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Development and validation of a ferroptosis-related prognostic model in pancreatic cancer

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Summary

Background: The purpose of this study was to identify ferroptosis-related genes (FRGs) associated with the prognosis of pancreatic cancer and to construct a prognostic model based on FRGs. Methods: Based on pancreatic cancer data obtained from The Cancer Genome Atlas database, we established a prognostic model from 232 FRGs. A nomogram was constructed by combining the prognostic model and clinicopathological features. Gene Expression Omnibus datasets and tissue samples obtained from our center were utilized to validate the model. The relationship between risk score and immune cell infiltration was explored by CIBERSORT and TIMER. Results: The prognostic model was established based on four FRGs (ENPP2, ATG4D, SLC2A1 and MAP3K5), and the risk score was demonstrated to be an independent risk factor in pancreatic cancer (HR 1.648, 95% CI 1.335–2.035, p < 0.001). Based on the median risk score, patients were divided into a high-risk group and a low-risk group. The low-risk group had a better prognosis than the high-risk group. In the high-risk group, patients treated with chemotherapy had a better prognosis. The nomogram showed that the model was the most important element. Gene set enrichment analysis identified three key pathways, namely, TGFβ signaling, HIF signaling pathway and the adherens junction. The prognostic model may be associated with infiltration of immune cells such as M0 macrophages, M1 macrophages, CD4 + T cells and CD8 + T cells. Conclusion: The ferroptosis-related prognostic model can be employed to predict the prognosis of pancreatic cancer. Ferroptosis is an important marker, and immunotherapy may be a potential therapeutic target for pancreatic cancer.

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Data availability

All data generated or analyzed during this study are included in this published article and supplementary information files.

Abbreviations

FRG:

Ferroptosis-related genes

DE-FRG:

Differentially expressed ferroptosis-related genes

TCGA:

The Cancer Genome Atlas

LASSO:

Least absolute shrinkage and selection operator

GEO:

Gene Expression Omnibus

OS:

Overall survival

GSEA:

Gene set enrichment analysis

ROS:

Reactive oxygen species

GO:

Gene Ontology

KEGG:

Kyoto Encyclopedia of Genes and Genomes

BP:

Biological processes

CC:

Cellular components

MF:

Molecular functions

PPI:

Protein–protein interaction

KM:

Kaplan-Meier

ROC:

Receiver operating characteristic

AUC:

The area under the curve;

RT-qPCR:

Real-time quantitative polymerase chain reaction

FDR:

False discovery rate

SCNA:

Somatic number alteration

TIMER:

Tumor Immune Estimation Resource

References

  1. Siegel RL, Miller KD, Jemal A (2020) Cancer statistics, 2020. CA Cancer J Clin 70:7–30

    Article  PubMed  Google Scholar 

  2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424

    Article  PubMed  Google Scholar 

  3. Mizrahi JD, Surana R, Valle JW, Shroff RT (2020) Pancreatic cancer. Lancet 395:2008–2020

    Article  CAS  PubMed  Google Scholar 

  4. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM (2014) Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74:2913–2921

    Article  CAS  PubMed  Google Scholar 

  5. Neoptolemos JP, Kleeff J, Michl P, Costello E, Greenhalf W, Palmer DH (2018) Therapeutic developments in pancreatic cancer: current and future perspectives. Nat Rev Gastroenterol Hepatol 15:333–348

    Article  PubMed  Google Scholar 

  6. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd, Stockwell BR (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149:1060–1072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Louandre C, Marcq I, Bouhlal H, Lachaier E, Godin C, Saidak Z, Francois C, Chatelain D, Debuysscher V, Barbare JC, Chauffert B, Galmiche A (2015) The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells. Cancer Lett 356:971–977

    Article  CAS  PubMed  Google Scholar 

  8. Zhang X, Du L, Qiao Y, Zhang X, Zheng W, Wu Q, Chen Y, Zhu G, Liu Y, Bian Z, Guo S, Yang Y, Ma L, Yu Y, Pan Q, Sun F, Wang J (2019) Ferroptosis is governed by differential regulation of transcription in liver cancer. Redox Biol 24:101211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, Thomas AG, Gleason CE, Tatonetti NP, Slusher BS, Stockwell BR (2014) Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife 3:e02523

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Mao C, Wang X, Liu Y, Wang M, Yan B, Jiang Y, Shi Y, Shen Y, Liu X, Lai W, Yang R, Xiao D, Cheng Y, Liu S, Zhou H, Cao Y, Yu W, Muegge K, Yu H, Tao Y (2018) A G3BP1-interacting lncRNA promotes Ferroptosis and apoptosis in Cancer via nuclear sequestration of p53. Cancer Res 78:3484–3496

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Lachaier E, Louandre C, Godin C, Saidak Z, Baert M, Diouf M, Chauffert B, Galmiche A (2014) Sorafenib induces ferroptosis in human cancer cell lines originating from different solid tumors. Anticancer Res 34:6417–6422

    CAS  PubMed  Google Scholar 

  12. Kasukabe T, Honma Y, Okabe-Kado J, Higuchi Y, Kato N, Kumakura S (2016) Combined treatment with cotylenin a and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells. Oncol Rep 36:968–976

    Article  CAS  PubMed  Google Scholar 

  13. Eling N, Reuter L, Hazin J, Hamacher-Brady A, Brady NR (2015) Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. Oncoscience 2:517–532

    Article  PubMed  PubMed Central  Google Scholar 

  14. Torii S, Shintoku R, Kubota C, Yaegashi M, Torii R, Sasaki M, Suzuki T, Mori M, Yoshimoto Y, Takeuchi T, Yamada K (2016) An essential role for functional lysosomes in ferroptosis of cancer cells. Biochem J 473:769–777

    Article  CAS  PubMed  Google Scholar 

  15. Yu H, Guo P, Xie X, Wang Y, Chen G (2017) Ferroptosis, a new form of cell death, and its relationships with tumourous diseases. J Cell Mol Med 21:648–657

    Article  CAS  PubMed  Google Scholar 

  16. Yamaguchi Y, Kasukabe T, Kumakura S (2018) Piperlongumine rapidly induces the death of human pancreatic cancer cells mainly through the induction of ferroptosis. Int J Oncol 52:1011–1022

    CAS  PubMed  Google Scholar 

  17. Zhu S, Zhang Q, Sun X, Zeh HJ 3rd, Lotze MT, Kang R, Tang D (2017) HSPA5 regulates Ferroptotic cell death in Cancer cells. Cancer Res 77:2064–2077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ 3rd, Kang R, Tang D (2016) Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 12:1425–1428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yan J, Wu L, Jia C, Yu S, Lu Z, Sun Y, Chen J (2020) Development of a four-gene prognostic model for pancreatic cancer based on transcriptome dysregulation. Aging (Albany NY) 12:3747–3770

    Article  CAS  Google Scholar 

  20. Liang JY, Wang DS, Lin HC, Chen XX, Yang H, Zheng Y, Li YH (2020) A novel Ferroptosis-related gene signature for overall survival prediction in patients with hepatocellular carcinoma. Int J Biol Sci 16:2430–2441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wu G, Wang Q, Xu Y, Li Q, Cheng L (2020) A new survival model based on ferroptosis-related genes for prognostic prediction in clear cell renal cell carcinoma. Aging (Albany NY) 12:14933–14948

    Article  CAS  Google Scholar 

  22. Liu HJ, Hu HM, Li GZ, Zhang Y, Wu F, Liu X, Wang KY, Zhang CB, Jiang T (2020) Ferroptosis-related gene signature predicts Glioma cell death and Glioma patient progression. Front Cell Dev Biol 8:538

    Article  PubMed  PubMed Central  Google Scholar 

  23. Augustin R (2010) The protein family of glucose transport facilitators: It's not only about glucose after all. IUBMB Life 62:315–333

    CAS  PubMed  Google Scholar 

  24. Cheng Y, Wang K, Geng L, Sun J, Xu W, Liu D, Gong S, Zhu Y (2019) Identification of candidate diagnostic and prognostic biomarkers for pancreatic carcinoma. EBioMedicine 40:382–393

    Article  PubMed  PubMed Central  Google Scholar 

  25. Nagarajan A, Dogra SK, Sun L, Gandotra N, Ho T, Cai G, Cline G, Kumar P, Cowles RA, Wajapeyee N (2017) Paraoxonase 2 facilitates pancreatic Cancer growth and metastasis by stimulating GLUT1-mediated glucose transport. Mol Cell 67:685–701 e6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yu M, Zhou Q, Zhou Y, Fu Z, Tan L, Ye X, Zeng B, Gao W, Zhou J, Liu Y, Li Z, Lin Y, Lin Q, Chen R (2015) Metabolic phenotypes in pancreatic cancer. PLoS One 10:e0115153

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Jiang Y, Mao C, Yang R, Yan B, Shi Y, Liu X, Lai W, Liu Y, Wang X, Xiao D, Zhou H, Cheng Y, Yu F, Cao Y, Liu S, Yan Q, Tao Y (2017) EGLN1/c-Myc induced lymphoid-specific helicase inhibits Ferroptosis through lipid metabolic gene expression changes. Theranostics 7:3293–3305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Perrakis A, Moolenaar WH (2014) Autotaxin: structure-function and signaling. J Lipid Res 55:1010–1018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhao Z, Xiao Y, Elson P, Tan H, Plummer SJ, Berk M, Aung PP, Lavery IC, Achkar JP, Li L, Casey G, Xu Y (2007) Plasma lysophosphatidylcholine levels: potential biomarkers for colorectal cancer. J Clin Oncol 25:2696–2701

    Article  CAS  PubMed  Google Scholar 

  30. Bai YT, Chang R, Wang H, Xiao FJ, Ge RL, Wang LS (2018) ENPP2 protects cardiomyocytes from erastin-induced ferroptosis. Biochem Biophys Res Commun 499:44–51

    Article  CAS  PubMed  Google Scholar 

  31. Nakai Y, Ikeda H, Nakamura K, Kume Y, Fujishiro M, Sasahira N, Hirano K, Isayama H, Tada M, Kawabe T, Komatsu Y, Omata M, Aoki J, Koike K, Yatomi Y (2011) Specific increase in serum autotaxin activity in patients with pancreatic cancer. Clin Biochem 44:576–581

    Article  CAS  PubMed  Google Scholar 

  32. Quan M, Cui JJ, Feng X, Huang Q (2017) The critical role and potential target of the autotaxin/lysophosphatidate axis in pancreatic cancer. Tumour Biol 39:1010428317694544

    PubMed  Google Scholar 

  33. Gao M, Monian P, Pan Q, Zhang W, Xiang J, Jiang X (2016) Ferroptosis is an autophagic cell death process. Cell Res 26:1021–1032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Luo Y, Gao S, Hao Z, Yang Y, Xie S, Li D, Liu M, Zhou J (2016) Apoptosis signal-regulating kinase 1 exhibits oncogenic activity in pancreatic cancer. Oncotarget 7:75155–75164

    Article  PubMed  PubMed Central  Google Scholar 

  35. Matsuzawa A, Saegusa K, Noguchi T, Sadamitsu C, Nishitoh H, Nagai S, Koyasu S, Matsumoto K, Takeda K, Ichijo H (2005) ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity. Nat Immunol 6:587–592

    Article  CAS  PubMed  Google Scholar 

  36. Hattori K, Ishikawa H, Sakauchi C, Takayanagi S, Naguro I, Ichijo H (2017) Cold stress-induced ferroptosis involves the ASK1-p38 pathway. EMBO Rep 18:2067–2078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jin X, Dai L, Ma Y, Wang J, Liu Z (2020) Implications of HIF-1alpha in the tumorigenesis and progression of pancreatic cancer. Cancer Cell Int 20:273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zou Y, Palte MJ, Deik AA, Li H, Eaton JK, Wang W, Tseng YY, Deasy R, Kost-Alimova M, Dancik V, Leshchiner ES, Viswanathan VS, Signoretti S, Choueiri TK, Boehm JS, Wagner BK, Doench JG, Clish CB, Clemons PA, Schreiber SL (2019) A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat Commun 10:1617

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Yang M, Chen P, Liu J, Zhu S, Kroemer G, Klionsky DJ, Lotze MT, Zeh HJ, Kang R, Tang D (2019) Clockophagy is a novel selective autophagy process favoring ferroptosis. Sci Adv 5:eaaw2238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hu G, He N, Cai C, Cai F, Fan P, Zheng Z, Jin X (2019) HDAC3 modulates cancer immunity via increasing PD-L1 expression in pancreatic cancer. Pancreatology 19:383–389

    Article  CAS  PubMed  Google Scholar 

  41. Feng M, Xiong G, Cao Z, Yang G, Zheng S, Song X, You L, Zheng L, Zhang T, Zhao Y (2017) PD-1/PD-L1 and immunotherapy for pancreatic cancer. Cancer Lett 407:57–65

    Article  CAS  PubMed  Google Scholar 

  42. Wang S, Yao F, Lu X, Li Q, Su Z, Lee JH, Wang C, Du L (2019) Temozolomide promotes immune escape of GBM cells via upregulating PD-L1. Am J Cancer Res 9:1161–1171

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the staff from the pancreas center of the First Affiliated Hospital of Nanjing Medical University who gave us support throughout the experiments.

Funding

This work was supported by the Wu Jieping Medical Foundation (Grant/Award Number: 320.2710.1802).

Author information

Author notes

  1. Chen-jie Qiu, Xue-bing Wang and Zi-ruo Zheng contributed equally to this work.

Authors and Affiliations

  1. Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China

    Chen-jie Qiu, Xue-bing Wang, Zi-ruo Zheng, Chao-zhi Yang, Kai Lin, Kai Zhang, Min Tu, Kui-rong Jiang & Wen-tao Gao

  2. Pancreas Institute, Nanjing Medical University, Nanjing, Jiangsu, China

    Chen-jie Qiu, Xue-bing Wang, Zi-ruo Zheng, Chao-zhi Yang, Kai Lin, Kai Zhang, Min Tu, Kui-rong Jiang & Wen-tao Gao

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  1. Chen-jie Qiu
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Contributions

Chen-jie Qiu and Xue-bing Wang performed the experimental design and data analysis. Zi-ruo Zheng wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Kui-rong Jiang or Wen-tao Gao.

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The study was approved by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University.

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Qiu, Cj., Wang, Xb., Zheng, Zr. et al. Development and validation of a ferroptosis-related prognostic model in pancreatic cancer. Invest New Drugs 39, 1507–1522 (2021). https://doi.org/10.1007/s10637-021-01114-5

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  • DOI: https://doi.org/10.1007/s10637-021-01114-5

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