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07-08-2023 | Hepatocellular Carcinoma | Translational Research

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

Authors: Maki Hiromatsu, Katsuya Toshida, MD, Shinji Itoh, MD, PhD, Noboru Harada, MD, PhD, Kenichi Kohashi, MD, PhD, Yoshinao Oda, MD, PhD, Tomoharu Yoshizumi, MD, PhD

Published in: Annals of Surgical Oncology | Issue 13/2023

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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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.CrossRefPubMedPubMedCentral

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.CrossRef

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRef

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRef

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.PubMedPubMedCentral

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.CrossRefPubMed

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.PubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMed

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.CrossRefPubMedPubMedCentral

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.CrossRefPubMedPubMedCentral

Title: Transferrin Receptor is Associated with Sensitivity to Ferroptosis Inducers in Hepatocellular Carcinoma
Authors: Maki Hiromatsu
Katsuya Toshida, MD
Shinji Itoh, MD, PhD
Noboru Harada, MD, PhD
Kenichi Kohashi, MD, PhD
Yoshinao Oda, MD, PhD
Tomoharu Yoshizumi, MD, PhD
Publication date: 07-08-2023
Publisher: Springer International Publishing
Keywords: Hepatocellular Carcinoma
Hepatocellular Carcinoma
Lenvatinib
Sorafenib
Published in: Annals of Surgical Oncology / Issue 13/2023
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-023-14053-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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