Cancers. 2022; 14: 3173.

[26] Hu K, Zhang X, Zhou L, Li J. Downregulated PRNP facilitates cell proliferation and invasion and has effect on the immune regulation in ovarian cancer. Journal of Immunology Research. 2022; 2022: 1–11.

[27] Mao J, Sun Z, Cui Y, Du N, Guo H, Wei J, et al. PCBP2 promotes the development of glioma by regulating FHL3/TGF-β/Smad signaling pathway. Journal of Cellular Physiology. 2020; 235: 3280–3291.

[28] Chen C, Lei J, Zheng Q, Tan S, Ding K, Yu C. Poly(rC) binding protein 2 (PCBP2) promotes the viability of human gastric cancer cells by regulating CDK2. FEBS Open Bio. 2018; 8: 764–773.

[29] Li Y, Zhao Z, Lin C, Liu Y, Staveley-OCarroll KF, Li G, et al. Silencing PCBP2 normalizes desmoplastic stroma and improves the antitumor activity of chemotherapy in pancreatic cancer. Theranostics. 2021; 11: 2182–2200.

[30] Quan J, Bode AM, Luo X. ACSL family: the regulatory mechanisms and therapeutic implications in cancer. European Journal of Pharmacology. 2021; 909: 174397.

[31] Shao G, Qian Y, Lu L, Liu Y, Wu T, Ji G, et al. Research progress in the role and mechanism of LPCAT3 in metabolic related diseases and cancer. Journal of Cancer. 2022; 13: 2430–2439.

[32] Ke P, Bao X, Liu C, Zhou B, Huo M, Chen Y, et al. LPCAT3 is a potential prognostic biomarker and may be correlated with immune infiltration and ferroptosis in acute myeloid leukemia: a pan-cancer analysis. Translational Cancer Research. 2022; 11: 3491–3505.