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Transferrin Receptor is Associated with Sensitivity to Ferroptosis Inducers in Hepatocellular Carcinoma

  • Translational Research
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Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Transferrin receptor (TFR), a membrane protein that has a critical role in the transport of iron into cells, is known to be a ferroptosis-related marker. Although TFR is reported to be abundantly expressed in tumor cells, its relationship with ferroptosis inducers in hepatocellular carcinoma (HCC) remains unclear.

Methods

The authors performed immunohistochemical staining of TFR and divided 350 HCC patients into two groups according to its expression. They analyzed the association between TFR expression and prognosis or clinicopathologic factors. In addition, the regulation of malignant activity and its effect on the efficacy of ferroptosis inducers were investigated in vitro.

Results

For this study, 350 patients were divided into TFR-positive (n =180, 51.4%) and TFR-negative (n = 170, 48.6%) groups. The TFR-positive group had more hepatitis B surface antigen (HBs-Ag) (p = 0.0230), higher α-fetoprotein (AFP) levels (p = 0.0023), higher des-gamma-carboxyprothrombin (DCP) levels (p = 0.0327), a larger tumor size (p = 0.0090), greater proportions of Barcelona Clinic Liver Cancer (BCLC) stage B or C (p = 0.0005), poor differentiation (p < 0.0001), and microscopic intrahepatic metastasis (p = 0.0066). In the multivariate analyses, TFR expression was an independent prognostic factor in disease-free survival (p = 0.0315). In vitro, TFRC knockdown decreased cell motility. In addition, TFRC knockdown abolished artesunate (AS)-, lenvatinib-, and sorafenib-induced ferroptosis in HCC cell lines. The study demonstrated that simultaneous treatment of AS with multi-kinase inhibitor augmented the ferroptosis-inducing effects of AS in HCC cell lines.

Conclusion

TFR expression is a poor prognostic factor in HCC, but its expression increases sensitivity to ferroptosis-inducing agents.

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References

  1. Singal AG, Lampertico P, Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: new trends. J Hepatol. 2020;72:250–61. https://doi.org/10.1016/j.jhep.2019.08.025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Okamura Y, Sugiura T, Ito T, et al. Changes in patient background and prognosis after hepatectomy for hepatocellular carcinoma by hepatitis virus infection status: new trends in Japan. Ann Gastroenterological Surg. 2021;5:553–66. https://doi.org/10.1002/ags3.12451.

    Article  Google Scholar 

  3. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a envatinib phase 3 non-inferiority trial. Lancet. 2018;391:1163–73. https://doi.org/10.1016/s0140-6736(18)30207-1.

    Article  CAS  PubMed  Google Scholar 

  4. Cheng AL, Qin S, Ikeda M, et al. Updated efficacy and safety data from Imbrave150: atezolizumab plus bevacizumab vs sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76:862–73. https://doi.org/10.1016/j.jhep.2021.11.030.

    Article  CAS  PubMed  Google Scholar 

  5. Itoh S, Yoshizumi T, Yugawa K, et al. Impact of immune response on outcomes in hepatocellular carcinoma: association with vascular formation. Hepatology. 2020;72:1987–99. https://doi.org/10.1002/hep.31206.

    Article  CAS  PubMed  Google Scholar 

  6. Itoh S, Yoshizumi T, Kitamura Y, et al. Impact of metabolic activity in hepatocellular carcinoma: association with immune status and vascular formation. Hepatology Commun. 2021;5:1278–89. https://doi.org/10.1002/hep4.1715.

    Article  CAS  Google Scholar 

  7. Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72. https://doi.org/10.1016/j.cell.2012.03.042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lei G, Zhuang L, Gan B. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer. 2022;22:381–96. https://doi.org/10.1038/s41568-022-00459-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gao M, Monian P, Quadri N, Ramasamy R, Jiang X. Glutaminolysis and transferrin regulate ferroptosis. Mol Cell. 2015;59:298–308. https://doi.org/10.1016/j.molcel.2015.06.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Adachi M, Kai K, Yamaji K, et al. Transferrin receptor 1 overexpression is associated with tumour de-differentiation and acts as a potential prognostic indicator of hepatocellular carcinoma. Histopathology. 2019;75:63–73. https://doi.org/10.1111/his.13847.

    Article  PubMed  Google Scholar 

  11. Li ZJ, Dai HQ, Huang XW, et al. Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma. Acta Pharmacol Sin. 2021;42:301–10. https://doi.org/10.1038/s41401-020-0478-3.

    Article  CAS  PubMed  Google Scholar 

  12. Farshidfar F, Zheng S, Gingras MC, et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep. 2017;18:2780–94. https://doi.org/10.1016/j.celrep.2017.02.033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Vasaikar SV, Straub P, Wang J, Zhang B. LinkedOmics: analyzing multi-omics data within and across 32 cancer types. Nucleic Acids Res. 2017. https://doi.org/10.1093/nar/gkx1090.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Itoh S, Tomiyama T, Morinaga A, et al. Clinical effects of the use of the indocyanine green fluorescence imaging technique in laparoscopic partial liver resection. Ann Gastroenterol Surg. 2022;6:688–94. https://doi.org/10.1002/ags3.12563.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Toshida K, Itoh S, Harada N, et al. Cancer-associated fibroblasts promote tumor cell growth via miR-493-5p in intrahepatic cholangiocarcinoma. Cancer Sci. 2023;114:937–47. https://doi.org/10.1111/cas.15644.

    Article  CAS  PubMed  Google Scholar 

  16. Itoh S, Taketomi A, Harimoto N, et al. Antineoplastic effects of gamma linolenic acid on hepatocellular carcinoma cell lines. J Clin Biochem Nutr. 2010;47:81–90. https://doi.org/10.3164/jcbn.10-24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lin W, Tsai W, Shao R, et al. Hepatitis C virus regulates transforming growth factor β1 production through the generation of reactive oxygen species in a nuclear factor κB-dependent manner. Gastroenterology. 2010;138:2509-2518.e1. https://doi.org/10.1053/j.gastro.2010.03.008.

    Article  CAS  PubMed  Google Scholar 

  18. Yang X, Zheng Y, Liu L, Huang J, Wang F, Zhang J. Progress on the study of the anticancer effects of artesunate. Oncol Lett. 2021;22:750. https://doi.org/10.3892/ol.2021.13011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kawabata H. Transferrin and transferrin receptors update. Free Radical Bio Med. 2019;133:46–54. https://doi.org/10.1016/j.freeradbiomed.2018.06.037.

    Article  CAS  Google Scholar 

  20. Shen Y, Li X, Dong D, Zhang B, Xue Y, Shang P. Transferrin receptor 1 in cancer: a new sight for cancer therapy. Am J Cancer Res. 2018;8:916–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Shen Y, Li X, Zhao B, et al. Iron metabolism gene expression and prognostic features of hepatocellular carcinoma. J Cell Biochem. 2018;119:9178–204. https://doi.org/10.1002/jcb.27184.

    Article  CAS  PubMed  Google Scholar 

  22. Sun H, Qian X, Yang W, et al. Novel prognostic signature based on HRAS, MAPK3, and TFRC identified to be associated with ferroptosis and the immune microenvironment in hepatocellular carcinoma. Am J Transl Res. 2022;14:6924–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Asare GA, Mossanda KS, Kew MC, Paterson AC, Kahler-Venter CP, Siziba K. Hepatocellular carcinoma caused by iron overload: a possible mechanism of direct hepatocarcinogenicity. Toxicology. 2006;219:41–52. https://doi.org/10.1016/j.tox.2005.11.006.

    Article  CAS  PubMed  Google Scholar 

  24. Sorrentino P, D’Angelo S, Ferbo U, Micheli P, Bracigliano A, Vecchione R. Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis. J Hepatol. 2009;50:351–7. https://doi.org/10.1016/j.jhep.2008.09.011.

    Article  CAS  PubMed  Google Scholar 

  25. Malumbres M, Barbacid M. Cell cycle, CDKs, and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153–66. https://doi.org/10.1038/nrc2602.

    Article  CAS  PubMed  Google Scholar 

  26. Li J, Cao F, Yin HL, et al. Ferroptosis: past, present, and future. Cell Death Dis. 2020;11:88. https://doi.org/10.1038/s41419-020-2298-2.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Sun X, Ou Z, Chen R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 2016;63:173–84. https://doi.org/10.1002/hep.28251.

    Article  CAS  PubMed  Google Scholar 

  28. Yao F, Deng Y, Zhao Y, et al. A targetable LIFR−NF-κB−LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis. Nat Commun. 2021;12:7333. https://doi.org/10.1038/s41467-021-27452-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bekric D, Ocker M, Mayr C, et al. Ferroptosis in hepatocellular carcinoma: mechanisms, drug targets, and approaches to clinical translation. Cancers. 2022;14:1826. https://doi.org/10.3390/cancers14071826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hino K, Yanatori I, Hara Y, Nishina S. Iron and liver cancer: an inseparable connection. Febs J. 2022;289:7810–29. https://doi.org/10.1111/febs.16208.

    Article  CAS  PubMed  Google Scholar 

  31. Iseda N, Itoh S, Toshida K, et al. Ferroptosis is induced by lenvatinib through fibroblast growth factor receptor-4 inhibition in hepatocellular carcinoma. Cancer Sci. 2022;113:2272–87. https://doi.org/10.1111/cas.15378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dixon SJ, Patel DN, Welsch M, et al. Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife. 2014;3:e02523. https://doi.org/10.7554/elife.02523.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported by JSPS KAKENHI (Grant No. JP-19K09198) and by the Takeda Science Foundation. The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the article for publication. We thank Ms. Saori Tsurumaru, Ms. Asuka Nakamura, Ms. Yuko Kubota, and Ms. Miki Nakashima for technical support. We also thank H. Nikki March, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this report.

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Author notes

  1. Maki Hiromatsu and Katsuya Toshida have contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Maki Hiromatsu, Katsuya Toshida MD, Shinji Itoh MD, PhD, Noboru Harada MD, PhD & Tomoharu Yoshizumi MD, PhD

  2. Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Kenichi Kohashi MD, PhD & Yoshinao Oda MD, PhD

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  1. Maki Hiromatsu
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Contributions

MH and KT participated in the study conception and design, analysis, and drafting of the article. SI participated in the study conception and design, and in the critical revision of the manuscript. NH and KK participated in the data acquisition, analysis, and interpretation. YO and TY participated in the analysis participated in the critical revision of the manuscript.

Corresponding author

Correspondence to Shinji Itoh MD, PhD.

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The authors declare that they have no conflict of interest.

Informed Consent

All patients provided informed consent. Registry and the Registration No. of the study: This retrospective study was approved by the ethics committee of Kyushu University (approval code: 2021-467).

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10434_2023_14053_MOESM1_ESM.tiff

Fig. S1 Gene set enrichment analysis (GSEA) shows that TFRC is highly related to the cell cycle. A Normal enrichment score (NES). B Cell cycle-related enrichment plots (TIFF 33973 KB)

10434_2023_14053_MOESM2_ESM.tiff

Fig. S2 Relationship between intracellular iron levels and efficacy of ferroptosis inducers. A Intracellular iron levels in DFO-treated cells 48 h after treatment. B Intracellular iron levels in TFRC knockdown (KD) cells 48 h after gene-silencing. C Cell proliferation ability was reduced in iron-chelated cells. Data are presented as median ± range. *p < 0.05. **p < 0.001. ***p < 0.0001. DFO, deferoxamine mesylate (TIFF 33973 KB)

10434_2023_14053_MOESM3_ESM.tiff

Fig. S3 Combination treatment augments the efficacy of sorafenib (SOR) multi-kinase inhibitor. Huh7 and PLC cells were treated with artesunate (AS) (25 µmol) and/or SOR (40 µmol). Cell viability, ROS, and MDA levels were measured 72 h after cell seeding. Combination treatment with lenvatinib (LEN) and AS resulted in (A) reduced cell viability, (B) increased ROS, and (C) MDA accumulation, indicating increased sensitivity to ferroptosis compared with SOR treatment alone. Data are presented as median ± range. *p < 0.05. **p < 0.001. ***p < 0.0001. MDA, malondialdehyde (TIFF 33973 KB)

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Hiromatsu, M., Toshida, K., Itoh, S. et al. Transferrin Receptor is Associated with Sensitivity to Ferroptosis Inducers in Hepatocellular Carcinoma. Ann Surg Oncol 30, 8675–8689 (2023). https://doi.org/10.1245/s10434-023-14053-7

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