Cited by 135Iron Metabolism and DisordersFerroptosis and cancer prognosisNeurological diseases and metabolism

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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

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Cozzi, Anna, Corsi, Barbara, Levi, Sonia, Santambrogio, Paolo, Biasiotto, Giorgio, Arosio, Paolo·2004·Blood

DOI 10.1182/blood-2003-06-1842

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Abstract

We describe the use of small interfering RNAs (siRNAs) to down-regulate H- and L-ferritin levels in HeLa cells. siRNAs repressed H- and L-ferritin expression to about 20% to 25% of the background level in both stable and transient transfections. HeLa cells transfected with H- and L-ferritin cDNAs were analyzed in parallel to compare the effects of ferritin up- and down-regulation. We found that large modifications of L-ferritin levels did not affect iron availability in HeLa cells but positively affected cell proliferation rate in an iron-independent manner. The transient down-regulation of H-ferritin modified cellular iron availability and resistance to oxidative damage, as expected. In contrast, the stable suppression of H-ferritin in HeLa cell clones transfected with siRNAs did not increase cellular iron availability but made cells less resistant to iron supplementation and chelation. The results indicate that L-ferritin has no direct effects on cellular iron homeostasis in HeLa cells, while it has new, iron-unrelated functions. In addition, they suggest that H-ferritin function is to act as an iron buffer.

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Background
Role of intracellular labile iron, ferritin, and antioxidant defence in resistance of chronically adapted Jurkat T cells to hydrogen peroxide
Al-Qenaei, A., Yiakouvaki, A., Reelfs, O., Santambrogio, P., Levi, S., Hall, N. D., Tyrrell, R. M., & Pourzand, C. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.12.006 · Cited by 37
“Accordingly FtL knockdown did not have a significant impact on intracellular iron availability [63].”
BackgroundSelf-citation
Identification and functional characterization of a novel ferritin subunit from the tropical sea cucumber, Stichopus monotuberculatus
Ren, C., Chen, T., Jiang, X., Wang, Y., & Hu, C. (2014) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2014.03.022 · Cited by 37
Repression of ferritin light chain translation by human eIF3
Pulos-Holmes, M. C., Srole, D. N., Lee, A. S. Y., Juarez, M. G., McSwiggen, D. T., Ingolia, N. T., & Cate, J. H. D. (2019) · eLife · doi:10.7554/elife.48193 · Cited by 34
“Primers for the qPCR were as follows: FTL forward: 5’ -ACCTCTCTCTGGGCTTCTAT-3’, FTL reverse: 5’ -AGCTGGC TTCTTGATGTCCT-3’ (Cozzi et al., 2004), ACTB forward: 5’-CTCTTCCAGCCTTCCTTCCT-3’, ACTB reverse: 5’-AGCACTGTGTTGGCGTACAG-3’ (Chen et al., 2008), PSMB6 forward: 5’-GGACTCCAGAACAACCACTG-3’, PSMB6 reverse: 5’-CAGCTGAGCC…”
Method
Neurons lacking iron regulatory protein-2 are highly resistant to the toxicity of hemoglobin
Regan, R. F., Chen, M., Li, Z., Zhang, X., Benvenisti‐Zarom, L., & Chen‐Roetling, J. (2008) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.04.008 · Cited by 33
“H-ferritin knockdown markedly increased HeLa cell vulnerability to hydrogen peroxide, while upregulation was protective; modulation of L-ferritin levels had no significant effect (Cozzi et al., 2004).”
Ferroportin gene silencing induces iron retention and enhances ferritin synthesis in human macrophages
Gallì, A., Bergamaschi, G., Recalde, H. R., Biasiotto, G., Santambrogio, P., Boggi, S., Levi, S., Arosio, P., & Cazzola, M. (2004) · British Journal of Haematology · doi:10.1111/j.1365-2141.2004.05238.x · Cited by 32
“Recent studies support the hypothesis that ferroportin plays an important role in macrophage recycling of iron from senescent red blood cells (Yang et al, 2002; Knutson et al, 2003; Ludwiczek et al, 2003; Cozzi et al, 2004).”
BackgroundResultSelf-citation
Ferritin L is the Sole Serum Ferritin Constituent and a Positive Hepatic Acute-Phase Protein
Naz, N., Moriconi, F., Ahmad, S., Amanzada, A., Khan, S., Mihm, S., Ramadori, G., & Malik, I. A. (2013) · Shock · doi:10.1097/shk.0b013e31829266b9 · Cited by 31
“tissue-specific regulations, whereas multiple conditions activate FTH gene transcription (7, 8), including cell differentiation, changes in the cell proliferation status (9), cytokines, and heme.”
Background
IRP1-independent alterations of cardiac iron metabolism in doxorubicin-treated mice
Corna, G., Galy, B., Hentze, M. W., & Cairo, G. (2006) · Journal of Molecular Medicine · doi:10.1007/s00109-006-0068-y · Cited by 32
“Further evidence for this protective role of ferritin stems from the demonstration of higher H2O2 toxicity in HeLa cells depleted of ferritin H-chain by small interfering RNAs [38].”
Background
H ferritin silencing induces protein misfolding in K562 cells: A Raman analysis
Zolea, F., Biamonte, F., Candeloro, P., Sanzo, M. D., Cozzi, A., Vito, A. D., Quaresima, B., Lobello, N., Trecroci, F., Fabrizio, E. M. D., et al. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.07.161 · Cited by 30
“In this work, we confirmed this ferritin primary role and uncovered an unexpected and interesting effect on protein folding in K562 cells caused by the silencing of the H-ferritin chain.”
ResultInfluentialSelf-citation
Light-Induced Retinal Degeneration Correlates with Changes in Iron Metabolism Gene Expression, Ferritin Level, and Aging
Picard, É., Ranchon‐Cole, I., Jonet, L., Beaumont, C., Béhar‐Cohen, F., Courtois, Y., & Jeanny, J. (2010) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.10-5705 · Cited by 33
Neuroferritinopathy
Keogh, M. J., Morris, C. M., & Chinnery, P. F. (2013) · International review of neurobiology · doi:10.1016/b978-0-12-410502-7.00006-5 · Cited by 28
Ferritin L and Ferritin H are differentially located within hepatic and extra hepatic organs under physiological and acute phase conditions.
Ahmad, S., Moriconi, F., Naz, N., Sultan, S., Sheikh, N., Ramadori, G. P., & Malik, I. A. (2013) · Europe PMC (PubMed Central) · Cited by 28
Mycobacterium avium infection induces H-ferritin expression in mouse primary macrophages by activating Toll-like receptor 2
Silva-Gomes, S., Bouton, C., Silva, T., Santambrogio, P., Rodrigues, P., Appelberg, R., & Gomes, M. S. (2013) · PLoS ONE · doi:10.1371/journal.pone.0082874 · Cited by 26
“On the other hand, H-ferritin has also been implicated in protection against oxidative stress [32,33] and apoptosis [34].”
BackgroundSelf-citation
Integrated Analysis Reveals Critical Ferroptosis Regulators and FTL Contribute to Cancer Progression in Hepatocellular Carcinoma
Ke, S., Wang, C., Su, Z., Lin, S., & Wu, G. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.897683 · Cited by 26
Serum hepcidin levels and muscle iron proteins in humans injected with low‐ or high‐dose erythropoietin
Robach, P., Recalcati, S., Girelli, D., Campostrini, N., Kempf, T., Wollert, K. C., Corbella, M., Santambrogio, P., Perbellini, L., Brasse‐Lagnel, C., et al. (2013) · European Journal Of Haematology · doi:10.1111/ejh.12122 · Cited by 25
“Ferritin concentrations were determined in cell lysates by ELISA based on monoclonal antibodies specific for the human H and L subunits, as previously described (32).”
MethodSelf-citation
Behavioral Characterization of Mouse Models of Neuroferritinopathy
Capoccia, S., Maccarinelli, F., Buffoli, B., Rodella, L. F., Cremona, O., Arosio, P., & Cirulli, F. (2015) · PLoS ONE · doi:10.1371/journal.pone.0118990 · Cited by 24
Self-citation
Ferritin as prognostic marker in multiple myeloma patients undergoing autologous transplantation
Strasser‐Weippl, K., & Ludwig, H. (2014) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.3109/10428194.2014.891025 · Cited by 23
Chapter Five – Neuroferritinopathy
Keogh, M. J., Morris, C. M., & Chinnery, P. F. (2013) · International review of neurobiology · Cited by 21
3‐Hydroxybutyrate dehydrogenase‐2 and ferritin‐H synergistically regulate intracellular iron
Liu, Z., Velpula, K. K., & Devireddy, L. R. (2014) · FEBS Journal · doi:10.1111/febs.12794 · Cited by 22
Ferritin as an Effective Prognostic Factor and Potential Cancer Biomarker
Szymulewska-Konopko, K., Reszeć-Giełażyn, J., & Małeczek, M. (2025) · Current Issues in Molecular Biology · doi:10.3390/cimb47010060 · Cited by 27
“It is involved in the proliferation [63,64], angiogenesis [64], and provision of iron [65,66].”
Pathophysiology of perioperative anaemia
Singh, S. P., Gudzenko, V., & Fink, M. P. (2012) · Best practice & research. Clinical anaesthesiology · doi:10.1016/j.bpa.2012.11.002 · Cited by 21
Effective inhibition of infectious bursal disease virus replication in vitro by DNA vector-based RNA interference
Gao, Y., Liu, W. Y., Gao, H., Qi, X., Lin, H., Wang, X., & Shen, R.-X. (2008) · Antiviral Research · doi:10.1016/j.antiviral.2007.11.007 · Cited by 20
Neurodegeneration with Brain Iron Accumulation
Schneider, S. A. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-410529-4.00042-5 · Cited by 19
Molecular Characterization and Functional Analysis of a Ferritin Heavy Chain Subunit from the Eri-Silkworm, Samia cynthia ricini
Yu, H., Zhang, S.-Z., Ma, Y., Fei, D.-Q., Li, B., Yang, L.-A., Wang, J., Li, Z., Muhammad, A., & Xu, J. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18102126 · Cited by 17
“Treatment of HeLa cells with H2O2 could produce ROS, whereas overexpression of ferritin could reduce the cellular levels of ROS and oxidative stress [51].”
Background
Cloning and characterization of two ferritin subunit genes from bay scallop, Argopecten irradians (Lamarck 1819)
He, X., Zhang, Y., Wu, X., Xiao, S., & Yu, Z. (2010) · Molecular Biology Reports · doi:10.1007/s11033-010-0339-0 · Cited by 16
“In mammalian cells, over-expression of ferritin H subunit shows an enhanced ability to reduce anti-oxidative stress [12].”
Background
Altered Ferritin Subunit Composition: Change in Iron Metabolism in Lens Epithelial Cells and Downstream Effects on Glutathione Levels and VEGF Secretion
Harned, J., Ferrell, J., Lall, M. M., Fleisher, L. N., Nagar, S., Goralska, M., & McGahan, M. C. (2010) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.09-3861 · Cited by 16
“Indeed, transfection of HeLa cells with siRNA for H- or L-chain ferritin far more effectively reduced ferritin chain synthesis than did antisense treatment.(9) In this earlier study, FLsiRNA had no direct effect on cellular iron homeostasis but enhanced cellular proliferation.”
BackgroundInfluential
Ferritin Expression in Rat Hepatocytes and Kupffer Cells after Lead Nitrate Treatment
Yang, F., Yamada, T., Shimizu, T., Nanashima, N., Akita, M., Suto, K., & Tsuchida, S. (2009) · Toxicologic Pathology · doi:10.1177/0192623308328544 · Cited by 16
“1995), cell proliferation (Cozzi et al. 2004; Kikyo et al. 1994), and apoptosis (Cozzi et al.”
Background
Increasing expression of H- or L-ferritin protects cortical astrocytes from hemin toxicity
Li, Z., Chen‐Roetling, J., & Regan, R. F. (2009) · Free Radical Research · doi:10.1080/10715760902942808 · Cited by 16
“[8] reported that iron availability was negatively regulated by increasing expression of H-ferritin by gene transfer, but that L-ferritin had no effect per se.”
Background
Molecular characterization and gene expression of ferritin in blunt snout bream ( Megalobrama amblycephala )
Sun, S., Zhu, J. X., Ge, X., & Zhang, W. (2016) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2016.08.029 · Cited by 13
Elevated intracellular calcium increases ferritin H expression through an NFAT-independent post-transcriptional mechanism involving mRNA stabilization
Mackenzie, E. L., & Tsuji, Y. (2008) · Biochemical Journal · doi:10.1042/bj20071544 · Cited by 13
FTL: a novel predictor in gastric cancer.
Zhang, L., Chen, Z., & Xu, A. (2017) · PubMed Central · Cited by 13
Detection and functional analysis of an SNP in the promoter of the human ferritin H gene that modulates the gene expression
Faniello, M. C., Fregola, A., Nisticò, A., Quaresima, B., Crugliano, T., Faraonio, R., Puzzonia, P., Baudi, F., Parlato, G., Cuda, G., et al. (2006) · Gene · doi:10.1016/j.gene.2006.02.034 · Cited by 13
Targeting the Nrf2/HO-1 aixs: A therapeutic strategy against regulated cell death in Alzheimer’s disease
Wang, Z., Feng, W., Li, X., Yun, X., Wu, S., Du, L., & Wang, H. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103035 · Cited by 15
Iron Binding in the Ferroxidase Site of Human Mitochondrial Ferritin
Ciambellotti, S., Pratesi, A., Tassone, G., Turano, P., Mangani, S., & Pozzi, C. (2021) · Chemistry - A European Journal · doi:10.1002/chem.202102270 · Cited by 12
Soluble Urokinase-Type Plasminogen Activator Receptor and Ferritin Concentration in Patients with Advanced Alimentary Tract Carcinoma. Relationship to Localization, Surgical Treatment and the Stage of the Disease – Preliminary Report
Usnarska‐Zubkiewicz, L., Strutyńska−Karpińska, M., Zubkiewicz‐Kucharska, A., Zarębski, P., & Grabowski, K. (2014) · Advances in Clinical and Experimental Medicine · doi:10.17219/acem/30817 · Cited by 12
The Chemistry of Nature's Iron Biominerals in Ferritin Protein Nanocages
Theil, E. C., & Behera, R. K. (2013) · doi:10.1002/9781118571811.ch1 · Cited by 12

Authors: Cozzi, A., Corsi, B., Levi, S., Santambrogio, P., Biasiotto, G., & Arosio, P.
Affiliations: IRCCS San Raffaele Roma (IT)
ORCID: Cozzi, Anna
Levi, Sonia
Santambrogio, Paolo
Biasiotto, Giorgio
Arosio, Paolo
Venue: Blood
Publisher: American Society of Hematology
Published: 2004-03-15
Volume: 103
Issue: 6
Pages: 2377-2383
ISSN: 0006-4971 (ISSN-L)
1528-0020
DOI: 10.1182/blood-2003-06-1842
OpenAlex: W1519013154
Cited by: 132
References: 43
Citations by year: 2026: 2 · 2025: 2 · 2024: 3 · 2023: 7 · 2022: 3 · 2021: 2 · 2020: 6 · 2019: 5 · 2018: 1 · 2017: 3 · 2016: 4 · 2015: 7 · 2014: 9 · 2013: 21 · 2012: 4
FWCI: 3.07
Type: journal article
Language: en
Open access: green
www.openaccessrepository.it
Licence: other-oa
Locations: Blood (publishedVersion)
PubMed (publishedVersion)
INFM-OAR (INFN Catania) (submittedVersion, other-oa)
Topics: Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
Keywords: H-ferritin, L-ferritin, HeLa cells, cell proliferation, iron homeostasis, iron availability, iron supplementation, chelation, siRNA knockdown
MeSH terms: Quaternary Ammonium Compounds, Buffers, Cell Division, Ferric Compounds, Ferritins, HeLa Cells, Humans, Iron, Transfection, Down-Regulation, Up-Regulation, Gene Expression, DNA, Complementary, Oxidative Stress, RNA, Small Interfering

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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

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