Low Ferroptosis Score Predicts Chemotherapy Responsiveness and Immune-activation in Colorectal Cancer

Overview

Journal Cancer Med

Specialty Oncology

Date 2022 Jul 20

PMID 35855531

Authors

Yang Lv

Qing-Yang Feng

Zhi-Yuan Zhang

Peng Zheng

De-Xiang Zhu

Qi Lin

Si-Min Chen

Yi-Hao Mao

Yu-Qiu Xu

Mei-Ling Ji

Jian-Min Xu

Guo-Dong He

Affiliations

Soon will be listed here.

Abstract

Background: Existing studies for ferroptosis and prognosis in colorectal cancer (CRC) were limited. In this study, we aim to investigate the prognostic role of ferroptosis markers in patients with CRC and exploration of its micro-environmental distributions.

Methods: Immunohistochemical staining was performed for CRC patients' tissue microarray. Selection and prognostic validation of markers were based on mRNA data from the cancer genome atlas (TCGA) database. Gene Set Enrichment Analysis (GSEA) was performed to indicate relative immune landmarks and hallmarks. Ferroptosis and immune contexture were examined by CIBERSORT. Survival outcomes were analyzed by Kaplan-Meier analysis and cox analysis.

Results: A panel of 42 genes was selected. Through mRNA expression difference and prognosis analysis, GPX4, NOX1 and ACSL4 were selected as candidate markers. By IHC, increased GPX4, decreased NOX1 and decreased FACL4 indicate poor prognosis and worse clinical characteristics. Ferroptosis score based on GPX4, NOX1 and ACSL4 was constructed and validated with high C-index. Low ferroptosis score can also demonstrate the better progression free survival and better adjuvant chemotherapy (ACT) responsiveness. Moreover, tumor with low ferroptosis score tend to be infiltrated with more CD4+ T cells, CD8+ T cells and less M1 macrophage. Finally, we found that IFN-γ was potentially the central molecule at the crossroad between ferroptosis and onco-immune response.

Conclusion: Ferroptosis plays important role on CRC tumor progression, ACT response and prognosis. Ferroptosis contributes to immune-supportive responses and IFN-γ was the central molecule for this process.

Citing Articles

METTL14 modulates the progression and ferroptosis of colitis by regulating the stability of m6A-modified GPX4.

Chen Y, Fan W, Lyu Y, Liao J, Zhou Y Eur J Med Res. 2025; 30(1):88.

PMID: 39920858 PMC: 11806865. DOI: 10.1186/s40001-025-02334-8.

Research progress on ferroptosis in colorectal cancer.

Li Y, Bi Y, Li W, Piao Y, Piao J, Wang T Front Immunol. 2024; 15:1462505.

PMID: 39359721 PMC: 11444962. DOI: 10.3389/fimmu.2024.1462505.

IL6ST: A Novel Therapeutic Target for Managing and Treating Colorectal Cancer Via Ferroptosis.

Zhao K, He B, Xue K, Cao B, Ren K, Jin Y Turk J Gastroenterol. 2024; 35(9):690-698.

PMID: 39344518 PMC: 11391227. DOI: 10.5152/tjg.2024.23353.

MiRNA-449 family is epigenetically repressed and sensitizes to doxorubicin through ACSL4 downregulation in triple-negative breast cancer.

Torres-Ruiz S, Garrido-Cano I, Lameirinhas A, Burgues O, Hernando C, Martinez M Cell Death Discov. 2024; 10(1):372.

PMID: 39174500 PMC: 11341569. DOI: 10.1038/s41420-024-02128-7.

Ferroptosis: the balance between death and survival in colorectal cancer.

Fan S, Zhou L, Zhang W, Wang D, Tang D Int J Biol Sci. 2024; 20(10):3773-3783.

PMID: 39113707 PMC: 11302868. DOI: 10.7150/ijbs.96828.

References

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z . GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017; 45(W1):W98-W102. PMC: 5570223. DOI: 10.1093/nar/gkx247. View

Liu Y, Zhang X, Zhang J, Tan J, Li J, Song Z . Development and Validation of a Combined Ferroptosis and Immune Prognostic Classifier for Hepatocellular Carcinoma. Front Cell Dev Biol. 2021; 8:596679. PMC: 7785857. DOI: 10.3389/fcell.2020.596679. View

Ji M, Feng Q, He G, Yang L, Tang W, Lao X . Silencing homeobox C6 inhibits colorectal cancer cell proliferation. Oncotarget. 2016; 7(20):29216-27. PMC: 5045391. DOI: 10.18632/oncotarget.8703. View

Fan Z, Wirth A, Chen D, Wruck C, Rauh M, Buchfelder M . Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis. Oncogenesis. 2017; 6(8):e371. PMC: 5608917. DOI: 10.1038/oncsis.2017.65. View

Wang W, Green M, Choi J, Gijon M, Kennedy P, Johnson J . CD8 T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 2019; 569(7755):270-274. PMC: 6533917. DOI: 10.1038/s41586-019-1170-y. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Toyokuni S, Yanatori I, Kong Y, Zheng H, Motooka Y, Jiang L . Ferroptosis at the crossroads of infection, aging and cancer. Cancer Sci. 2020; 111(8):2665-2671. PMC: 7419040. DOI: 10.1111/cas.14496. View

Hassannia B, Vandenabeele P, Vanden Berghe T . Targeting Ferroptosis to Iron Out Cancer. Cancer Cell. 2019; 35(6):830-849. DOI: 10.1016/j.ccell.2019.04.002. View

Murphy M . Metabolic control of ferroptosis in cancer. Nat Cell Biol. 2018; 20(10):1104-1105. DOI: 10.1038/s41556-018-0209-x. View

10.

Elliott M, Ravichandran K . The Dynamics of Apoptotic Cell Clearance. Dev Cell. 2016; 38(2):147-60. PMC: 4966906. DOI: 10.1016/j.devcel.2016.06.029. View

11.

Jia J, Wang W, Sun H, Zhu X, Liu L, Zhuang P . High expression of macrophage colony-stimulating factor-1 receptor in peritumoral liver tissue is associated with poor outcome in hepatocellular carcinoma after curative resection. Oncologist. 2010; 15(7):732-43. PMC: 3228006. DOI: 10.1634/theoncologist.2009-0170. View

12.

Benson A, Venook A, Al-Hawary M, Cederquist L, Chen Y, Ciombor K . Rectal Cancer, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018; 16(7):874-901. PMC: 10203817. DOI: 10.6004/jnccn.2018.0061. View

13.

Conrad M, Friedmann Angeli J, Vandenabeele P, Stockwell B . Regulated necrosis: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2016; 15(5):348-66. PMC: 6531857. DOI: 10.1038/nrd.2015.6. View

14.

Chen Y, Zhu G, Liu Y, Wu Q, Zhang X, Bian Z . O-GlcNAcylated c-Jun antagonizes ferroptosis via inhibiting GSH synthesis in liver cancer. Cell Signal. 2019; 63:109384. DOI: 10.1016/j.cellsig.2019.109384. View

15.

Xu J, Fan J, Qin X, Cai J, Gu J, Wang S . Chinese guidelines for the diagnosis and comprehensive treatment of colorectal liver metastases (version 2018). J Cancer Res Clin Oncol. 2018; 145(3):725-736. DOI: 10.1007/s00432-018-2795-1. View

16.

Maag J . gganatogram: An R package for modular visualisation of anatograms and tissues based on ggplot2. F1000Res. 2018; 7:1576. PMC: 6208569. DOI: 10.12688/f1000research.16409.2. View

17.

Doll S, Proneth B, Tyurina Y, Panzilius E, Kobayashi S, Ingold I . ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2016; 13(1):91-98. PMC: 5610546. DOI: 10.1038/nchembio.2239. View

18.

Rink J, Lin A, McMahon K, Calvert A, Yang S, Taxter T . Targeted reduction of cholesterol uptake in cholesterol-addicted lymphoma cells blocks turnover of oxidized lipids to cause ferroptosis. J Biol Chem. 2020; 296:100100. PMC: 7949030. DOI: 10.1074/jbc.RA120.014888. View

19.

Huang Y, Tian C, Li Q, Xu Q . Knockdown Inhibits LPS/IFN-γ-Induced M1 Macrophage Polarization through the NF-κB Pathway in THP-1 Cells. Int J Mol Sci. 2019; 20(8). PMC: 6514734. DOI: 10.3390/ijms20082023. View

20.

Mou Y, Wang J, Wu J, He D, Zhang C, Duan C . Ferroptosis, a new form of cell death: opportunities and challenges in cancer. J Hematol Oncol. 2019; 12(1):34. PMC: 6441206. DOI: 10.1186/s13045-019-0720-y. View