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Kora AJ, Madhavi K, Meeravali NN. Development of Suspended Droplet Microextraction Method for Spectrophotometric Determination of Serum Iron. ANALYTICAL SCIENCE ADVANCES 2025; 6:e70022. [PMID: 40371266 PMCID: PMC12077757 DOI: 10.1002/ansa.70022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 04/28/2025] [Accepted: 04/30/2025] [Indexed: 05/16/2025]
Abstract
A facile, selective and sensitive method was devised for the Fe3+ quantification in low volume samples, such as bovine serum based on suspended droplet microextraction (SDME). Various process parameters such as concentrations of acid (1.5% hydrochloric acid), complexing agent (0.7% ammonium thiocyanate), quaternary ammonium salt (0.2% Aliquat 336) and extracting solvent (500 µL octanol) were optimised. Ammonium thiocyanate forms water soluble, red coloured, anionic ferric thiocyanate complex [Fe(SCN)6]3- with Fe3+ ions released from the iron-protein complex under an acidic medium. Negatively charged [Fe(SCN)6]3- complex forms hydrophobic ion associate Fe(SCN)6 3--Aliquat 3363 3+ with hydrophilic NH4 + head groups of Aliquat 336 and drives out the formed micelle from aqueous solution along with the iron complex. After stirring, ion associate bonded micelles are separated into a hanging micro droplet of octanol. Red coloured ferric thiocyanate complex in a suspended droplet is solubilised in methanol and Fe3+ concentration in serum samples is obtained by recording the spectrophotometric absorbance at 505 nm. The recoveries ranged from 96.2%-98.8% with relative standard deviation (RSD) (%) values from 1.4% to 5.0% at 100-400 ng/mL confirming interference free quantification at optimised conditions. The developed method was linear over the range of 20-1000 ng/mL of Fe3+ with a limit of detection of 2.4 ng/mL for the serum matrix. The developed method is applied to various bovine serum samples and Fe3+ concentration values ranged from 62.7 to 1582.5 ng/mL. The obtained values were in accordance with the results obtained from the electrothermal atomic absorption spectrometry at 99% confidence level using t-test indicating the accuracy of the developed method. The proposed procedure offers various advantages such as enhanced sensitivity of the spectrophotometer towards iron determination, low-cost complexing agent, low sample volume, metal and biological interference free, simplicity and selectivity. Thus, the developed method can be an alternative to the routine spectrophotometric analysis of low volume samples such as serum and other biological fluids.
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Affiliation(s)
- Aruna Jyothi Kora
- National Centre for Compositional Characterisation of Materials (NCCCM)Bhabha Atomic Research Centre (BARC)HyderabadTelanganaIndia
- Homi Bhabha National Institute (HBNI)MumbaiMaharashtraIndia
| | - K. Madhavi
- National Centre for Compositional Characterisation of Materials (NCCCM)Bhabha Atomic Research Centre (BARC)HyderabadTelanganaIndia
| | - N. N. Meeravali
- National Centre for Compositional Characterisation of Materials (NCCCM)Bhabha Atomic Research Centre (BARC)HyderabadTelanganaIndia
- Homi Bhabha National Institute (HBNI)MumbaiMaharashtraIndia
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2
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He M, Tao K, Sun J, Tang R, Jin R. Association between blood metal elements and lung cancer: a cross-sectional and Mendelian randomization study. Transl Cancer Res 2025; 14:2207-2219. [PMID: 40386263 PMCID: PMC12079208 DOI: 10.21037/tcr-24-1430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 01/22/2025] [Indexed: 05/20/2025]
Abstract
Background The association between exposure to certain heavy metals and an increased risk of lung cancer has been confirmed, but the exact relationship remains uncertain. This research shed light on the association between blood metal elements and lung cancer, and examined their causal association through Mendelian randomization (MR). Methods This study retrospectively included 48,132 participants from 1999 to 2018 National Health and Nutrition Examination Survey (NHANES). Weighted logistic regression was employed for exploring the relationship between blood metal elements (cadmium, lead, mercury, selenium, manganese, cobalt, copper, iron, and zinc) and lung cancer. Additionally, MR analysis was carried out to investigate potential causal association between blood metal elements and the progression of lung cancer. Results A positive association was observed between cadmium and lung cancer, while a negative association was noted between iron and lung cancer when all confounders in the NHANES were fully taken into account. MR analysis further demonstrated that iron was negatively linked with lung adenocarcinoma (LUAD) in Europeans [odds ratio (OR)ivw =0.77, 95% confidence interval (CI): 0.65-0.92, P=0.004; ORweighted median =0.75, 95% CI: 0.61-0.92, P=0.006]. Sensitivity analyses confirmed the robustness and reliability of this finding (P>0.05). Conclusions Iron is inversely related to the incidence of lung cancer, with MR analysis supporting its protective role in LUAD. These findings necessitate further validation in large-scale prospective cohort studies.
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Affiliation(s)
- Meng He
- Department of Respiratory and Critical Care Medicine, Shaoxing People’s Hospital (The First Affiliated Hospital of Shaoxing University), Shaoxing, China
| | - Kelong Tao
- Department of Gastrointestinal Surgery, Shaoxing People’s Hospital (The First Affiliated Hospital of Shaoxing University), Shaoxing, China
| | - Jian Sun
- Department of Respiratory and Critical Care Medicine, Shaoxing People’s Hospital (The First Affiliated Hospital of Shaoxing University), Shaoxing, China
| | - Renqi Tang
- School of Medicine, Shaoxing University, Shaoxing, China
| | - Rongyao Jin
- Department of Traditional Chinese Medicine, Shaoxing People’s Hospital (The First Affiliated Hospital of Shaoxing University), Shaoxing, China
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Lu CL, Liu J, Yang JF. LncRNA-XIST Promotes Lung Adenocarcinoma Growth and Inhibits Ferroptosis by Regulating GPX4. Mol Biotechnol 2025; 67:187-195. [PMID: 38153663 DOI: 10.1007/s12033-023-00993-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 11/13/2023] [Indexed: 12/29/2023]
Abstract
This study aimed to explore the regulatory effects and molecular mechanisms of long non-coding RNA X-inactive-specific transcript (LncRNA-XIST) in lung adenocarcinoma. si-XIST or glutathione peroxidase 4 (GPX4) plasmids were transfected in PC-9 cells to suppress LncRNA-XIST expression or over-express GPX4, respectively. The mRNA expression levels of LncRNA-XIST and GPX4 in lung adenocarcinoma tissues or cells were assessed using RT-qPCR. CCK-8 assay was performed to examine cell activity, and corresponding biochemical kits were used to measure the levels of Fe2+, reactive oxygen species (ROS), malondialdehyde (MDA) in cells. Western blot is used to examine relative protein expression of FANCD2, SLC7A11, and GPX4 in lung adenocarcinoma cells. The mRNA and protein expression levels of LncRNA-XIST in clinical tissues and cells of lung adenocarcinoma were significantly higher than those in adjacent tissues and normal cells. Functional analysis showed that knockdown of LncRNA-XIST notably weakened the viability of lung adenocarcinoma cells and promoted ferroptosis (manifested by significantly up-regulated levels of ROS, MDA, and Fe2+ and down-regulated the expression of SLC7A11 and FANCD2, P < 0.05). Further mechanism analysis revealed that knockdown of LncRNA-XIST markedly inhibited the expression of GPX4 in lung adenocarcinoma cells and that GPX4 was significantly over-expressed in clinical tissues and cells of lung adenocarcinoma. Notably, the expression of GPX4 was positively correlated with that of LncRNA-XIST. Over-expression of GPX4 remarkably promoted cell proliferation and inhibited ferroptosis in lung adenocarcinoma. Besides, the GPX4 over-expression reversed the LncRNA-XIST knockdown-induced ferroptosis and decrease in lung adenocarcinoma cell viability. LncRNA-XIST increases the activity of lung adenocarcinoma cells and inhibits ferroptosis by up-regulating GPX4. Knocking down LncRNA-XIST may be an effective treatment for lung adenocarcinoma.
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Affiliation(s)
- Chen-Lin Lu
- Department of Respiratory and Critical Care Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, 225300, China
| | - Jie Liu
- Department of Orthopedics, The Affiliated Taizhou People's Hospital of Nanjing Medical University Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, 225300, China
| | - Jun-Fa Yang
- Department of Respiratory and Critical Care Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, 225300, China.
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Nanda S, Ganguly A, Mandi M, Das K, Rajak P. Unveiling the physical, behavioural, and biochemical effects of clothianidin on a non-target organism, Drosophila melanogaster. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 956:177198. [PMID: 39471953 DOI: 10.1016/j.scitotenv.2024.177198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 10/23/2024] [Accepted: 10/23/2024] [Indexed: 11/01/2024]
Abstract
Clothianidin is a novel neonicotinoid pesticide globally used in agriculture to enhance crop production. However, unintentional exposure to clothianidin via contaminated environmental matrices and food products can be detrimental to non-target organisms, including humans. Hence, to unravel the potential health risks at organismal and sub-organismal levels, first instar larvae of a non-target organism, Drosophila melanogaster, were exposed to sub-lethal concentrations (0.05 to 0.1 μg/mL) of clothianidin till their third instar stage (chronic exposure). Larvae from the control and clothianidin-exposed groups were examined for their body weight, physical activity, behaviour, and enzymatic activities using in vivo and molecular docking approaches. Results have suggested that clothianidin at sub-lethal concentrations reduces body weight and physical fitness of D. melanogaster. Interestingly, AChE activity in larvae was reduced by 35 % and 41.13 % following exposure to 0.07 and 0.1 μg/mL of clothianidin, respectively. Further, the activity of mitoferrin, a major importer of iron inside the mitochondrial matrix and malate dehydrogenase, an integral component of the TCA cycle, were down-regulated by 58 % and 45.93 %, respectively, at 0.1 μg/mL clothianidin. Additionally, the activities of glucose 6-phosphate dehydrogenase, a vital enzyme of the pentose phosphate pathway and angiotensin-converting enzyme, responsible for maintaining optimum body physiology, were significantly declined by 43.58 % and 57.63 % at 0.1 μg/mL concentration of clothianidin. Binding affinity analyses have revealed that clothianidin can potentially bind with these enzymes using varying numbers of hydrogen bonds and other hydrophobic interactions to subvert their catalytic functions. Therefore, results of the present study equivocally suggest that chronic exposure to clothianidin, even at low concentrations, can disturb the physical, behavioural, and enzymatic activities of non-target organisms.
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Affiliation(s)
- Sayantani Nanda
- Toxicology Research Laboratory, Department of Animal Science, Kazi Nazrul University, Asansol, West Bengal, India
| | - Abhratanu Ganguly
- Toxicology Research Laboratory, Department of Animal Science, Kazi Nazrul University, Asansol, West Bengal, India
| | - Moutushi Mandi
- Toxicology Research Unit, Department of Zoology, The University of Burdwan, Purba Bardhaman, West Bengal, India
| | - Kanchana Das
- Toxicology Research Unit, Department of Zoology, The University of Burdwan, Purba Bardhaman, West Bengal, India
| | - Prem Rajak
- Toxicology Research Laboratory, Department of Animal Science, Kazi Nazrul University, Asansol, West Bengal, India.
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Zeidan RS, Yoon HS, Yang JJ, Sobh A, Braithwaite D, Mankowski R, Leeuwenburgh C, Anton S. Iron and cancer: overview of the evidence from population-based studies. Front Oncol 2024; 14:1393195. [PMID: 39246326 PMCID: PMC11377248 DOI: 10.3389/fonc.2024.1393195] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 07/23/2024] [Indexed: 09/10/2024] Open
Abstract
Iron is an essential nutrient required for various physiological processes in the body. However, iron imbalance can potentially contribute to initiating and promoting cancer development. Epidemiological studies have investigated the relationship between dietary iron intake and the risk of different types of cancer, yet, not all studies have consistently shown a significant association between dietary iron and cancer risk. Also, studies have shown different effects of dietary heme and non-heme iron intake on cancer risk. While some epidemiological studies suggest a possible link between high dietary iron (mainly heme-iron) intake and increased cancer risk, the evidence remains inconsistent. Moreover, multiple iron biomarkers, which can mirror physiological iron status, have demonstrated varied correlations with the risk of cancer, contingent upon the specific biomarker analyzed and the type of cancer being investigated. Here, we have investigated the current evidence on the potential relationship between dietary iron intake on one hand, and iron biomarkers on the other hand, with the risk of developing different types of cancer, including breast, prostate, lung, pancreatic, colon, colorectal, and liver cancers. Further research is warranted to better understand the complex relationship between dietary iron, physiological iron and cancer development. Future research should account for factors that affect and interact with dietary iron and physiological iron levels, such as genetic susceptibility, overall diet quality, and lifestyle habits.
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Affiliation(s)
- Rola S Zeidan
- Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL, United States
- Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Hyung-Suk Yoon
- Cancer Control and Population Science Division, University of Florida Health Cancer Center, Gainesville, FL, United States
- Division of Hematology and Oncology, University of Florida Health Cancer Center, Gainesville, FL, United States
| | - Jae Jeong Yang
- Cancer Control and Population Science Division, University of Florida Health Cancer Center, Gainesville, FL, United States
- Division of Hematology and Oncology, University of Florida Health Cancer Center, Gainesville, FL, United States
| | - Amin Sobh
- Division of Hematology and Oncology, University of Florida Health Cancer Center, Gainesville, FL, United States
| | - Dejana Braithwaite
- Cancer Control and Population Science Division, University of Florida Health Cancer Center, Gainesville, FL, United States
- Department of Surgery, University of Florida College of Medicine, Gainesville, FL, United States
| | - Robert Mankowski
- Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Christian Leeuwenburgh
- Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Stephen Anton
- Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL, United States
- Department of Clinical and Health Psychology, University of Florida, Gainesville, FL, United States
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Mohammadzadeh M, Bahrami A, Ghafouri-Taleghani F, Khalesi S, Abdi F, Hejazi E. Dietary iron and the risk of lung cancer. INT J VITAM NUTR RES 2024; 94:264-274. [PMID: 37469109 DOI: 10.1024/0300-9831/a000789] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/21/2023]
Abstract
Animal models have suggested the carcinogenic effect of iron due to its oxidative potential. The lung is particularly vulnerable to oxidative stress. However, epidemiological studies investigating the association between dietary iron and the risk of lung cancer have reported inconclusive results. In this systematic review and meta-analysis, we aimed to clarify this association. Methods: We searched PubMed, Web of Science, Scopus and Google scholar for eligible articles published through May 2023 reporting the Relative Risk (RR), Hazard Ratio (HR) or Odds Ratio (OR) with 95% confidence interval (95% CI). Case-control and cohort studies that examined the relationship between dietary iron and lung cancer risk were included and review and meta-analyses articles, experimental studies, abstracts, letters to editor and studies with insufficient data were excluded. Finally, three case-control studies and 6 cohort studies were included. Random effect models were used to calculate the pooled results. Results: Nine studies (cases n=21,943, participants n=1,542,993) were included. There were no significant associations between the highest dietary total iron (heme and non-heme) (RR: 1.09, 95% CI: 0.78 to 1.51) or heme iron (RR: 1.01, 95% CI: 0.73 to 1.38) intake compared to the lowest intake with lung cancer risk. Null-associations were also observed in the subgroup analysis based on smoking status and lung cancer histology. However, in the subgroup of women (cases n=5074), heme iron was associated with a 14% increase in the risk of lung cancer (RR: 1.14, 95% CI: 1.01 to 1.29). Conclusions: The current results demonstrated that there is no significant relationship between dietary iron intake and the risk of lung cancer. However, a positive association was observed between dietary heme iron and the risk of lung cancer in women, which may require further investigation.
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Affiliation(s)
- Milad Mohammadzadeh
- Student Research Committee, Department and Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Bahrami
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Ghafouri-Taleghani
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saman Khalesi
- Physical Activity Research Group, Appleton Institute & School of Health Medical and Applied Sciences, Central Queensland University, Brisbane, Australia
| | - Fatemeh Abdi
- Department of Nutrition, Faculty of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ehsan Hejazi
- Department of Clinical Nutrition and Dietetics, Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Singhania M, Zaher A, Pulliam CF, Bayanbold K, Searby CC, Schoenfeld JD, Mapuskar KA, Fath MA, Allen BG, Spitz DR, Petronek MS. Quantitative MRI Evaluation of Ferritin Overexpression in Non-Small-Cell Lung Cancer. Int J Mol Sci 2024; 25:2398. [PMID: 38397073 PMCID: PMC10889593 DOI: 10.3390/ijms25042398] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 02/13/2024] [Accepted: 02/15/2024] [Indexed: 02/25/2024] Open
Abstract
Cancer cells frequently present elevated intracellular iron levels, which are thought to facilitate an enhanced proliferative capacity. Targeting iron metabolism within cancer cells presents an avenue to enhance therapeutic responses, necessitating the use of non-invasive models to modulate iron manipulation to predict responses. Moreover, the ubiquitous nature of iron necessitates the development of unique, non-invasive markers of metabolic disruptions to develop more personalized approaches and enhance the clinical utility of these approaches. Ferritin, an iron storage enzyme that is often upregulated as a response to iron accumulation, plays a central role in iron metabolism and has been frequently associated with unfavorable clinical outcomes in cancer. Herein, we demonstrate the successful utility, validation, and functionality of a doxycycline-inducible ferritin heavy chain (FtH) overexpression model in H1299T non-small-cell lung cancer (NSCLC) cells. Treatment with doxycycline increased the protein expression of FtH with a corresponding decrease in labile iron in vitro and in vivo, as determined by calcein-AM staining and EPR, respectively. Moreover, a subsequent increase in TfR expression was observed. Furthermore, T2* MR mapping effectively detected FtH expression in our in vivo model. These results demonstrate that T2* relaxation times can be used to monitor changes in FtH expression in tumors with bidirectional correlations depending on the model system. Overall, this study describes the development of an FtH overexpression NSCLC model and its correlation with T2* mapping for potential use in patients to interrogate iron metabolic alterations and predict clinical outcomes.
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Affiliation(s)
- Mekhla Singhania
- Department of Radiation Oncology, Division of Free Radical and Radiation Biology, University of Iowa, Iowa City, IA 52242, USA
| | - Amira Zaher
- Department of Radiation Oncology, Division of Free Radical and Radiation Biology, University of Iowa, Iowa City, IA 52242, USA
| | - Casey F. Pulliam
- Department of Radiation Oncology, Division of Free Radical and Radiation Biology, University of Iowa, Iowa City, IA 52242, USA
| | - Khaliunaa Bayanbold
- Department of Radiation Oncology, Division of Free Radical and Radiation Biology, University of Iowa, Iowa City, IA 52242, USA
| | - Charles C. Searby
- Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA
| | - Joshua D. Schoenfeld
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
| | - Kranti A. Mapuskar
- Department of Radiation Oncology, Division of Free Radical and Radiation Biology, University of Iowa, Iowa City, IA 52242, USA
| | - Melissa A. Fath
- Department of Radiation Oncology, Division of Free Radical and Radiation Biology, University of Iowa, Iowa City, IA 52242, USA
| | - Bryan G. Allen
- Department of Radiation Oncology, Division of Free Radical and Radiation Biology, University of Iowa, Iowa City, IA 52242, USA
| | - Douglas R. Spitz
- Department of Radiation Oncology, Division of Free Radical and Radiation Biology, University of Iowa, Iowa City, IA 52242, USA
| | - Michael S. Petronek
- Department of Radiation Oncology, Division of Free Radical and Radiation Biology, University of Iowa, Iowa City, IA 52242, USA
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Pietrzak S, Marciniak W, Derkacz R, Matuszczak M, Kiljańczyk A, Baszuk P, Bryśkiewicz M, Sikorski A, Gronwald J, Słojewski M, Cybulski C, Gołąb A, Huzarski T, Dębniak T, Lener MR, Jakubowska A, Kluz T, Scott RJ, Lubiński J. Correlation between Selenium and Zinc Levels and Survival among Prostate Cancer Patients. Nutrients 2024; 16:527. [PMID: 38398851 PMCID: PMC10891521 DOI: 10.3390/nu16040527] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 02/09/2024] [Accepted: 02/12/2024] [Indexed: 02/25/2024] Open
Abstract
The most prevalent type of cancer among males is prostate cancer. Survival is considered quite good, but it can be further improved when risk factors are optimized. One of these factors is micronutrients, including Se and Zn. To our knowledge, the interaction between Se and Zn and prostate cancer remains undescribed. This study aimed to investigate the optimal levels of selenium (Se) and zinc (Zn) and their impact on the survival of individuals diagnosed with prostate cancer. A total of 338 prostate cancer patients were enrolled in this study, which was conducted in Poland between 2009 and 2015. Mass spectrometry, which uses inductively coupled plasma mass, was used to assess serum element levels before treatment. The study participants were categorized into quartiles (QI-QIV) based on the distributions of Se and Zn levels observed among surviving participants. Cox regression was used to assess the association between serum Se and Zn levels and the survival of prostate cancer patients. Our results reveal the effect of combined Se and Zn levels on survival in prostate cancer patients (SeQI-ZnQI vs. SeQIV-ZnQIV; HR = 20.9). These results need further research to establish Se/Zn norms for different populations.
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Affiliation(s)
- Sandra Pietrzak
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, ul. Unii Lubelskiej 1, 71-252 Szczecin, Poland; (S.P.); (M.M.); (A.K.); (P.B.); (M.B.); (J.G.); (C.C.); (T.H.); (T.D.); (M.R.L.); (A.J.)
| | - Wojciech Marciniak
- Read-Gene, Grzepnica, ul. Alabastrowa 8, 72-003 Dobra, Poland; (W.M.); (R.D.)
| | - Róża Derkacz
- Read-Gene, Grzepnica, ul. Alabastrowa 8, 72-003 Dobra, Poland; (W.M.); (R.D.)
| | - Milena Matuszczak
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, ul. Unii Lubelskiej 1, 71-252 Szczecin, Poland; (S.P.); (M.M.); (A.K.); (P.B.); (M.B.); (J.G.); (C.C.); (T.H.); (T.D.); (M.R.L.); (A.J.)
| | - Adam Kiljańczyk
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, ul. Unii Lubelskiej 1, 71-252 Szczecin, Poland; (S.P.); (M.M.); (A.K.); (P.B.); (M.B.); (J.G.); (C.C.); (T.H.); (T.D.); (M.R.L.); (A.J.)
| | - Piotr Baszuk
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, ul. Unii Lubelskiej 1, 71-252 Szczecin, Poland; (S.P.); (M.M.); (A.K.); (P.B.); (M.B.); (J.G.); (C.C.); (T.H.); (T.D.); (M.R.L.); (A.J.)
- Read-Gene, Grzepnica, ul. Alabastrowa 8, 72-003 Dobra, Poland; (W.M.); (R.D.)
| | - Marta Bryśkiewicz
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, ul. Unii Lubelskiej 1, 71-252 Szczecin, Poland; (S.P.); (M.M.); (A.K.); (P.B.); (M.B.); (J.G.); (C.C.); (T.H.); (T.D.); (M.R.L.); (A.J.)
| | - Andrzej Sikorski
- Department of Urology and Urological Oncology, Pomeranian Medical University in Szczecin, al. Powstańców Wielkopolskich 72, 71-899 Szczecin, Poland; (A.S.); (M.S.); (A.G.)
| | - Jacek Gronwald
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, ul. Unii Lubelskiej 1, 71-252 Szczecin, Poland; (S.P.); (M.M.); (A.K.); (P.B.); (M.B.); (J.G.); (C.C.); (T.H.); (T.D.); (M.R.L.); (A.J.)
- Read-Gene, Grzepnica, ul. Alabastrowa 8, 72-003 Dobra, Poland; (W.M.); (R.D.)
| | - Marcin Słojewski
- Department of Urology and Urological Oncology, Pomeranian Medical University in Szczecin, al. Powstańców Wielkopolskich 72, 71-899 Szczecin, Poland; (A.S.); (M.S.); (A.G.)
| | - Cezary Cybulski
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, ul. Unii Lubelskiej 1, 71-252 Szczecin, Poland; (S.P.); (M.M.); (A.K.); (P.B.); (M.B.); (J.G.); (C.C.); (T.H.); (T.D.); (M.R.L.); (A.J.)
- Read-Gene, Grzepnica, ul. Alabastrowa 8, 72-003 Dobra, Poland; (W.M.); (R.D.)
| | - Adam Gołąb
- Department of Urology and Urological Oncology, Pomeranian Medical University in Szczecin, al. Powstańców Wielkopolskich 72, 71-899 Szczecin, Poland; (A.S.); (M.S.); (A.G.)
| | - Tomasz Huzarski
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, ul. Unii Lubelskiej 1, 71-252 Szczecin, Poland; (S.P.); (M.M.); (A.K.); (P.B.); (M.B.); (J.G.); (C.C.); (T.H.); (T.D.); (M.R.L.); (A.J.)
- Read-Gene, Grzepnica, ul. Alabastrowa 8, 72-003 Dobra, Poland; (W.M.); (R.D.)
- Department of Clinical Genetics and Pathology, University of Zielona Góra, ul. Zyty 28, 65-046 Zielona Góra, Poland
| | - Tadeusz Dębniak
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, ul. Unii Lubelskiej 1, 71-252 Szczecin, Poland; (S.P.); (M.M.); (A.K.); (P.B.); (M.B.); (J.G.); (C.C.); (T.H.); (T.D.); (M.R.L.); (A.J.)
| | - Marcin R. Lener
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, ul. Unii Lubelskiej 1, 71-252 Szczecin, Poland; (S.P.); (M.M.); (A.K.); (P.B.); (M.B.); (J.G.); (C.C.); (T.H.); (T.D.); (M.R.L.); (A.J.)
| | - Anna Jakubowska
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, ul. Unii Lubelskiej 1, 71-252 Szczecin, Poland; (S.P.); (M.M.); (A.K.); (P.B.); (M.B.); (J.G.); (C.C.); (T.H.); (T.D.); (M.R.L.); (A.J.)
| | - Tomasz Kluz
- Department of Gynecology, Gynecology Oncology and Obstetrics, Fryderyk Chopin University Hospital No. 1, 35-055 Rzeszow, Poland;
- Institute of Medical Sciences, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
| | - Rodney J. Scott
- Priority Research Centre for Cancer Research, Innovation and Translation, Hunter Medical Research Institute, New Lambton, NSW 2305, Australia;
- School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia
- Division of Molecular Medicine, Pathology North, John Hunter Hospital, New Lambton, NSW 2305, Australia
| | - Jan Lubiński
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, ul. Unii Lubelskiej 1, 71-252 Szczecin, Poland; (S.P.); (M.M.); (A.K.); (P.B.); (M.B.); (J.G.); (C.C.); (T.H.); (T.D.); (M.R.L.); (A.J.)
- Read-Gene, Grzepnica, ul. Alabastrowa 8, 72-003 Dobra, Poland; (W.M.); (R.D.)
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Ge A, He Q, Zhao D, Li Y, Chen J, Deng Y, Xiang W, Fan H, Wu S, Li Y, Liu L, Wang Y. Mechanism of ferroptosis in breast cancer and research progress of natural compounds regulating ferroptosis. J Cell Mol Med 2024; 28:e18044. [PMID: 38140764 PMCID: PMC10805512 DOI: 10.1111/jcmm.18044] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 09/15/2023] [Accepted: 10/18/2023] [Indexed: 12/24/2023] Open
Abstract
Breast cancer is the most prevalent cancer worldwide and its incidence increases with age, posing a significant threat to women's health globally. Due to the clinical heterogeneity of breast cancer, the majority of patients develop drug resistance and metastasis following treatment. Ferroptosis, a form of programmed cell death dependent on iron, is characterized by the accumulation of lipid peroxides, elevated levels of iron ions and lipid peroxidation. The underlying mechanisms and signalling pathways associated with ferroptosis are intricate and interconnected, involving various proteins and enzymes such as the cystine/glutamate antiporter, glutathione peroxidase 4, ferroptosis inhibitor 1 and dihydroorotate dehydrogenase. Consequently, emerging research suggests that ferroptosis may offer a novel target for breast cancer treatment; however, the mechanisms of ferroptosis in breast cancer urgently require resolution. Additionally, certain natural compounds have been reported to induce ferroptosis, thereby interfering with breast cancer. Therefore, this review not only discusses the molecular mechanisms of multiple signalling pathways that mediate ferroptosis in breast cancer (including metastasis, invasion and proliferation) but also elaborates on the mechanisms by which natural compounds induce ferroptosis in breast cancer. Furthermore, this review summarizes potential compound types that may serve as ferroptosis inducers in future tumour cells, providing lead compounds for the development of ferroptosis-inducing agents. Last, this review proposes the potential synergy of combining natural compounds with traditional breast cancer drugs in the treatment of breast cancer, thereby suggesting future directions and offering new insights.
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Affiliation(s)
- Anqi Ge
- The First Hospital of Hunan University of Chinese MedicineChangshaChina
| | - Qi He
- People's Hospital of Ningxiang CityNingxiangChina
| | - Da Zhao
- The First Hospital of Hunan University of Chinese MedicineChangshaChina
- Hunan University of Chinese MedicineChangshaChina
| | - Yuwei Li
- Hunan University of Science and TechnologyXiangtanChina
| | - Junpeng Chen
- Hunan University of Science and TechnologyXiangtanChina
| | - Ying Deng
- People's Hospital of Ningxiang CityNingxiangChina
| | - Wang Xiang
- The First People's Hospital Changde CityChangdeChina
| | - Hongqiao Fan
- The First Hospital of Hunan University of Chinese MedicineChangshaChina
| | - Shiting Wu
- The First Hospital of Hunan University of Chinese MedicineChangshaChina
| | - Yan Li
- People's Hospital of Ningxiang CityNingxiangChina
| | - Lifang Liu
- The First Hospital of Hunan University of Chinese MedicineChangshaChina
| | - Yue Wang
- The First Hospital of Hunan University of Chinese MedicineChangshaChina
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10
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Bayanbold K, Singhania M, Fath MA, Searby CC, Stolwijk JM, Henrich JB, Pulliam CF, Schoenfeld JD, Mapuskar KA, Sho S, Caster JM, Allen BG, Buettner GR, Spies M, Goswami PC, Petronek MS, Spitz DR. Depletion of Labile Iron Induces Replication Stress and Enhances Responses to Chemoradiation in Non-Small-Cell Lung Cancer. Antioxidants (Basel) 2023; 12:2005. [PMID: 38001858 PMCID: PMC10669787 DOI: 10.3390/antiox12112005] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 10/31/2023] [Accepted: 11/09/2023] [Indexed: 11/26/2023] Open
Abstract
The intracellular redox-active labile iron pool (LIP) is weakly chelated and available for integration into the iron metalloproteins that are involved in diverse cellular processes, including cancer cell-specific metabolic oxidative stress. Abnormal iron metabolism and elevated LIP levels are linked to the poor survival of lung cancer patients, yet the underlying mechanisms remain unclear. Depletion of the LIP in non-small-cell lung cancer cell lines using the doxycycline-inducible overexpression of the ferritin heavy chain (Ft-H) (H1299 and H292), or treatment with deferoxamine (DFO) (H1299 and A549), inhibited cell growth and decreased clonogenic survival. The Ft-H overexpression-induced inhibition of H1299 and H292 cell growth was also accompanied by a significant delay in transit through the S-phase. In addition, both Ft-H overexpression and DFO in H1299 resulted in increased single- and double-strand DNA breaks, supporting the involvement of replication stress in the response to LIP depletion. The Ft-H and DFO treatment also sensitized H1299 to VE-821, an inhibitor of ataxia telangiectasis and Rad2-related (ATR) kinase, highlighting the potential of LIP depletion, combined with DNA damage response modifiers, to alter lung cancer cell responses. In contrast, only DFO treatment effectively reduced the LIP, clonogenic survival, cell growth, and sensitivity to VE-821 in A549 non-small-cell lung cancer cells. Importantly, the Ft-H and DFO sensitized both H1299 and A549 to chemoradiation in vitro, and Ft-H overexpression increased the efficacy of chemoradiation in vivo in H1299. These results support the hypothesis that the depletion of the LIP can induce genomic instability, cell death, and potentiate therapeutic responses to chemoradiation in NSCLC.
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Affiliation(s)
- Khaliunaa Bayanbold
- University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA (M.A.F.); (G.R.B.)
| | - Mekhla Singhania
- University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA (M.A.F.); (G.R.B.)
| | - Melissa A. Fath
- University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA (M.A.F.); (G.R.B.)
| | - Charles C. Searby
- University of Iowa Hospitals and Clinics, Department Pediatrics, University of Iowa, Iowa City, IA 52242, USA
| | - Jeffrey M. Stolwijk
- University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA (M.A.F.); (G.R.B.)
| | - John B. Henrich
- University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA (M.A.F.); (G.R.B.)
| | - Casey F. Pulliam
- University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA (M.A.F.); (G.R.B.)
| | - Joshua D. Schoenfeld
- University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA (M.A.F.); (G.R.B.)
| | - Kranti A. Mapuskar
- University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA (M.A.F.); (G.R.B.)
| | - Sei Sho
- University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA (M.A.F.); (G.R.B.)
| | - Joseph M. Caster
- University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA (M.A.F.); (G.R.B.)
| | - Bryan G. Allen
- University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA (M.A.F.); (G.R.B.)
| | - Garry R. Buettner
- University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA (M.A.F.); (G.R.B.)
| | - Maria Spies
- University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA (M.A.F.); (G.R.B.)
- University of Iowa Hospitals and Clinics, Holden Comprehensive Cancer Center, Department of Biochemistry and Molecular Biology, Iowa City, IA 52242, USA
| | - Prabhat C. Goswami
- University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA (M.A.F.); (G.R.B.)
| | - Michael S. Petronek
- University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA (M.A.F.); (G.R.B.)
| | - Douglas R. Spitz
- University of Iowa Hospitals and Clinics, Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA (M.A.F.); (G.R.B.)
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11
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Liu X, Ren J, Zhou R, Wen Z, Wen Z, Chen Z, He S, Zhang H. Construction of iron metabolism-related prognostic features of gastric cancer based on RNA sequencing and TCGA database. BMC Cancer 2023; 23:1106. [PMID: 37957566 PMCID: PMC10644585 DOI: 10.1186/s12885-023-11569-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 10/26/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND Researches have manifested that the disorder of iron metabolism is participated in Gastric cancer (GC), but whether iron metabolism-relevant genes (IMRGs) is related to the survival outcome of GC remain unknown. METHODS Eleven tumor as well as nine adjacent normal tissues from GC patients were underwent mRNA sequencing, and the The Cancer Genome Atlas Stomach Cancer (TCGA-STAD) datasets were acquired from the TCGA database. Cox analyses and least absolute shrinkage and selection operator (LASSO) regression were applied to build a IMRGs signature. The relationship between signature genes and the infiltration profiling of 24 immune cells were investigated using single-sample GSEA (ssGSEA). Meanwhile, the potential biological significance, genes that act synergistically with signature genes, and the upstream regulatory targets were predicted. Finally, the abundance of the signature genes were measured via the quantitative real-time PCR (qRT-PCR). RESULTS A IMRGs signature was constructed according to the expression and corresponding coefficient of DOHH, P4HA3 and MMP1 (The Schoenfeld individual test showed risk score was not significant with P values = 0.83). The prognostic outcome of patients in the high-risk group was terrible (p < 0.05). Receiver operating characteristic (ROC) curves confirmed that the IMRGs signature presented good efficiency for predicting GC prognosis (AUC > 0.6). The nomogram was performed well for clinical utilize (C-index = 0.60), and the MMP1 expression significantly increased in the cohorts at age > 60 and Stage II-IV (p < 0.05). The positive correlation of P4HA3 and MMP1 expression as well as the negative correlation of DOHH expression with risk score (p < 0.0001) and worse prognosis (p < 0.05) were detected as well. Furthermore, 11 differential immune cells were associated with these signature genes (most p < 0.01). Finally, qRT-PCR revealed that the abundance of DOHH, P4HA3 and MMP1 were high in tumor cases, indicating the complex mechanism between the high expression of DOHH as a protective factor and the high expression of P4HA3 and MMP1 as the risk factors in the development of GC. CONCLUSION An iron metabolism-related signature was constructed and has significant values for foretelling the OS of GC.
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Affiliation(s)
- Xihong Liu
- Department of Oncology First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Junyu Ren
- Department of Oncology First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Ruize Zhou
- Department of Oncology First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Zhengqi Wen
- Department of Oncology First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Zhengwei Wen
- Department of Oncology First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Zihao Chen
- Department of Oncology First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Shanshan He
- Department of Oncology First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Hongbin Zhang
- Department of Pediatric Surgery First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, P. R. China.
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12
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Hinokuma H, Kanamori Y, Ikeda K, Hao L, Maruno M, Yamane T, Maeda A, Nita A, Shimoda M, Niimura M, Takeshima Y, Li S, Suzuki M, Moroishi T. Distinct functions between ferrous and ferric iron in lung cancer cell growth. Cancer Sci 2023; 114:4355-4364. [PMID: 37688294 PMCID: PMC10637068 DOI: 10.1111/cas.15949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 08/19/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2023] Open
Abstract
Accumulating evidence suggests an association between iron metabolism and lung cancer progression. In biological systems, iron is present in either reduced (Fe2+ ; ferrous) or oxidized (Fe3+ ; ferric) states. However, ferrous and ferric iron exhibit distinct chemical and biological properties, the role of ferrous and ferric iron in lung cancer cell growth has not been clearly distinguished. In this study, we manipulated the balance between cellular ferrous and ferric iron status by inducing gene mutations involving the FBXL5-IRP2 axis, a ubiquitin-dependent regulatory system for cellular iron homeostasis, and determined its effects on lung cancer cell growth. FBXL5 depletion (ferrous iron accumulation) was found to suppress lung cancer cell growth, whereas IRP2 depletion (ferric iron accumulation) did not suppress such growth, suggesting that ferrous iron but not ferric iron plays a suppressive role in cell growth. Mechanistically, the depletion of FBXL5 impaired the degradation of the cyclin-dependent kinase inhibitor, p27, resulting in a delay in the cell cycle at the G1/S phase. FBXL5 depletion in lung cancer cells also improved the survival of tumor-bearing mice. Overall, this study highlights the important function of ferrous iron in cell cycle progression and lung cancer cell growth.
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Affiliation(s)
- Hironori Hinokuma
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
- Department of Thoracic and Breast Surgery, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Yohei Kanamori
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Koei Ikeda
- Department of Thoracic and Breast Surgery, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Li Hao
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Masataka Maruno
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Taishi Yamane
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Ayato Maeda
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Akihiro Nita
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Mayuko Shimoda
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Mayumi Niimura
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Yuki Takeshima
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Shuran Li
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
| | - Makoto Suzuki
- Department of Thoracic and Breast Surgery, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Toshiro Moroishi
- Department of Molecular and Medical Pharmacology, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
- Center for Metabolic Regulation of Healthy Aging, Faculty of Life SciencesKumamoto UniversityKumamotoJapan
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13
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Xie Y, Zhou Y, Wang J, Du L, Ren Y, Liu F. Ferroptosis, autophagy, tumor and immunity. Heliyon 2023; 9:e19799. [PMID: 37810047 PMCID: PMC10559173 DOI: 10.1016/j.heliyon.2023.e19799] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 08/20/2023] [Accepted: 09/01/2023] [Indexed: 10/10/2023] Open
Abstract
Ferroptosis was first proposed in 2012, a new form of cell death. Autophagy plays a crucial role in cell clearance and maintaining homeostasis. Autophagy is involved in the initial step of ferroptosis under the action of histone elements such as NCOA4, RAB7A, and BECN1. Ferroptosis and autophagy are involved in tumor progression, treatment, and drug resistance in the tumor microenvironment. In this review, we described the mechanisms of ferroptosis, autophagy, and tumor and immunotherapy, respectively, and emphasized the relationship between autophagy-related ferroptosis and tumor.
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Affiliation(s)
| | | | - Jiale Wang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Lijuan Du
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Yuanyuan Ren
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Fang Liu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150081, China
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14
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Xie Y, Hu T, Chen R, Chang H, Wang Q, Cheng J. Predicting acute radiation dermatitis in breast cancer: a prospective cohort study. BMC Cancer 2023; 23:537. [PMID: 37308936 DOI: 10.1186/s12885-023-10821-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Accepted: 04/06/2023] [Indexed: 06/14/2023] Open
Abstract
BACKGROUND Acute radiation dermatitis (ARD) is one of the most common acute adverse reactions in breast cancer patients during and immediately after radiotherapy. As ARD affects patient quality of life, it is important to conduct individualized risk assessments of patients in order to identify those patients most at risk of developing severe ARD. METHODS The data of breast cancer patients who received radiotherapy were prospectively collected and analyzed. Serum ferritin, high-sensitivity C-reactive protein (hs-CRP) levels, and percentages of lymphocyte subsets were measured before radiotherapy. ARD was graded (0-6 grade), according to the Oncology Nursing Society Skin Toxicity Scale. Univariate and multivariate logistic regression analyses were used and the odds ratio (OR) and 95% confidence interval (CI) of each factor were calculated. RESULTS This study included 455 breast cancer patients. After radiotherapy, 59.6% and 17.8% of patients developed at least 3 (3+) grade and at least 4 (4+) grade ARD, respectively. Multivariate logistic regression analysis found that body mass index (OR: 1.11, 95% CI: 1.01-1.22), diabetes (OR: 2.70, 95% CI: 1.11-6.60), smoking (OR: 3.04, 95% CI: 1.15-8.02), higher ferritin (OR: 3.31, 95% CI: 1.78-6.17), higher hs-CRP (OR: 1.96, 95% CI: 1.02-3.77), and higher CD3 + T cells (OR: 2.99, 95% CI: 1.10-3.58) were independent risk factors for 4 + grade ARD. Based on these findings, a nomogram model of 4 + grade ARD was further established. The nomogram AUC was 0.80 (95% CI: 0.75-0.86), making it more discriminative than any single factor. CONCLUSION BMI, diabetes, smoking history, higher ferritin, higher hs-CRP, and higher CD3 + T cells prior to radiotherapy for breast cancer are all independent risk factors for 4 + grade ARD. The results can provide evidence for clinicians to screen out high-risk patients, take precautions and carefully follow up on these patients before and during radiotherapy.
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Affiliation(s)
- Yuxiu Xie
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Ting Hu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Renwang Chen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Haiyan Chang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Qiong Wang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Jing Cheng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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15
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Hogea P, Tudorache E, Fira-Mladinescu O, Marc M, Manolescu D, Bratosin F, Rosca O, Mavrea A, Oancea C. The Association of IFN-γ, TNF-α, and Interleukins in Bronchoalveolar Lavage Fluid with Lung Cancer: A Prospective Analysis. J Pers Med 2023; 13:968. [PMID: 37373957 DOI: 10.3390/jpm13060968] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/04/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
Lung cancer is a leading cause of cancer-related mortality worldwide. Identifying novel diagnostic and prognostic biomarkers is essential for improving patient outcomes. This study aimed to investigate the predictive role of cytokines from bronchoalveolar lavage fluid (BALF) in lung cancer diagnosis and prognosis. A prospective study was conducted on 33 patients with suspected lung cancer, divided into inflammatory and non-inflammatory BALF groups. Inflammatory markers in BALF were assessed, and their association with lung cancer risk was analyzed using receiver operating characteristic (ROC) plot analysis, sensitivity and specificity percentages, and regression analysis. Statistically significant differences were observed between the inflammatory and non-inflammatory groups for several inflammatory markers, including IFN-gamma, IL-1b, IL-2, IL-6, IL-10, and IL-12p70. In the follow-up analysis, significant differences persisted for IFN-gamma, IL-1b, IL-2, IL-4, and IL-6. ROC plot analysis revealed that IL-12p70 had the highest area under the curve (AUC) value (0.702), followed by IL-2 (0.682), IL-6 (0.620), IL-4 (0.611), TNF-alpha (0.609), IL-10 (0.604), IL-1b (0.635), and IFN-gamma (0.521). IL-6 showed the highest sensitivity (73%), and IL-1b had the highest specificity (69%). Regression analysis demonstrated that IL-6 (cut-off = 25 pg/mL) and IL-12p70 (cut-off = 30 pg/mL) had the highest odds ratios for lung cancer risk, at 5.09 (95% CI: 2.38-9.24, p < 0.001) and 4.31 (95% CI: 1.85-8.16, p < 0.001), respectively. Cytokines from BALF, particularly IL-6 and IL-12p70, show potential as diagnostic and prognostic biomarkers for lung cancer. Further studies with larger cohorts are warranted to confirm these findings and elucidate the clinical implications of these markers in lung cancer management.
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Affiliation(s)
- Patricia Hogea
- Center for Research and Innovation in Precision Medicine of Respiratory Diseases, "Victor Babes" University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041 Timisoara, Romania
- Doctoral School, Faculty of General Medicine, "Victor Babes" University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041 Timisoara, Romania
| | - Emanuela Tudorache
- Center for Research and Innovation in Precision Medicine of Respiratory Diseases, "Victor Babes" University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041 Timisoara, Romania
- First Pulmonology Clinic, Clinical Hospital of Infectious Diseases and Pulmonology, "Victor Babes", Gheorghe Adam Street 13, 300310 Timisoara, Romania
| | - Ovidiu Fira-Mladinescu
- Center for Research and Innovation in Precision Medicine of Respiratory Diseases, "Victor Babes" University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041 Timisoara, Romania
- Second Pulmonology Clinic, Clinical Hospital of Infectious Diseases and Pulmonology, "Victor Babes", Gheorghe Adam Street 13, 300310 Timisoara, Romania
| | - Monica Marc
- Center for Research and Innovation in Precision Medicine of Respiratory Diseases, "Victor Babes" University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041 Timisoara, Romania
- Second Pulmonology Clinic, Clinical Hospital of Infectious Diseases and Pulmonology, "Victor Babes", Gheorghe Adam Street 13, 300310 Timisoara, Romania
| | - Diana Manolescu
- Center for Research and Innovation in Precision Medicine of Respiratory Diseases, "Victor Babes" University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041 Timisoara, Romania
- Discipline of Radiology, "Victor Babes" University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square 2, 300041 Timisoara, Romania
| | - Felix Bratosin
- Discipline of Infectious Diseases, "Victor Babes" University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square 2, 300041 Timisoara, Romania
| | - Ovidiu Rosca
- Discipline of Infectious Diseases, "Victor Babes" University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square 2, 300041 Timisoara, Romania
| | - Adelina Mavrea
- Department of Internal Medicine I, Cardiology Clinic, "Victor Babes" University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square 2, 300041 Timisoara, Romania
| | - Cristian Oancea
- Center for Research and Innovation in Precision Medicine of Respiratory Diseases, "Victor Babes" University of Medicine and Pharmacy, Eftimie Murgu Square 2, 300041 Timisoara, Romania
- First Pulmonology Clinic, Clinical Hospital of Infectious Diseases and Pulmonology, "Victor Babes", Gheorghe Adam Street 13, 300310 Timisoara, Romania
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16
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Li P, Wu X, Chen P, Gu Z. Prognostic Significance of Iron Metabolism Related Genes in Human Lung Adenocarcinoma. Cancer Manag Res 2023; 15:203-216. [PMID: 36860893 PMCID: PMC9968870 DOI: 10.2147/cmar.s398982] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 01/25/2023] [Indexed: 02/24/2023] Open
Abstract
Background Iron metabolism related genes participate in cell proliferation, cell growth, and redox cycling in multiple cancers. Limited studies have revealed the roles and clinical significance of iron metabolism in the pathogenesis and prognosis of lung cancer. Methods A total of 119 iron metabolism related genes were extracted from MSigDB database and their prognostic values were determined in The Cancer Genome Atlas lung adenocarcinoma (TCGA-LUAD) dataset and the Gene Expression Profiling Interactive Analysis 2 (GEPIA 2) database. Immunohistochemistry technique and correlations with immune cell infiltration, gene mutation and drug resistance were used to identify the potential and underlying mechanisms of STEAP1 and STEAP2 as prognostic biomarkers of LUAD. Results The expression of STEAP1 and STEAP2 are negatively associated with the prognosis of LUAD patients both at the mRNA and protein level. The expression of STEAP1 and STEAP2 was not only negatively correlated with the trafficking degree of CD4+ T immune cells and positively related to most immune cells' trafficking degree, but also significantly associated with gene mutation status, particularly with mutations on TP53 and STK11. Four types of drug resistance showed significant correlation with the expression level of STEAP1 while 13 types of drug resistance were associated with the expression level of STEAP2. Conclusion Multiple iron metabolism related genes including STEAP1 and STEAP2 are significantly associated with the prognosis of LUAD patients. STEAP1 and STEAP2 might affect the prognosis of LUAD patients partially through immune cell infiltration, gene mutation and drug resistance, which indicated they were independent prognostic factors for LUAD patients.
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Affiliation(s)
- Pu Li
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Xiaoqiong Wu
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Peizhan Chen
- Clinical Research Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201821, People’s Republic of China,Peizhan Chen, Clinical Research Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201821, People’s Republic of China, Tel +86 13918550745, Email
| | - Zhidong Gu
- Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China,Department of Laboratory Medicine, Ruijin-Hainan Hospital, Shanghai Jiao Tong University School of Medicine (Hainan Boao Research Hospital), Hainan, People’s Republic of China,Correspondence: Zhidong Gu, Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201821, People’s Republic of China, Tel +86 13801653534, Email
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17
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Tan X, Huang X, Niu B, Guo X, Lei X, Qu B. Targeting GSTP1-dependent ferroptosis in lung cancer radiotherapy: Existing evidence and future directions. Front Mol Biosci 2022; 9:1102158. [PMID: 36589232 PMCID: PMC9800622 DOI: 10.3389/fmolb.2022.1102158] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
Radiotherapy is applied in about 70% patients with tumors, yet radioresistance of tumor cells remains a challenge that limits the efficacy of radiotherapy. Ferroptosis, an iron-dependent lipid peroxidation regulated cell death, is involved in the development of a variety of tumors. Interestingly, there is evidence that ferroptosis inducers in tumor treatment can significantly improve radiotherapy sensitivity. In addition, related studies show that Glutathione S-transferase P1 (GSTP1) is closely related to the development of ferroptosis. The potential mechanism of targeting GSTP1 to inhibit tumor cells from evading ferroptosis leading to radioresistance has been proposed in this review, which implies that GSTP1 may play a key role in radiosensitization of lung cancer via ferroptosis pathway.
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Affiliation(s)
- Xin Tan
- Department of Radiation Oncology, The First Medical Center of Chinese PLA General Hospital, Beijing, China,Medical School of Chinese PLA, Beijing, China
| | - Xiang Huang
- Department of Radiation Oncology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Baolong Niu
- Department of Radiation Oncology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xingdong Guo
- Department of Radiation Oncology, The First Medical Center of Chinese PLA General Hospital, Beijing, China,Medical School of Chinese PLA, Beijing, China
| | - Xiao Lei
- Department of Radiation Oncology, The First Medical Center of Chinese PLA General Hospital, Beijing, China,*Correspondence: Xiao Lei, ; Baolin Qu,
| | - Baolin Qu
- Department of Radiation Oncology, The First Medical Center of Chinese PLA General Hospital, Beijing, China,*Correspondence: Xiao Lei, ; Baolin Qu,
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18
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Wang Q, Cui Q, Gao JP, Xing R. Role of iron biomarkers and iron intakes in lung cancer risk: A systematic review and meta-analysis. J Trace Elem Med Biol 2022; 74:127060. [PMID: 35987180 DOI: 10.1016/j.jtemb.2022.127060] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 08/03/2022] [Accepted: 08/10/2022] [Indexed: 10/15/2022]
Abstract
BACKGROUND The role of iron biomarkers and iron intake in the susceptibility to lung cancer is unclear. The purpose of this study was to conduct a systematic review and meta-analysis, to assess the relationship between iron levels in the body or iron intake and the risk of lung cancer. METHOD This review is registered with PROSPERO (number CRD 42020199776). PubMed, Web of Science, Scopus, Embase and Cochrane were used to search for studies assessing the relationship between iron and lung cancer, up to July 15, 2021. Qualitative and quantitative analysis was carried out to determine if there was a correlation between iron biomarkers/intakes and the risk of lung cancer. RESULT Twenty articles were included. Pooled analyses demonstrated that serum ferritin concentrations and transferrin saturation (TSAT) were significantly higher in patients with lung cancer than in healthy controls (ferritin: standardized mean differences [SMD], 0.235, 95% confidence interval [CI], 0.129, 0.341, I2 = 32.1 %; TSAT: SMD, 0.07, 95 % CI, 0.018, 0.121, I2 = 0 %). In contrast, serum transferrin concentrations were significantly lower in patients with lung cancer than in healthy controls (SMD, -0.591, 95 % CI, -1.18, -0.003, I2 = 87.7 %). No significant effects of serum iron, lung tissue iron, bronchoalveolar lavage fluid (BALF) ferritin, or iron intake (total iron, dietary iron, heme iron, or non-heme iron) were found on lung cancer incidence. CONCLUSION Among the different iron biomarkers analyzed, a trend in association was only detected with serum ferritin, TSAT and transferrin concentration and no associations were found between iron intakes and the risk of lung cancer. However, more prospective studies are needed to strengthen the current evidence.
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Affiliation(s)
- Qian Wang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qi Cui
- Department of Cold Environmental Medicine, College of High Altitude Military Medicine, Third Military Medical University (Army Medical University), Chongqing, China
| | - Jin-Ping Gao
- Department of Oncology, General Hospital of Northern Theater Command, Shenyang, China
| | - Rui Xing
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China.
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19
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Gao Y, Ge JT. Prognostic role of pretreatment serum ferritin concentration in lung cancer patients: A meta-analysis. World J Clin Cases 2022; 10:12230-12239. [PMID: 36483825 PMCID: PMC9724546 DOI: 10.12998/wjcc.v10.i33.12230] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 10/19/2022] [Accepted: 10/24/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND The association between pretreatment serum ferritin concentration (SFC) and long-term survival in lung cancer remains unclear now. AIM To identify the prognostic value of pretreatment SFC in lung cancer patients based on current evidence. METHODS The PubMed, EMBASE and Web of Science databases were searched from inception to May 29, 2022 for relevant studies. The primary endpoint was overall survival (OS) and the hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were combined to assess the predictive role of pretreatment SFC for long-term survival of lung cancer patients. The data were then extracted and assessed on the basis of the Reference Citation Analysis (https://www.referencecitationanalysis.com/). RESULTS Twelve retrospective studies involving 1654 patients were analyzed. The results manifested that increased pretreatment SFC was associated with worse OS (HR = 1.09, 95%CI: 1.03-1.15, P = 0.004). Subgroup analysis stratified by the country (China vs non-China) showed similar results. However, subgroup analysis stratified by tumor type revealed inconsistent results (lung cancer: HR = 1.39, P = 0.008; small cell lung cancer: HR = 1.99, P = 0.175; non-small cell lung cancer: HR = 1.03, P = 0.281). CONCLUSION Pretreatment SFC might serve as a promising prognostic indicator in lung cancer patients and elevated pretreatment SFC predicts worse prognosis. However, more high-quality studies with big sample sizes are still needed to further verify its prognostic value in lung cancer.
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Affiliation(s)
- Yang Gao
- Department of Cardiology Surgery, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huaian 223001, Jiangsu Province, China
| | - Jin-Tong Ge
- Department of Cardiology Surgery, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huaian 223001, Jiangsu Province, China
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20
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Rowińska K, Baszuk P, Rogoża-Janiszewska E, Deptuła J, Marciniak W, Derkacz R, Lener M, Cybulski C, Kiedrowicz M, Boer M, Marchlewicz M, Dębniak T, Lubiński J. Serum Iron Level and 10-Year Survival after Melanoma. Biomedicines 2022; 10:biomedicines10123018. [PMID: 36551774 PMCID: PMC9775579 DOI: 10.3390/biomedicines10123018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/14/2022] [Accepted: 11/22/2022] [Indexed: 11/25/2022] Open
Abstract
The malignant melanoma of the skin is a very aggressive tumor. The determination of prognostic biomarkers is important for the early detection of recurrence, and for the enrollment of the patients into different treatment regimens. An evaluation of a cohort of 375 Polish MM cases revealed that a low serum iron concentration (i.e., below 893.05 µg/L) was associated with increased mortality. The study group was followed up from the date of melanoma diagnosis until death or 2020. Patients were assigned to one of four categories in accordance with increasing iron level (I-IV quarters). Patients with a low iron level of below 893.05 µg/L (I quarter) had a significantly lower survival rate when compared to the subgroup with the highest iron level, above 1348.63 µg/L (IV quarter; HR = 4.12; p = 0.028 and HR = 4.66; p = 0.019 for uni- and multivariable models, respectively). Multivariable analysis took into account the following factors: iron levels, Clark, sex, and age. Future studies based upon the examination of a larger number of cases should be conducted to confirm our findings.
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Affiliation(s)
- Karolina Rowińska
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, 71-252 Szczecin, Poland
- Correspondence:
| | - Piotr Baszuk
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, 71-252 Szczecin, Poland
| | - Emilia Rogoża-Janiszewska
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, 71-252 Szczecin, Poland
| | - Jakub Deptuła
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, 71-252 Szczecin, Poland
| | - Wojciech Marciniak
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, 71-252 Szczecin, Poland
| | - Róża Derkacz
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, 71-252 Szczecin, Poland
| | - Marcin Lener
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, 71-252 Szczecin, Poland
| | - Cezary Cybulski
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, 71-252 Szczecin, Poland
| | - Magdalena Kiedrowicz
- Department of Skin Diseases and Venerology PUM, Pomeranian Medical University, 72-010 Police, Poland
| | - Magdalena Boer
- Department of Skin Diseases and Venerology PUM, Pomeranian Medical University, 72-010 Police, Poland
| | - Mariola Marchlewicz
- Department of Skin Diseases and Venerology PUM, Pomeranian Medical University, 72-010 Police, Poland
| | - Tadeusz Dębniak
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, 71-252 Szczecin, Poland
| | - Jan Lubiński
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, 71-252 Szczecin, Poland
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21
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Wei Z, Xie Y, Wei M, Zhao H, Ren K, Feng Q, Xu Y. New insights in ferroptosis: Potential therapeutic targets for the treatment of ischemic stroke. Front Pharmacol 2022; 13:1020918. [PMID: 36425577 PMCID: PMC9679292 DOI: 10.3389/fphar.2022.1020918] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 10/26/2022] [Indexed: 10/22/2023] Open
Abstract
Stroke is a common disease in clinical practice, which seriously endangers people's physical and mental health. The neurovascular unit (NVU) plays a key role in the occurrence and development of ischemic stroke. Different from other classical types of cell death such as apoptosis, necrosis, autophagy, and pyroptosis, ferroptosis is an iron-dependent lipid peroxidation-driven new form of cell death. Interestingly, the function of NVU and stroke development can be regulated by activating or inhibiting ferroptosis. This review systematically describes the NVU in ischemic stroke, provides a comprehensive overview of the regulatory mechanisms and key regulators of ferroptosis, and uncovers the role of ferroptosis in the NVU and the progression of ischemic stroke. We further discuss the latest progress in the intervention of ferroptosis as a therapeutic target for ischemic stroke and summarize the research progress and regulatory mechanism of ferroptosis inhibitors on stroke. In conclusion, ferroptosis, as a new form of cell death, plays a key role in ischemic stroke and is expected to become a new therapeutic target for this disease.
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Affiliation(s)
- Ziqing Wei
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Clinical Systems Biology Laboratories, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yi Xie
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mingze Wei
- The Second Clinical Medical College, Harbin Medical University, Harbin, China
| | - Huijuan Zhao
- Henan International Joint Laboratory of Thrombosis and Hemostasis, Basic Medical College, Henan University of Science and Technology, Luoyang, China
| | - Kaidi Ren
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou, China
- Henan Engineering Research Center for Application & Translation of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Qi Feng
- Research Institute of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Integrated Traditional and Western Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Province Research Center for Kidney Disease, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuming Xu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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22
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Characterization and Toxicity Analysis of Lab-Created Respirable Coal Mine Dust from the Appalachians and Rocky Mountains Regions. MINERALS 2022. [DOI: 10.3390/min12070898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Coal mine workers are continuously exposed to respirable coal mine dust (RCMD) in workplaces, causing severe lung diseases. RCMD characteristics and their relations with dust toxicity need further research to understand the adverse exposure effects to RCMD. The geographic clustering of coal workers’ pneumoconiosis (CWP) suggests that RCMD in the Appalachian region may exhibit more toxicity than other geographic regions such as the Rocky Mountains. This study investigates the RCMD characteristics and toxicity based on geographic location. Dissolution experiments in simulated lung fluids (SLFs) and in vitro responses were conducted to determine the toxicity level of samples collected from five mines in the Rocky Mountains and Appalachian regions. Dust characteristics were investigated using Fourier-transform infrared spectroscopy, scanning electron microscopy, the BET method, total microwave digestion, X-ray diffraction, and X-ray photoelectron spectroscopy. Inductively coupled plasma mass spectrometry was conducted to determine the concentration of metals dissolved in the SLFs. Finer particle sizes and higher mineral and elemental contents were found in samples from the Appalachian regions. Si, Al, Fe, Cu, Sr, and Pb were found in dissolution experiments, but no trends were found indicating higher dissolutions in the Appalachian region. In vitro studies indicated a proinflammatory response in epithelial and macrophage cells, suggesting their possible participation in pneumoconiosis and lung diseases development.
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23
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Barek MA, Jafrin S, Aziz MA, Islam MS. Catalase C262T genetic variation and cancer susceptibility: A comprehensive meta-analysis with meta-regression and trial sequential analysis. Int J Biol Markers 2022; 37:227-240. [DOI: 10.1177/03936155221104128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background Several genetic association studies have analyzed the link between the catalase ( CAT) C262T variant and different cancers, but the findings remain controversial. Our research centered on establishing a comprehensive correlation between the C262T variant and different cancers. Methods This study was conducted using RevMan 5.4 software following the PRISMA 2020 guidelines. For this meta-analysis, 53 case-control studies (18,258 cases and 47,476 controls) were chosen. Results The analysis revealed that three genetic models were statistically linked ( P < 0.05) to overall cancer susceptibility in codominant model 2 (COD2): odds ratio (OR) = 1.16, COD3: OR = 1.21, recessive model (RM): OR = 1.20). After stratification by ethnicity, a significant link ( P < 0.05) was found in Caucasians (COD2: OR = 1.18, COD3: OR = 1.17, over-dominant model (ODM): OR = 1.19) and Asians (COD3: OR = 1.49). Subgroup analyses revealed a significant correlation ( P < 0.05) with blood-and-bone-marrow-related cancer, skin cancer, gastrointestinal-tract-related cancer, prostate cancer, and gynecologic cancer. Three genetic models in population-based controls (COD2: OR = 1.19, COD3: OR = 1.17, RM: OR = 1.19) and two genetic models in hospital-based controls (COD3: OR = 1.40, RM: OR = 1.24) were found to be significantly correlated ( P < 0.05) with cancer. Also, three genetic models for polymerase chain reaction-restriction fragment length polymorphism (COD3: OR = 1.46; RM: OR = 1.34, ODM: OR = 0.80) and three models for MALDI-TOF + MassARRAY (COD2: OR = 1.32, RM: OR = 1.26, allele model: OR = 1.14) genotyping methods showed significant association ( P < 0.05) with cancer. The meta-regression showed that the quality scores might be a source of significant heterogeneity under the COD2 model (coefficient = 0.176, P = 0.029). Trial sequential analysis also validated the adequacy of the sample size on overall findings. Conclusion Our results indicate that CAT C262T variant is associated with overall cancer susceptibility, especially in Caucasians and Asians. This variant may also be associated with blood-and-bone-marrow-related, GIT-related, prostate, skin, and gynecological cancers.
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Affiliation(s)
- Md Abdul Barek
- Department of Pharmacy, Faculty of Science, Noakhali Science and Technology University, Noakhali, Bangladesh
- Laboratory of Pharmacogenomics and Molecular Biology, Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Sarah Jafrin
- Department of Pharmacy, Faculty of Science, Noakhali Science and Technology University, Noakhali, Bangladesh
- Laboratory of Pharmacogenomics and Molecular Biology, Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Md. Abdul Aziz
- Department of Pharmacy, Faculty of Pharmacy and Health Sciences, State University of Bangladesh, Dhaka, Bangladesh
| | - Mohammad Safiqul Islam
- Department of Pharmacy, Faculty of Science, Noakhali Science and Technology University, Noakhali, Bangladesh
- Laboratory of Pharmacogenomics and Molecular Biology, Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh
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24
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Chen Y, Fan Z, Hu S, Lu C, Xiang Y, Liao S. Ferroptosis: A New Strategy for Cancer Therapy. Front Oncol 2022; 12:830561. [PMID: 35252001 PMCID: PMC8888853 DOI: 10.3389/fonc.2022.830561] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 01/25/2022] [Indexed: 01/10/2023] Open
Abstract
Ferroptosis is a newly discovered form of iron-dependent cell death, which is different from other death forms. The main characteristics of ferroptosis are: (1) Amino acid metabolism. (2) Iron metabolism; (3) Lipid metabolism and Reactive oxygen species (ROS). Ferroptosis is related to the occurrence and development of a variety of cancers, especially in the drug resistance. This article reviews the research progress of iron death in tumors, and provides a theoretical reference for its further research and clinical application.
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Affiliation(s)
- Yu Chen
- Department of Pediatric Surgery, Guangdong Women and Children Hospital, Guangzhou, China
- *Correspondence: Yu Chen,
| | - Zhihua Fan
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
| | - Shen Hu
- Department of Obstetrics, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chengchao Lu
- Department of Pediatric Surgery, Guangdong Women and Children Hospital, Guangzhou, China
| | - Yi Xiang
- Department of Pediatric Surgery, Guangdong Women and Children Hospital, Guangzhou, China
| | - Shuzhi Liao
- Department of Pediatric Surgery, Guangdong Women and Children Hospital, Guangzhou, China
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25
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Jiang M, Hu R, Yu R, Tang Y, Li J. A narrative review of mechanisms of ferroptosis in cancer: new challenges and opportunities. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1599. [PMID: 34790805 PMCID: PMC8576726 DOI: 10.21037/atm-21-4863] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 09/28/2021] [Indexed: 12/22/2022]
Abstract
Objective This article reviews the specific mechanism of ferroptosis in cancer and introduces in detail the opportunities and challenges of ferroptosis-based cancer therapy, aiming to provide a new research direction for tumor therapy. Background Ferroptosis is a newly discovered programmed non-apoptotic form of cell death. Involving changes in metabolic processes and the accumulation of peroxidation caused by factors such as drugs or genes which destruct the cell membrane structure, this kind of cell death has been linked with the pathological process of diseases such as tumors, neurological diseases, ischemia-reperfusion injury, kidney injury, and hemopathy. This kind of cell death can play a vital role in inhibiting tumorigenesis by eliminating the adaptive characteristics of malignant cells and removing cells that are unable to obtain key nutritional factors or are infected and damaged by environmental changes. The present focus of research on the regulation of ferroptosis-related diseases involves the use of small molecule compounds. Methods We described the mechanism of ferroptosis and its related small molecules compounds, which involved in the regulatory mechanism, and analyzed the role and regulatory mechanism of ferroptosis in different tumors. Conclusions This article reviewed the mechanism of ferroptosis and its role and mechanism in different tumors, and showed it can inhibit the occurrence and development of different tumors and may reduce the adverse effects of current treatment methods.
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Affiliation(s)
- Mingyan Jiang
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Ruolan Hu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Ruixin Yu
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Yiwei Tang
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Jinrong Li
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.,Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
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26
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Mani S, Swargiary G, Ralph SJ. Targeting the redox imbalance in mitochondria: A novel mode for cancer therapy. Mitochondrion 2021; 62:50-73. [PMID: 34758363 DOI: 10.1016/j.mito.2021.11.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 10/14/2021] [Accepted: 11/01/2021] [Indexed: 12/19/2022]
Abstract
Changes in reactive oxygen species (ROS) levels affect many aspects of cell behavior. During carcinogenesis, moderate ROS production modifies gene expression to alter cell function, elevating metabolic activity and ROS. To avoid extreme ROS-activated death, cancer cells increase antioxidative capacity, regulating sustained ROS levels that promote growth. Anticancer therapies are exploring inducing supranormal, cytotoxic oxidative stress levels either inhibiting antioxidative capacity or promoting excess ROS to selectively destroy cancer cells, triggering mechanisms such as apoptosis, autophagy, necrosis, or ferroptosis. This review exemplifies pro-oxidants (natural/synthetic/repurposed drugs) and their clinical significance as cancer therapies providing revolutionary approaches.
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Affiliation(s)
- Shalini Mani
- Centre for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, India.
| | - Geeta Swargiary
- Centre for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, India
| | - Stephen J Ralph
- School of Medical Science, Griffith University, Southport, Australia.
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Ramírez-Carmona W, Díaz-Fabregat B, Yuri Yoshigae A, Musa de Aquino A, Scarano WR, de Souza Castilho AC, Avansini Marsicano J, Leal do Prado R, Pessan JP, de Oliveira Mendes L. Are Serum Ferritin Levels a Reliable Cancer Biomarker? A Systematic Review and Meta-Analysis. Nutr Cancer 2021; 74:1917-1926. [PMID: 34607491 DOI: 10.1080/01635581.2021.1982996] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Although serum ferritin (SF) has been shown in several studies to be a potential cancer biomarker, the results are inconsistent. Herein, a systematic review was performed to investigate the clinical SF levels in different types of tumors in order to verify the role of SF levels as a biomarker for cancer diagnosis. The search was performed using the PubMed/Medline, Cochrane Library, and Scopus databases. Observational studies comparing SF levels between healthy adults and patients with cancer were included. The meta-analysis was carried out according to the inverse variance and random effects model. The standardized mean differences (SMDs) were assessed at 95% confidence intervals (CIs). We found that SF was higher in patients with cancer (SMD 3.07; CI 1.96,4.17), especially for head and neck cancer (SMD 3.88; CI 0.42,7.34), lung cancer (SMD 1.72; CI 0.67,2.78), pancreatic cancer (SMD 6.79; CI 5.66,7.91), and renal cell carcinoma (SMD 1.77; CI 0.48,3.05). Moreover, in the advanced stages (Stages III and IV), ferritin levels were higher than in healthy adults (SMD 4.89; CI 2.72,7.06, and SMD 8.40; CI 6.99,9.82, respectively). SF acts as a biomarker for pancreatic cancer, renal cell carcinoma, lung cancer, and head and neck cancer and is a sensitive biomarker for the detection of advanced stages of tumors.
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Affiliation(s)
| | - Beatriz Díaz-Fabregat
- Department of Pediatric Dentistry and Public Heatlhy, Araçatuba Dental School, Univ. Estadual Paulista (UNESP), Araçatuba, SP, Brazil
| | | | - Ariana Musa de Aquino
- Department of Structural and Functional Biology, Institute of Biosciences, Univ. Estadual Paulista (UNESP), Botucatu, SP, Brazil
| | - Wellerson Rodrigo Scarano
- Department of Structural and Functional Biology, Institute of Biosciences, Univ. Estadual Paulista (UNESP), Botucatu, SP, Brazil
| | | | | | | | - Juliano Pelim Pessan
- Department of Pediatric Dentistry and Public Heatlhy, Araçatuba Dental School, Univ. Estadual Paulista (UNESP), Araçatuba, SP, Brazil
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28
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Julián-Serrano S, Yuan F, Wheeler W, Benyamin B, Machiela MJ, Arslan AA, Beane-Freeman LE, Bracci PM, Duell EJ, Du M, Gallinger S, Giles GG, Goodman PJ, Kooperberg C, Marchand LL, Neale RE, Shu XO, Van Den Eeden SK, Visvanathan K, Zheng W, Albanes D, Andreotti G, Ardanaz E, Babic A, Berndt SI, Brais LK, Brennan P, Bueno-de-Mesquita B, Buring JE, Chanock SJ, Childs EJ, Chung CC, Fabiánová E, Foretová L, Fuchs CS, Gaziano JM, Gentiluomo M, Giovannucci EL, Goggins MG, Hackert T, Hartge P, Hassan MM, Holcátová I, Holly EA, Hung RI, Janout V, Kurtz RC, Lee IM, Malats N, McKean D, Milne RL, Newton CC, Oberg AL, Perdomo S, Peters U, Porta M, Rothman N, Schulze MB, Sesso HD, Silverman DT, Thompson IM, Wactawski-Wende J, Weiderpass E, Wenstzensen N, White E, Wilkens LR, Yu H, Zeleniuch-Jacquotte A, Zhong J, Kraft P, Li D, Campbell PT, Petersen GM, Wolpin BM, Risch HA, Amundadottir LT, Klein AP, Yu K, Stolzenberg-Solomon RZ. Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies. Am J Clin Nutr 2021; 114:1408-1417. [PMID: 34258619 PMCID: PMC8488877 DOI: 10.1093/ajcn/nqab217] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 06/08/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis. OBJECTIVES The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC. METHODS We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs. RESULTS The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association. CONCLUSIONS Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.
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Affiliation(s)
| | - Fangcheng Yuan
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | | | - Beben Benyamin
- Australian Centre for Precision Health, Allied Health and Human Performance, University of South Australia, Adelaide, Australia
- South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Mitchell J Machiela
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Alan A Arslan
- Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY, USA
| | - Laura E Beane-Freeman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Paige M Bracci
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Eric J Duell
- Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | - Mengmeng Du
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Steven Gallinger
- Lunenfeld–Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
| | - Graham G Giles
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia
| | - Phyllis J Goodman
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Charles Kooperberg
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Loic Le Marchand
- Department of Epidemiology, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Rachel E Neale
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Xiao-Ou Shu
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt–Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | | | - Kala Visvanathan
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt–Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Gabriella Andreotti
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Eva Ardanaz
- Navarra Public Health Institute, Pamplona, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
| | - Ana Babic
- Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, USA
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Lauren K Brais
- Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, USA
| | - Paul Brennan
- International Agency for Research on Cancer (IARC), Lyon, France
| | - Bas Bueno-de-Mesquita
- Department for Determinants of Chronic Diseases, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Julie E Buring
- Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Stephen J Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Erica J Childs
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Charles C Chung
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Eleonora Fabiánová
- Specialized Institute of Hygiene and Epidemiology, Banska Bystrica, Slovakia
| | - Lenka Foretová
- Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Charles S Fuchs
- Yale Cancer Center and Smilow Cancer Hospital, New Haven, CT, USA
| | | | - Manuel Gentiluomo
- Department of Biology, University of Pisa, Italy
- Genomic Epidemiology Group, German Cancer Research Center, (DKFZ), Heidelberg, Germany
| | | | - Michael G Goggins
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Thilo Hackert
- Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Patricia Hartge
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Manal M Hassan
- Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ivana Holcátová
- Institute of Public Health and Preventive Medicine, Second Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Elizabeth A Holly
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Rayjean I Hung
- Lunenfeld–Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
| | - Vladimir Janout
- Faculty of Health Sciences, University of Olomouc, Olomouc, Czech Republic
| | - Robert C Kurtz
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - I-Min Lee
- Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Núria Malats
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - David McKean
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Roger L Milne
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia
| | - Christina C Newton
- Department of Population Science, American Cancer Society, Atlanta, GA, USA
| | - Ann L Oberg
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Sandra Perdomo
- International Agency for Research on Cancer (IARC), Lyon, France
| | - Ulrike Peters
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Miquel Porta
- Hospital del Mar Institute of Medical Research (IMIM), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Nathaniel Rothman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Matthias B Schulze
- Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
- Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - Howard D Sesso
- Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Debra T Silverman
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Ian M Thompson
- CHRISTUS Santa Rosa Hospital–Medical Center, San Antonio, TX, USA
| | - Jean Wactawski-Wende
- Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY, USA
| | - Elisabete Weiderpass
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Nicolas Wenstzensen
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Emily White
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Lynne R Wilkens
- Department of Epidemiology, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Herbert Yu
- Department of Epidemiology, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Anne Zeleniuch-Jacquotte
- Department of Population Health and Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA
| | - Jun Zhong
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Peter Kraft
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Dounghui Li
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Peter T Campbell
- Department of Population Science, American Cancer Society, Atlanta, GA, USA
| | - Gloria M Petersen
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Brian M Wolpin
- Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, USA
| | - Harvey A Risch
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
| | - Laufey T Amundadottir
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Alison P Klein
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Kai Yu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
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29
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Zhang L, Zhang J, Jin Y, Yao G, Zhao H, Qiao P, Wu S. Nrf2 Is a Potential Modulator for Orchestrating Iron Homeostasis and Redox Balance in Cancer Cells. Front Cell Dev Biol 2021; 9:728172. [PMID: 34589492 PMCID: PMC8473703 DOI: 10.3389/fcell.2021.728172] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 08/16/2021] [Indexed: 12/16/2022] Open
Abstract
Iron is an essential trace mineral element in almost all living cells and organisms. However, cellular iron metabolism pathways are disturbed in most cancer cell types. Cancer cells have a high demand of iron. To maintain rapid growth and proliferation, cancer cells absorb large amounts of iron by altering expression of iron metabolism related proteins. However, iron can catalyze the production of reactive oxygen species (ROS) through Fenton reaction. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an important player in the resistance to oxidative damage by inducing the transcription of antioxidant genes. Aberrant activation of Nrf2 is observed in most cancer cell types. It has been revealed that the over-activation of Nrf2 promotes cell proliferation, suppresses cell apoptosis, enhances the self-renewal capability of cancer stem cells, and even increases the chemoresistance and radioresistance of cancer cells. Recently, several genes involving cellular iron homeostasis are identified under the control of Nrf2. Since cancer cells require amounts of iron and Nrf2 plays pivotal roles in oxidative defense and iron metabolism, it is highly probable that Nrf2 is a potential modulator orchestrating iron homeostasis and redox balance in cancer cells. In this hypothesis, we summarize the recent findings of the role of iron and Nrf2 in cancer cells and demonstrate how Nrf2 balances the oxidative stress induced by iron through regulating antioxidant enzymes and iron metabolism. This hypothesis provides new insights into the role of Nrf2 in cancer progression. Since ferroptosis is dependent on lipid peroxide and iron accumulation, Nrf2 inhibition may dramatically increase sensitivity to ferroptosis. The combination of Nrf2 inhibitors with ferroptosis inducers may exert greater efficacy on cancer therapy.
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Affiliation(s)
- Lingyan Zhang
- Institute of Laboratory Animal Science, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Jian Zhang
- Institute of Laboratory Animal Science, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Yuanqing Jin
- Institute of Laboratory Animal Science, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Gang Yao
- Institute of Laboratory Animal Science, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Hai Zhao
- Institute of Laboratory Animal Science, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Penghai Qiao
- Institute of Laboratory Animal Science, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Shuguang Wu
- Institute of Laboratory Animal Science, Guizhou University of Traditional Chinese Medicine, Guiyang, China
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30
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Zhou J, Wang X, Li Z, Jiang R. Construction and analysis of a novel ferroptosis-related gene signature predicting prognosis in lung adenocarcinoma. FEBS Open Bio 2021; 11:3005-3018. [PMID: 34499810 PMCID: PMC8564102 DOI: 10.1002/2211-5463.13288] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 08/10/2021] [Accepted: 09/06/2021] [Indexed: 12/25/2022] Open
Abstract
Ferroptosis is a newly discovered, iron‐dependent, nonapoptotic form of programmed cell death that plays an important role in the development of lung adenocarcinoma (LUAD). In this study, ferroptosis‐related genes (FRGs) were identified from the FerrDb dataset, and the mRNA expression profiles and corresponding clinical data of LUAD patients were downloaded from the University of California, Santa Cruz (UCSC) databases. Data from LUAD patients from the Gene Expression Omnibus (GEO) dataset were used as the verification set. Cox and Lasso regression analyses were used to screen the FRGs with prognostic value, and six prognostic‐related FRGs were selected to construct prognostic risk score signatures. Immunohistochemistry was utilized to manifest the differential expression of six FRGs in tumor and normal tissues at the protein level. Functional enrichment analysis indicated that FRGs were mainly enriched in ferroptosis‐related pathways. Patients were divided into high‐ and low‐risk groups based on the median risk score. The Kaplan–Meier survival curves confirmed that patients with a high score had significantly worse overall survival. Receiver operating characteristic (ROC) curves proved that the prognostic signature has good sensitivity and specificity for predicting the prognosis of LUAD patients. Nomogram analysis showed that the prognostic signature has potential independent prognostic value. Moreover, the prognostic signature has been shown to be significantly associated with some clinical features (T stage, N stage, tumor stage, and survival status) as well as many immune‐activity‐related genes and immune‐checkpoint‐related genes. In conclusion, we constructed a prognostic signature consisting of six FGRs, which can provide a reference for predicting the prognosis of LUAD patients.
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Affiliation(s)
- Jing Zhou
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, China.,Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute & Hospital, Tianjin Medical University, China
| | - Xinyue Wang
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, China.,Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute & Hospital, Tianjin Medical University, China
| | - Zhaona Li
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, China.,Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute & Hospital, Tianjin Medical University, China
| | - Richeng Jiang
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China.,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.,Tianjin's Clinical Research Center for Cancer, China.,Department of Thoracic Oncology, Tianjin Lung Cancer Center, Tianjin Cancer Institute & Hospital, Tianjin Medical University, China
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31
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Qin J, Xu Z, Deng K, Qin F, Wei J, Yuan L, Sun Y, Zheng T, Li S. Development of a gene signature associated with iron metabolism in lung adenocarcinoma. Bioengineered 2021; 12:4556-4568. [PMID: 34323652 PMCID: PMC8806683 DOI: 10.1080/21655979.2021.1954840] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
There are few studies on the role of iron metabolism genes in predicting the prognosis of lung adenocarcinoma (LUAD). Therefore, our research aims to screen key genes and to establish a prognostic signature that can predict the overall survival rate of lung adenocarcinoma patients. RNA-Seq data and corresponding clinical materials of 594 adenocarcinoma patients from The Cancer Genome Atlas(TCGA) were downloaded. GSE42127 of Gene Expression Omnibus (GEO) database was further verified. The multi-gene prognostic signature was constructed by the Cox regression model of the Least Absolute Shrinkage and Selection Operator (LASSO). We constructed a prediction signature with 12 genes (HAVCR1, SPN, GAPDH, ANGPTL4, PRSS3, KRT8, LDHA, HMMR, SLC2A1, CYP24A1, LOXL2, TIMP1), and patients were split into high and low-risk groups. The survival graph results revealed that the survival prognosis between the high and low-risk groups was significantly different (TCGA: P < 0.001, GEO: P = 0.001). Univariate and multivariate Cox regression analysis confirmed that the risk value is a predictor of patient OS (P < 0.001). The area under the time-dependent ROC curve (AUC) indicated that our signature had a relatively high true positive rate when predicting the 1-year, 3-year, and 5-year OS of the TCGA cohort, which was 0.735, 0.711, and 0.601, respectively. In addition, immune-related pathways were highlighted in the functional enrichment analysis. In conclusion, we developed and verified a 12-gene prognostic signature, which may be help predict the prognosis of lung adenocarcinoma and offer a variety of targeted options for the precise treatment of lung cancer.
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Affiliation(s)
- Junqi Qin
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P. R. China
| | - Zhanyu Xu
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P. R. China
| | - Kun Deng
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P. R. China
| | - Fanglu Qin
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P. R. China.,School of Information and Management, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P. R. China
| | - Jiangbo Wei
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P. R. China
| | - Liqiang Yuan
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P. R. China
| | - Yu Sun
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P. R. China
| | - Tiaozhan Zheng
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P. R. China
| | - Shikang Li
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, P. R. China
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32
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Lossow K, Schwarz M, Kipp AP. Are trace element concentrations suitable biomarkers for the diagnosis of cancer? Redox Biol 2021; 42:101900. [PMID: 33642247 PMCID: PMC8113050 DOI: 10.1016/j.redox.2021.101900] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 02/04/2021] [Accepted: 02/12/2021] [Indexed: 12/24/2022] Open
Abstract
Despite advances in cancer research, cancer is still one of the leading causes of death worldwide. An early diagnosis substantially increases the survival rate and treatment success. Thus, it is important to establish biomarkers which could reliably identify cancer patients. As cancer is associated with changes in the systemic trace element status and distribution, serum concentrations of selenium, iron, copper, and zinc could contribute to an early diagnosis. To test this hypothesis, case control studies measuring trace elements in cancer patients vs. matched controls were selected and discussed focusing on lung, prostate, breast, and colorectal cancer. Overall, cancer patients had elevated serum copper and diminished zinc levels, while selenium and iron did not show consistent changes for all four cancer types. Within the tumor tissue, mainly copper and selenium are accumulating. Whether these concentrations also predict the survival probability of cancer patients needs to be further investigated.
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Affiliation(s)
- Kristina Lossow
- Department of Molecular Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, 07743, Germany; TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena-Wuppertal, Germany
| | - Maria Schwarz
- Department of Molecular Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, 07743, Germany; TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena-Wuppertal, Germany
| | - Anna P Kipp
- Department of Molecular Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, 07743, Germany; TraceAge-DFG Research Unit on Interactions of Essential Trace Elements in Healthy and Diseased Elderly, Potsdam-Berlin-Jena-Wuppertal, Germany.
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33
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Ying JF, Lu ZB, Fu LQ, Tong Y, Wang Z, Li WF, Mou XZ. The role of iron homeostasis and iron-mediated ROS in cancer. Am J Cancer Res 2021; 11:1895-1912. [PMID: 34094660 PMCID: PMC8167679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 03/01/2021] [Indexed: 06/12/2023] Open
Abstract
As an important trace element, iron plays an essential role in many biology processes like cell proliferation, metabolism, and mitochondrial function. However, the disruption of iron homeostasis tends to cells death and human diseases due to it servers as mediator to promote the production of reactive oxygen species (ROS). In this review, first we introduced the mechanism of complex iron-mediated ROS involved in apoptosis, necroptosis, ferroptosis and pyroptosis. Next, we discussed the controversial role of excess iron and iron deficiency in tumor. Finally, we discussed the anti-cancer effects of iron on both sides, and novel iron-related strategies. This review outlined the mechanisms and regulation of iron homeostasis and iron-mediated ROS in tumors, and discussed the iron-related treatments.
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Affiliation(s)
- Jia-Fu Ying
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
- Clinical Research Institute, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
- Key Laboratory of Molecular Animal Nutrition of The Ministry of Education, Institute of Feed Science, College of Animal Sciences, Zhejiang UniversityHangzhou 310058, Zhejiang Province, P. R. China
| | - Ze-Bei Lu
- Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, P. R. China
| | - Luo-Qin Fu
- Clinical Research Institute, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
| | - Yu Tong
- Clinical Research Institute, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
| | - Zhen Wang
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
| | - Wei-Fen Li
- Key Laboratory of Molecular Animal Nutrition of The Ministry of Education, Institute of Feed Science, College of Animal Sciences, Zhejiang UniversityHangzhou 310058, Zhejiang Province, P. R. China
| | - Xiao-Zhou Mou
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
- Clinical Research Institute, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
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Ronco AL, Martínez-López W, Calderón JM, Golomar W. Dietary acid load and lung cancer risk: A case-control study in men. Cancer Treat Res Commun 2021; 28:100382. [PMID: 33957561 DOI: 10.1016/j.ctarc.2021.100382] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 04/16/2021] [Accepted: 04/20/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND Dysregulation of the endogenous acid-base balance can contribute to inflammation and cancer development if metabolic acidosis is sustained. The epidemiologic evidence on the association between diet-dependent acid load and cancer risk is scarce and inconsistent. We aim to explore the possible role of dietary acid load in lung cancer (LC) risk. METHODS A case-control study was performed on 843 LC cases and 1466 controls by using a multi-topic questionnaire, including a food frequency questionnaire. Controls were matched to cases by age-frequency, urban/rural residence, and region. Food-derived nutrients were calculated from available databases. The dietary acid load was calculated using validated measures as potential renal acid load (PRAL) score and net endogenous acid production (NEAP) score. Odds ratios (ORs) were estimated by logistic regression. RESULTS We found direct associations between dietary acid load and LC risk. The highest quartile of the NEAP score was significantly associated (OR=2.22, ptrend<0.001). The PRAL score displayed similar associations in simpler regression models, but there was no association when a more complex one was used (OR=0.99, ptrend =0.94). The NEAP score was associated with a significant risk increase in all cell types, except for small cell cancers, but the PRAL score did not show any association. CONCLUSIONS The NEAP scores, directly associated with meat intake and inversely associated with plant-based foods intake, suggest that a high acid load dietary style may increase LC risk. Studies focused on food groups, and nutritional patterns are in line with our findings. Although the data shown here represent the first one to be published on this issue, further studies are needed to confirm these findings.
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Affiliation(s)
- Alvaro L Ronco
- Unit of Oncology and Radiotherapy, Pereira Rossell Women's Hospital, Bvar. Artigas 1590, Montevideo 11600, Uruguay; School of Medicine, CLAEH University, Prado and Salt Lake, Maldonado 20100, Uruguay; Biomedical Sciences Center, University of Montevideo, Puntas de Santiago 1604, Montevideo 11500, Uruguay.
| | - Wilner Martínez-López
- Epigenetics and Genomics Instability Laboratory and Biodosimetry Service, Instituto de Investigaciones Biológicas Clemente Estable, Av. Italia 3318, Montevideo 11600, Uruguay
| | - Juan M Calderón
- Biomedical Sciences Center, University of Montevideo, Puntas de Santiago 1604, Montevideo 11500, Uruguay
| | - Wilson Golomar
- Unit of Thoracic Oncology, National Cancer Institute, Joanicó 3265, Montevideo 11600, Uruguay
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Wei J, Gao X, Qin Y, Liu T, Kang Y. An Iron Metabolism-Related SLC22A17 for the Prognostic Value of Gastric Cancer. Onco Targets Ther 2020; 13:12763-12775. [PMID: 33363382 PMCID: PMC7751842 DOI: 10.2147/ott.s287811] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 12/03/2020] [Indexed: 12/18/2022] Open
Abstract
Purpose Gastric cancer (GC) is a type of malignant cancer with a poor prognosis. The iron’s metabolism plays an important role in the process of GC. The aim of this study was to evaluate the effectiveness of SLC22A17, associated with iron metabolism, in predicting the prognosis of GC patients. Materials and Methods We analyzed genes related to iron metabolism of gastric cancer mRNA-seq data from TCGA database. We identified an iron metabolism-related SLC22A17 as an independent prognostic factor using univariate and multivariate Cox regression analysis. Results Further research showed that SLC22A17 was related with many pathways involved in the process of gastric cancer, and the expression was associated with diverse cancer-infiltrating immune cells. The expression of SLC22A17 was associated with T (Topography). Conclusion We validated that SLC22A17 associated with iron metabolism could serve as a prognostic biomarker for GC patients.
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Affiliation(s)
- Jianming Wei
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China
| | - Xibo Gao
- Department of Dermatology, Tianjin Children's Hospital, Tianjin 300074, People's Republic of China
| | - Yulan Qin
- School of Biomedical Engineering, Bio-ID Center, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China
| | - Tong Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China
| | - Yani Kang
- School of Biomedical Engineering, Bio-ID Center, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China
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Khan A, Singh P, Srivastava A. Iron: Key player in cancer and cell cycle? J Trace Elem Med Biol 2020; 62:126582. [PMID: 32673942 DOI: 10.1016/j.jtemb.2020.126582] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 12/31/2019] [Accepted: 06/09/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Iron is an essential element for growth and metabolic activities of all living organisms but remains in its oxyhydroxide ferric ion form in the surrounding. Unavailability of iron in soluble ferrous form led to development of specific pathways and machinery in different organisms to make it available for use and maintain its homeostasis. Iron homeostasis is essential as under different circumstances iron in excess as well as deprivation leads to different pathological conditions in human. OBJECTIVE This review highlights the current findings related to iron excess as well as deprivation with regards to cellular proliferation. CONCLUSIONS Iron excess is extensively associated with different types of cancers viz. colorectal cancer, breast cancer etc. by producing an oxidative stressed condition and alteration of immune system. Ironically its deprivation also results in anaemic conditions and leads to cell cycle arrest at different phases with mechanism yet to be explored. Iron deprivation arrests cell cycle at G1/S and in some cases at G2/M checkpoints resulting in growth arrest. However, in some cases iron overload arrests cell cycle at G1 phase by blocking certain signalling pathways. Certain natural and synthetic iron chelators are being explored from few decades to combat diseases caused by alteration in iron homeostasis.
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Affiliation(s)
- Azmi Khan
- Department of Life Science, School of Earth, Biological and Environmental Sciences, Central University of South Bihar, Gaya, Bihar, India
| | - Pratika Singh
- Department of Life Science, School of Earth, Biological and Environmental Sciences, Central University of South Bihar, Gaya, Bihar, India
| | - Amrita Srivastava
- Department of Life Science, School of Earth, Biological and Environmental Sciences, Central University of South Bihar, Gaya, Bihar, India.
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Iron Dysregulation in Human Cancer: Altered Metabolism, Biomarkers for Diagnosis, Prognosis, Monitoring and Rationale for Therapy. Cancers (Basel) 2020; 12:cancers12123524. [PMID: 33255972 PMCID: PMC7761132 DOI: 10.3390/cancers12123524] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/21/2020] [Accepted: 11/24/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Iron is the more abundant metal ion in humans. It is essential for life as it has a role in various cellular processes involved, for instance, in cell metabolism and DNA synthesis. These functions are crucial for cell proliferation, and it is therefore not surprising that iron is accumulated in tumors. In this review, we describe normal and altered iron homeostasis mechanisms. We also provide a vision of iron-related proteins with altered expression in cancers and discuss their potential as diagnostic and/or prognostic biomarkers. Finally, we give an overview of therapeutic strategies acting on iron metabolism to fight against cancers. Abstract Iron (Fe) is a trace element that plays essential roles in various biological processes such as DNA synthesis and repair, as well as cellular energy production and oxygen transport, and it is currently widely recognized that iron homeostasis is dysregulated in many cancers. Indeed, several iron homeostasis proteins may be responsible for malignant tumor initiation, proliferation, and for the metastatic spread of tumors. A large number of studies demonstrated the potential clinical value of utilizing these deregulated proteins as prognostic and/or predictive biomarkers of malignancy and/or response to anticancer treatments. Additionally, the iron present in cancer cells and the importance of iron in ferroptosis cell death signaling pathways prompted the development of therapeutic strategies against advanced stage or resistant cancers. In this review, we select relevant and promising studies in the field of iron metabolism in cancer research and clinical oncology. Besides this, we discuss some co-existing discrepant findings. We also present and discuss the latest lines of research related to targeting iron, or its regulatory pathways, as potential promising anticancer strategies for human therapy. Iron chelators, such as deferoxamine or iron-oxide-based nanoparticles, which are already tested in clinical trials, alone or in combination with chemotherapy, are also reported.
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Molecular Mechanisms of Ferroptosis and Its Role in Pulmonary Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:9547127. [PMID: 32685102 PMCID: PMC7338975 DOI: 10.1155/2020/9547127] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 05/20/2020] [Indexed: 12/27/2022]
Abstract
Ferroptosis is a new mode of cell death that is characterized by the excessive accumulation of iron and lipid peroxides. It has unique morphological changes and disparate biochemical features and plays an intricate role in many pathophysiological processes. A great deal of researches confirms that ferroptosis can be regulated by numerous molecules through different mechanisms, supporting great potentials for novel pharmacological therapeutics. Recently, several studies reveal that ferroptosis is also closely associated with the initiation and development of respiratory disease. Understanding the specific mechanism, the molecular trait of ferroptosis and their relationship with pulmonary disease could provide significant references regarding effective treatment of these obstinate disease.
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Abedi M, Rahgozar S, Esmaeili A. Iron protects childhood acute lymphoblastic leukemia cells from methotrexate cytotoxicity. Cancer Med 2020; 9:3537-3550. [PMID: 32176452 PMCID: PMC7221302 DOI: 10.1002/cam4.2982] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 02/19/2020] [Accepted: 02/22/2020] [Indexed: 12/14/2022] Open
Abstract
Drug resistance is a fundamental clinical concern in pediatric acute lymphoblastic leukemia (pALL), and methotrexate (MTX) is an essential chemotherapy drug administered for the treatment. In the current study, the effect of iron in response to methotrexate and its underlying mechanisms were investigated in pALL cells. CCRF-CEM and Nalm6 cell lines were selected as T and B-ALL subtypes. Cells were pretreated with ferric ammonium citrate, exposed to the IC50 concentration of MTX and cell viability was assessed using MTT, colony formation, and flow cytometry assays. Iron-loaded cells were strongly resistant to MTX cytotoxicity. The inhibitory effect of N-acetyl cysteine to reverse the acquired MTX resistance was greater than that of the iron chelator, deferasirox, highlighting the importance of iron-mediated ROS in MTX resistance. Subsequently, the upregulation of BCL2, SOD2, NRF2, and MRP1 was confirmed using quantitative RT-PCR. Moreover, a positive correlation was demonstrated between the MRP1 expression levels and bone marrow iron storage in pALL patients. Further supporting our findings were the hematoxylin and eosin-stained histological sections showing that iron-treated nude mice xenografts demonstrated significantly more liver damage than those unexposed to iron. Overall, iron is introduced as a player with a novel role contributing to methotrexate resistance in pALL. Our findings suggest that the patients' bone marrow iron stores are necessary to be assessed during the chemotherapy, and transfusions should be carefully administrated.
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Affiliation(s)
- Marjan Abedi
- Department of Cell and Molecular biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Soheila Rahgozar
- Department of Cell and Molecular biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Abolghasem Esmaeili
- Department of Cell and Molecular biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
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Nesterova DS, Midya V, Zacharia BE, Proctor EA, Lee SY, Stetson LC, Lathia JD, Rubin JB, Waite KA, Berens ME, Barnholtz-Sloan JS, Connor JR. Sexually dimorphic impact of the iron-regulating gene, HFE, on survival in glioblastoma. Neurooncol Adv 2020; 2:vdaa001. [PMID: 32642673 PMCID: PMC7212901 DOI: 10.1093/noajnl/vdaa001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background The median survival for patients with glioblastoma (GBM), the most common primary malignant brain tumor in adults, has remained approximately 1 year for more than 2 decades. Recent advances in the field have identified GBM as a sexually dimorphic disease. It is less prevalent in females and they have better survival compared to males. The molecular mechanism of this difference has not yet been established. Iron is essential for many biological processes supporting tumor growth and its regulation is impacted by sex. Therefore, we interrogated the expression of a key component of cellular iron regulation, the HFE (homeostatic iron regulatory) gene, on sexually dimorphic survival in GBM. Methods We analyzed TCGA microarray gene expression and clinical data of all primary GBM patients (IDH-wild type) to compare tumor mRNA expression of HFE with overall survival, stratified by sex. Results In low HFE expressing tumors (below median expression, n = 220), survival is modulated by both sex and MGMT status, with the combination of female sex and MGMT methylation resulting in over a 10-month survival advantage (P < .0001) over the other groups. Alternatively, expression of HFE above the median (high HFE, n = 240) is associated with significantly worse overall survival in GBM, regardless of MGMT methylation status or patient sex. Gene expression analysis uncovered a correlation between high HFE expression and expression of genes associated with immune function. Conclusions The level of HFE expression in GBM has a sexually dimorphic impact on survival. Whereas HFE expression below the median imparts a survival benefit to females, high HFE expression is associated with significantly worse overall survival regardless of established prognostic factors such as sex or MGMT methylation.
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Affiliation(s)
- Darya S Nesterova
- Department of Neurosurgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Vishal Midya
- Division of Biostatistics & Bioinformatics, Pennsylvania State University, Hershey, Pennsylvania, USA
| | - Brad E Zacharia
- Department of Neurosurgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Elizabeth A Proctor
- Department of Neurosurgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.,Department of Pharmacology, Pennsylvania State University, Hershey, Pennsylvania, USA.,Department of Biomedical Engineering, Pennsylvania State University, University Park, Pennsylvania, USA
| | - Sang Y Lee
- Department of Neurosurgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Lindsay C Stetson
- Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Justin D Lathia
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Lerner Research Institute, Cleveland, Ohio, USA.,Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio, USA.,Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Joshua B Rubin
- Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Kristin A Waite
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.,Department of Population Health and Quantitative Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Michael E Berens
- Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona, USA
| | - Jill S Barnholtz-Sloan
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.,Department of Population Health and Quantitative Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - James R Connor
- Department of Neurosurgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
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Mitochondria regulation in ferroptosis. Eur J Cell Biol 2019; 99:151058. [PMID: 31810634 DOI: 10.1016/j.ejcb.2019.151058] [Citation(s) in RCA: 411] [Impact Index Per Article: 68.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 09/27/2019] [Accepted: 10/29/2019] [Indexed: 12/21/2022] Open
Abstract
Ferroptosis is recognized as a new form of regulated cell death which is initiated by severe lipid peroxidation relying on reactive oxygen species (ROS) generation and iron overload. This iron-dependent cell death manifests evident morphological, biochemical and genetic differences from other forms of regulated cell death, such as apoptosis, autophagy, necrosis and pyroptosis. Ferroptosis was primarily characterized by condensed mitochondrial membrane densities and smaller volume than normal mitochondria, as well as the diminished or vanished of mitochondria crista and outer membrane ruptured. Mitochondria take the center role in iron metabolism, as well as substance and energy metabolism as it's the major organelle in iron utilization, catabolic and anabolic pathways. Interference of key regulators of mitochondrial lipid metabolism (e.g., ASCF2 and CS), iron homeostasis (e.g., ferritin, mitoferrin1/2 and NEET proteins), glutamine metabolism and other signaling pathways make a difference to ferroptotic sensitivity. Targeted induction of ferroptosis was also considered as a potential therapeutic strategy to some oxidative stress diseases, including neurodegenerative disorders, ischemia-reperfusion injury, traumatic spinal cord injury. However, the pertinence between mitochondria and ferroptosis is still in dispute. Here we systematic elucidate the morphological characteristics and metabolic regulation of mitochondria in the regulation of ferroptosis.
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Kuang Y, Wang Q. Iron and lung cancer. Cancer Lett 2019; 464:56-61. [DOI: 10.1016/j.canlet.2019.08.007] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 07/18/2019] [Accepted: 08/15/2019] [Indexed: 01/10/2023]
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Iron homeostasis and iron-regulated ROS in cell death, senescence and human diseases. Biochim Biophys Acta Gen Subj 2019; 1863:1398-1409. [DOI: 10.1016/j.bbagen.2019.06.010] [Citation(s) in RCA: 345] [Impact Index Per Article: 57.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 06/17/2019] [Accepted: 06/18/2019] [Indexed: 01/10/2023]
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Can Serum Iron Concentrations in Early Healthy Pregnancy Be Risk Marker of Pregnancy-Induced Hypertension? Nutrients 2019; 11:nu11051086. [PMID: 31100832 PMCID: PMC6566422 DOI: 10.3390/nu11051086] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 05/10/2019] [Accepted: 05/13/2019] [Indexed: 12/17/2022] Open
Abstract
The aim of this study was to assess the relationship between serum iron concentrations in early healthy pregnancy and the risk of pregnancy-induced hypertension. The data comes from our prospective cohort study in which we recruited healthy women in week 10–14 of single pregnancy. We examined a study group (n = 121) consisting of women subsequently developing pregnancy-induced hypertension and a control group (n = 363) of matched women remaining normotensive. We measured iron concentrations in the serum collected in 10–14 gestational week, using the ICP-MS technique (mass spectrometry with inductively coupled plasma). The odds ratios of the disease (95% confidence intervals) for iron concentrations were assessed in multivariate logistic regression. We found that the mean microelement concentration was lower in the case group compared to normotensive controls (p = 0.011). Women in the lowest quartile of iron (≤801.20 µg/L) had a 2.19-fold increase in pregnancy-induced hypertension risk compared with women in the highest quartile (>1211.75 µg/L) (odds ratio (OR) = 2.19; 95% CI: 1.24–3.88; p = 0.007). This result was sustained after adjusted for all the accepted confounders. Women in the higher Q2 quartile (801.20–982.33 µg/L) had a 17% lower risk, compared with those in the highest quartile (OR = 0.83; 95% CI: 0.65–2.32; p = 0.519).
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