Proliferation and migration of oral squamous cell carcinoma via ferritin heavy chain. A systematic review.
DOI:
https://doi.org/10.51168/sjhrafrica.v7i3.2474Keywords:
Ferritin, oral cancer, serum, Iron, Ferroptosis, PrognosisAbstract
Background
Dysregulated iron metabolism is increasingly recognized as a driver of tumor progression in head and neck malignancies. Ferritin heavy chain (FTH1), a central regulator of intracellular iron storage and redox balance, has been implicated in ferroptosis resistance, proliferation and metastatic behaviour. Its mechanistic relevance in oral squamous cell carcinoma (OSCC) requires structured synthesis.
Objective
To systematically evaluate evidence regarding the role of FTH1 in promoting proliferation, migration and therapeutic resistance in OSCC and related head and neck squamous cell carcinoma (HNSCC).
Methods
A systematic review was conducted according to PRISMA guidelines. Electronic databases including PubMed, Scopus, Embase, Web of Science and LILACS were searched for studies published between 2020 and 2024 using combinations of the terms “ferritin,” “FTH1,” “oral cancer,” “OSCC,” “HNSCC,” and “ferroptosis.” Eligible studies included original research evaluating FTH1 expression, functional assays, mechanistic pathways, or clinical correlations in OSCC/HNSCC. Reviews, editorials and unrelated iron metabolism studies were excluded. Data extracted included study design, sample type, FTH1 expression patterns, molecular pathways, effects on proliferation, migration, EMT, ferroptosis and prognostic associations.
Results
Five eligible studies demonstrated consistent overexpression of FTH1 in OSCC/HNSCC tissues compared with controls. Functional analyses revealed that FTH1 promotes tumor cell proliferation and invasion by maintaining iron homeostasis, suppressing lipid peroxidation and inhibiting ferroptosis. Knockdown experiments increased reactive oxygen species accumulation and reduced migratory capacity. Clinically, elevated FTH1 expression correlated with lymph node metastasis, poor prognosis and resistance to chemotherapy and radiotherapy.
Future Directions
Larger OSCC-specific cohorts and mechanistic studies focusing on ferroptosis modulation, tumor microenvironment interactions and therapeutic targeting of FTH1 are required to validate its biomarker and translational potential.
References
Johnson DE, Burtness B, Leemans CR, Lui VW, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nature reviews Disease primers. 2020 Nov 26;6(1):92. doi: 10.1038/s41572-020-00224-3
Addison GM, Beamish MR, Hales CN, Hodgkins M, Jacobs A, Llewellin P. An immunoradiometric assay for ferritin in the serum of normal subjects and patients with iron deficiency and iron overload. Journal of Clinical Pathology. 1972 Apr 1;25(4):326-9. doi: 10.1136/jcp.25.4.326.
Wang W, Knovich MA, Coffman LG, Torti FM, Torti SV. Serum ferritin: past, present and future. Biochimica et Biophysica Acta (BBA)-General Subjects. 2010 Aug 1;1800(8):760-9. doi: 10.1016/j.bbagen.2010.03.011.
Torti SV, Torti FM. Iron and cancer: more ore to be mined. Nature Reviews Cancer. 2013 May;13(5):342-55. DOI: 10.1038/nrc3495
Harigae H, Hino K, Toyokuni S. Iron as soul of life on earth revisited: from chemical reaction, ferroptosis to therapeutics. Free Radical Biology and Medicine. 2019 Mar;133:1-2. doi: 10.1016/j.freeradbiomed.2019.01.042.
Arosio P, Elia L, Poli M. Ferritin, cellular iron storage and regulation. IUBMB life. 2017 Jun;69(6):414-22. doi: 10.1002/iub.1621
Conrad M, Pratt DA. The chemical basis of ferroptosis. Nature chemical biology. 2019 Dec;15(12):1137-47. doi: 10.1038/s41589-019-0408-1.
Torti SV, Manz DH, Paul BT, Blanchette-Farra N, Torti FM. Iron and cancer. Annual review of nutrition. 2018 Aug 21;38(1):97-125. DOI: 10.1146/annurev-nutr-082117-051732
Knovich MA, Storey JA, Coffman LG, Torti SV, Torti FM. Ferritin for the clinician. Blood reviews. 2009 May 1;23(3):95-104. doi: 10.1016/j.blre.2008.08.001
Drysdale J, Arosio P, Invernizzi R, Cazzola M, Volz A, Corsi B, Biasiotto G, Levi S. Mitochondrial ferritin: a new player in iron metabolism. Blood Cells, Molecules and Diseases. 2002 Nov 1;29(3):376-83. doi: 10.1006/bcmd.2002.0577
Shi ZH, Shi FF, Wang YQ, Sheftel AD, Nie G, Zhao YS, You LH, Gou YJ, Duan XL, Zhao BL, Xu HM. Mitochondrial ferritin, a new target for inhibiting neuronal tumor cell proliferation. Cellular and Molecular Life Sciences. 2015 Mar;72(5):983-97. doi: 10.1007/s00018-014-1730-0
Surguladze N, Thompson KM, Beard JL, Connor JR, Fried MG. Interactions and reactions of ferritin with DNA. Journal of Biological Chemistry. 2004 Apr 9;279(15):14694-702. doi: 10.1074/jbc.M313348200.
Liu X, Madhankumar AB, Slagle-Webb B, Sheehan JM, Surguladze N, Connor JR. Heavy chain ferritin siRNA delivered by cationic liposomes increases sensitivity of cancer cells to chemotherapeutic agents. Cancer research. 2011 Mar 15;71(6):2240-9. DOI: 10.1158/0008-5472.CAN-10-1375
Ravi V, Madhankumar AB, Abraham T, Slagle-Webb B, Connor JR. Liposomal delivery of ferritin heavy chain 1 (FTH1) siRNA in patient xenograft derived glioblastoma initiating cells suggests different sensitivities to radiation and distinct survival mechanisms. PLoS One. 2019 Sep 6;14(9):e0221952. doi: 10.1371/journal.pone.0221952
Baharvand M, Manifar S, Akkafan R, Mortazavi H, Sabour S. Serum levels of ferritin, copper and zinc in patients with oral cancer. Biomedical journal. 2014 Sep 1;37(5). DOI: 10.4103/2319-4170.132888
Ouyang S, Li H, Lou L, Huang Q, Zhang Z, Mo J, Li M, Lu J, Zhu K, Chu Y, Ding W. Inhibition of STAT3-ferroptosis negative regulatory axis suppresses tumor growth and alleviates chemoresistance in gastric cancer. Redox biology. 2022 Jun 1;52:102317. doi: 10.1016/j.redox.2022.102317
Hu W, Zhou C, Jing Q, Li Y, Yang J, Yang C, Wang L, Hu J, Li H, Wang H, Yuan C. FTH promotes the proliferation and renders the HCC cells specifically resist to ferroptosis by maintaining iron homeostasis. Cancer Cell International. 2021 Dec 29;21(1):709. doi: 10.1186/s12935-021-02420-x.
Philpott CC, Ryu MS, Frey A, Patel S. Cytosolic iron chaperones: proteins delivering iron cofactors in the cytosol of mammalian cells. Journal of Biological Chemistry. 2017 Aug 4;292(31):12764-71. doi: 10.1074/jbc.R117.791962.
Ryu MS, Duck KA, Philpott CC. Ferritin iron regulators, PCBP1 and NCOA4, respond to cellular iron status in developing red cells. Blood Cells, Molecules and Diseases. 2018 Mar 1;69:75-81. doi: 10.1016/j.bcmd.2017.09.009.
Ahmad S, Moriconi F, Naz N, Sultan S, Sheikh N, Ramadori G, Malik IA. Ferritin L and Ferritin H are differentially located within hepatic and extra hepatic organs under physiological and acute phase conditions. International journal of clinical and experimental pathology. 2013 Mar 15;6(4):622. PMID: 23573308
Basuli D, Tesfay L, Deng Z, Paul B, Yamamoto Y, Ning G, Xian W, McKeon F, Lynch M, Crum CP, Hegde P. Iron addiction: a novel therapeutic target in ovarian cancer. Oncogene. 2017 Jul;36(29):4089-99. doi: 10.1038/onc.2017.11
Gray CP, Franco AV, Arosio P, Hersey P. Immunosuppressive effects of melanoma‐derived heavy‐chain ferritin are dependent on stimulation of IL‐10 production. International journal of cancer. 2001 Jun 15;92(6):843-50. DOI: 10.1002/ijc.1269
Alkhateeb AA, Han B, Connor JR. Ferritin stimulates breast cancer cells through an iron-independent mechanism and is localized within tumor-associated macrophages. Breast cancer research and treatment. 2013 Feb;137(3):733-44. DOI: 10.1007/s10549-012-2405-x
Cozzi A, Corsi B, Levi S, Santambrogio P, Biasiotto G, Arosio P. Analysis of the biologic functions of H-and L-ferritins in HeLa cells by transfection with siRNAs and cDNAs: evidence for a proliferative role of L-ferritin. Blood. 2004 Mar 15;103(6):2377-83. DOI: 10.1182/blood-2003-06-1842
Yang DC, Jiang XI, Elliott RL, Head JF. Antisense ferritin oligonucleotides inhibit growth and induce apoptosis in human breast carcinoma cells. Anticancer research. 2002 May 1;22(3):1513-24. PMID: 12168831
Baldi A, Lombardi D, Russo P, Palescandolo E, De Luca A, Santini D, Baldi F, Rossiello L, Dell'Anna ML, Mastrofrancesco A, Maresca V. Ferritin contributes to melanoma progression by modulating cell growth and sensitivity to oxidative stress. Clinical cancer research. 2005 May 1;11(9):3175-83. doi: 10.1158/1078-0432.CCR-04-0631.
Pozzi C, Di Pisa F, Bernacchioni C, Ciambellotti S, Turano P, Mangani S. Iron binding to human heavy-chain ferritin. Biological Crystallography. 2015 Sep 1;71(9):1909-20. https://doi.org/10.1107/S1399004715013073Digital Object Identifier (DOI)
Hu Z, Wang L, Han Y, Li F, Zheng A, Xu Y, Wang F, Xiao B, Chen C, Tao Z. Ferritin: A potential serum marker for lymph node metastasis in head and neck squamous cell carcinoma. Oncology letters. 2019 Jan;17(1):314-22. doi: 10.3892/ol.2018.9642.
Khanna V, Karjodkar F, Robbins S, Behl M, Arya S, Tripathi A. Estimation of serum ferritin level in potentially malignant disorders, oral squamous cell carcinoma and treated cases of oral squamous cell carcinoma. Journal of Cancer Research and Therapeutics. 2017 Jul 1;13(3):550-5. DOI: 10.4103/0973-1482.181182
Torti FM, Torti SV. Regulation of ferritin genes and protein. Blood, The Journal of the American Society of Hematology. 2002 May 15;99(10):3505-16. DOI: 10.1182/blood.v99.10.3505
Rychtarcikova Z, Lettlova S, Tomkova V, Korenkova V, Langerova L, Simonova E, Zjablovskaja P, Alberich-Jorda M, Neuzil J, Truksa J. Tumor-initiating cells of breast and prostate origin show alterations in the expression of genes related to iron metabolism. Oncotarget. 2016 Dec 22;8(4):6376. DOI: 10.18632/oncotarget.14093
Raggi C, Gammella E, Correnti M, Buratti P, Forti E andersen JB, Alpini G, Glaser S, Alvaro D, Invernizzi P, Cairo G. Dysregulation of iron metabolism in cholangiocarcinoma stem-like cells. Scientific reports. 2017 Dec 15;7(1):17667. DOI: 10.1038/s41598-017-17804-1
Ghanaati S, Udeabor SE, Winter A, Sader R, Heselich A. Cancer recurrence in operated primary oral squamous cell carcinoma patients seems to be independent of the currently available postoperative therapeutic approach: a retrospective clinical study. Current oncology. 2025 Apr 1;32(4):208. DOI: 10.3390/curroncol32040208
Zhou Y, Wang L, Liu M, Jiang H, Wu Y. Oral squamous cell carcinoma: Insights into cellular heterogeneity, drug resistance and evolutionary trajectories. Cell Biology and Toxicology. 2025 Jun 12;41(1):101. doi: 10.1007/s10565-025-10048-0
Hsu PC, Tsai CC, Lin YH, Kuo CY. Therapeutic targeting of apoptosis, autophagic cell death, necroptosis, pyroptosis and ferroptosis pathways in oral squamous cell carcinoma: Molecular mechanisms and potential strategies. Biomedicines. 2025 Jul 16;13(7):1745. doi: 10.3390/biomedicines13071745.
Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B. Ferroptosis: an iron-dependent form of nonapoptotic cell death. cell. 2012 May 25;149(5):1060-72. DOI: 10.1016/j.cell.2012.03.042
Zhou Q, Meng Y, Li D, Yao L, Le J, Liu Y, Sun Y, Zeng F, Chen X, Deng G. Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies. Signal transduction and targeted therapy. 2024 Mar 8;9(1):55. DOI: 10.1038/s41392-024-01769-5
Vijayarangam V, Balasubramanian P, Palaniyandi T, Ravindran R, Suliman M, Saeed M, Natarajan S, Sivaji A, Baskar G. Ferroptosis as a hero against oral cancer. Pathology-Research and Practice. 2024 Nov 1;263:155637. DOI: 10.1016/j.prp.2024.155637
Tan Y, Wang Z, Xu M, Li B, Huang Z, Qin S, Nice EC, Tang J, Huang C. Oral squamous cell carcinomas: state of the field and emerging directions. International journal of oral science. 2023 Sep 22;15(1):44. DOI: 10.1038/s41368-023-00249-w
Yang Z, Sun P, Dahlstrom KR, Gross N, Li G. Joint effect of human papillomavirus exposure, smoking and alcohol on risk of oral squamous cell carcinoma. BMC cancer. 2023 May 19;23(1):457. DOI: 10.1186/s12885-023-10948-6
Hentze MW, Keim S, Papadopoulos P, O'Brien S, Modi W, Drysdale J, Leonard WJ, Harford JB, Klausner RD. Cloning, characterization, expression and chromosomal localization of a human ferritin heavy-chain gene. Proceedings of the National Academy of Sciences. 1986 Oct;83(19):7226-30. DOI: 10.1073/pnas.83.19.7226
Nagai K, Nakahata S, Shimosaki S, Tamura T, Kondo Y, Baba T, Taki T, Taniwaki M, Kurosawa G, Sudo Y, Okada S. Development of a complete human anti‐human transferrin receptor C antibody as a novel marker of oral dysplasia and oral cancer. Cancer medicine. 2014 Aug;3(4):1085-99. DOI: 10.1002/cam4.267
Zhang KH, Tian HY, Gao X, Lei WW, Hu Y, Wang DM, Pan XC, Yu ML, Xu GJ, Zhao FK, Song JG. Ferritin heavy chain–mediated iron homeostasis and subsequent increased reactive oxygen species production are essential for epithelial-mesenchymal transition. Cancer research. 2009 Jul 1;69(13):5340-8. DOI: 10.1158/0008-5472.CAN-09-0112
Pomella S, Melaiu O, Cifaldi L, Bei R, Gargari M, Campanella V, Barillari G. biomarkers identification in the microenvironment of oral squamous cell carcinoma: A systematic review of proteomic studies. International Journal of Molecular Sciences. 2024 Aug 16;25(16):8929. DOI: 10.3390/ijms25168929
Szymulewska-Konopko K, Reszeć-Giełażyn J, Małeczek M. Ferritin as an effective prognostic factor and potential cancer biomarker. Current issues in molecular biology. 2025 Jan 16;47(1):60. DOI: 10.3390/cimb47010060
Buch SA, Babu SG, Castelino RL, Pillai DS, Bhat S, Devi UH. Ferritin levels in serum and saliva of oral cancer and oral potentially malignant disorders. Eur. J. Ther. 2022;28:109-14. DOI: https://doi.org/10.54614/eurjther.2021.0048
Panigrahi C, Yuwanati M, Senthil MM, Priyadharshini R. Determination of Intracellular Iron in Oral Squamous Cell Carcinoma Using Perl’s Prussian Blue Iron Stain. Clinical Cancer Investigation Journal. 2022;11(5-2022):7-10.doi. 10.51847/VxCgwzzIDV
Lin L, Yin X, Guan Y. Decoding iron deficiency in cancer: mechanisms, immune modulation and therapeutic potential. Frontiers in Nutrition. 2025 Oct 20;12:1650929. DOI: 10.3389/fnut.2025.1650929
Lee J, Seo Y, Roh JL. Ferroptosis and Nrf2 signaling in head and neck cancer: resistance mechanisms and therapeutic prospects. Antioxidants. 2025 Aug 13;14(8):993. DOI: 10.3390/antiox14080993
Roh JL. Targeting ferroptosis suppressor protein 1 in cancer therapy: Implications and perspectives, with emphasis on head and neck cancer. Critical Reviews in Oncology/Hematology. 2024 Oct 1;202:104440. DOI: 10.1016/j.critrevonc.2024.104440
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Dr. Karthik Shunmugavelu, Dr. N . Parthiban M.D.S
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
