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Currie C, Bjerknes C, Nicol M, Kumar S, Framroze B. Assessing the potential for in vivo modulation of FTH1 gene expression with small peptides to restore and enhance androgen receptor pathway inhibition in prostate cancer. Cancer Biol Ther 2025; 26:2503417. [PMID: 40340699 PMCID: PMC12068333 DOI: 10.1080/15384047.2025.2503417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 03/21/2025] [Accepted: 04/30/2025] [Indexed: 05/10/2025] Open
Abstract
Increased levels of intratumoral free iron drive more aggressive behavior with the development of treatment resistance and spread in a range of cancers including prostate cancer (PCa). This phenotype is associated with an increase in TFRC expression and a decrease in FTH1, a profile supporting increased iron acquisition. In this study we investigated the anti-oncogenic effects of two small peptides (FT-002 and FT-005) that upregulate FTH1 expression and downregulate TFRC expression when combined with standard androgen receptor pathway inhibitors (ARPIs) in xenograft models of PCa in male athymic nude mice. The PC3 cell line was used to establish xenografts representing highly aggressive, androgen-resistant PCa and the LNCaP cell line as a model of androgen-sensitive PCa. Both peptides enhanced the anti-tumor efficacy of ARPI therapy. Efficacy was more marked with the combination of the second-generation APRI enzalutamide than the first-generation agent bicalutamide, a result consistent with known resistance mechanisms to different ARPI therapy. Further, the FT-peptide/enzalutamide combination drove tumor regression whereas enzalutamide monotherapy only slowed growth, even in the hormone-sensitive xenograft. The FT-002a-enzalutamide combination was more effective than FT-005 in reducing tumor mass and volume and modulating FTH1 and TFRC expression. The reversal by the peptides of this oncogenic expression pattern points to a reduction in the tumor free iron via increased iron storage in ferritin and a reduction in iron influx via the transferrin receptor. Peptide-mediated modulation of tumor iron metabolism may therefore offer a novel means to enhance ARPI efficacy and delay resistance in advanced prostate cancer.
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Affiliation(s)
- Crawford Currie
- Research & Development, HBC Immunology Inc, Menlo Park, CA, USA
| | | | - McKayla Nicol
- Research & Development, BioModels LLC, Waltham, MA, USA
| | - Sateesh Kumar
- Research & Development, Adgyl Lifesciences Ltd., Bengaluru, India
| | - Bomi Framroze
- Research & Development, HBC Immunology Inc, Menlo Park, CA, USA
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Zhao Y, Li G, Tian Z, Zhu M, Han S, Jin M, Huang Y, Li Y. Quantitative Estimation of Iron and Fat Content in Prostate Cancer by Multiparametric MRI and Its Application in Optimizing D'Amico Score. J Magn Reson Imaging 2025; 61:2223-2233. [PMID: 39529304 DOI: 10.1002/jmri.29661] [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: 08/20/2024] [Revised: 10/23/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND The risk of biochemical recurrence (BCR) in prostate cancer (PCa) is typically assessed using D'Amico score. However, iron and fat content in PCa are closely related to tumor cell proliferation and the risk of BCR may be estimated using multiparametric MRI (mpMRI). PURPOSE To noninvasively estimate fat and iron content in PCa and to evaluate their utility in enhancing D'Amico scores for predicting BCR in PCa patients. STUDY TYPE Prospective. SUBJECTS Forty-eight male patients in the BCR group (age 71.31 ± 5.74 years) and 27 male patients in the non-BCR group (age 70.3 ± 6.04 years). FIELD STRENGTH/SEQUENCE 3.0 T, Turbo-spin echo T2-weighted imaging, diffusion-weighted imaging (DWI), dynamic contrast-enhanced (DCE) imaging, Gradient echo Q-Dixon sequence. ASSESSMENT The mean fat fraction (FF) and T2* values of lesions were extracted from the FF map and the T2* map. Additionally, prostate volume, mean apparent diffusion coefficient (ADC) value, periprostatic fat thickness (PPFT), subcutaneous fat thickness (SFT), blood lipid content, pre- and post-operative prostate-specific antigen (PSA) values were collected. STATISTICAL TESTS Stepwise-COX regression analysis was employed to identify the significant predictors of BCR, which led to the construction of an improvement-adjusted (IA) model. Then the IA model as well as the D'Amico score were evaluated using C-index and time-dependent AUC, decision-curve analysis, and Kaplan-Meier curve. P < 0.05 was statistically significant. RESULTS Significant differences were observed in PSA, D'Amico score, ISUP grade, T2*, FF, and ADC values of the lesions in the BCR group compared with the non-BCR group. Mean T2*, FF, and ADC values of the lesions were screened to construct the IA model incorporated into the D'Amico score (IA Model: C-index = 0.749; AUC = 0.812; D'Amico score: C-index = 0.672; AUC = 0.723). DATA CONCLUSION This study demonstrated that mpMRI can quantitatively estimate fat and iron within PCa lesions. By integrating ADC, FF, and T2* values into the D'Amico score, the preoperative-risk assessment for BCR can be improved. EVIDENCE LEVEL 2 TECHNICAL EFFICACY: Stage 2.
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Affiliation(s)
- Yunshu Zhao
- Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Guangzheng Li
- Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Zhen Tian
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Mengying Zhu
- Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Shuting Han
- Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Minmin Jin
- Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yuhua Huang
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yonggang Li
- Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
- Institute of Medical Imaging, Soochow University, Suzhou, Jiangsu, China
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Luo S, Wu H, Xiao F, Yang T, Wang W, Du H, Su P. Association Between Heavy Metal Exposure and Central Nervous System Tumors: A Case-Control Study Using Single and Multi-Metal Models. TOXICS 2025; 13:92. [PMID: 39997910 PMCID: PMC11860643 DOI: 10.3390/toxics13020092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 01/13/2025] [Accepted: 01/22/2025] [Indexed: 02/26/2025]
Abstract
(1) Background: Neoplasms of the central nervous system (CNS) encompass a cluster of malignant diseases originating from tissues or structures within the CNS. Environmental factors, including heavy metals, may contribute to their development. Therefore, this research was to investigate the association between heavy metal exposure and CNS tumor susceptibility using single and muti-metal models. (2) Methods: 63 CNS tumor patients and 71 controls were included. Urine samples from the CNS tumor patients and controls were analyzed for 47 metals using inductively coupled plasma-mass spectrometry in this study. Statistical analyses included conditional Wilcoxon rank-sum tests, logistic regression, Least Absolute Shrinkage and Selection Operator (LASSO) regression, and Bayesian Kernel Machine Regression (BKMR). (3) Results: In the single metal model, higher levels of seventeen metals might be associated with a lower incidence of CNS tumor, while higher exposure levels of five metals are associated with a higher incidence of tumor. LASSO regression selected nine metals for further BKMR analysis. The joint effects showed decreased tumor risk with increased metal mixture concentration. The level of the metals Ge, As, Rb, Zr, and Sn may be related to the incidence of meningiomas and gliomas. (4) Conclusions: This study explored the association between various metals and CNS tumors, providing ideas for future prospective cohort studies and laboratory studies, and providing a foundation for new ideas in the prevention and treatment of CNS tumors.
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Affiliation(s)
- Sen Luo
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China;
| | - Haixia Wu
- Department of Nursing, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China;
| | - Fang Xiao
- Department of Orthopedics, Sichuan Provincial People’s Hospital, Chengdu 610072, China;
| | - Tianwen Yang
- Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning, The First Affiliated Hospital of Chongqing Medical and Pharmaceutical College, Chongqing 400060, China; (T.Y.); (W.W.)
| | - Wei Wang
- Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning, The First Affiliated Hospital of Chongqing Medical and Pharmaceutical College, Chongqing 400060, China; (T.Y.); (W.W.)
| | - Hang Du
- Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning, The First Affiliated Hospital of Chongqing Medical and Pharmaceutical College, Chongqing 400060, China; (T.Y.); (W.W.)
| | - Peng Su
- Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China;
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Shao W, Liu F, Zhu L, Qian W, Meng Q, Zhang A, Jin S, Lu J, Yan SG. Ferroportin inhibits the proliferation and migration of fibroblast-like synoviocytes in rheumatoid arthritis via regulating ROS/PI3K/AKT signaling pathway. Eur J Pharmacol 2025; 987:177205. [PMID: 39672225 DOI: 10.1016/j.ejphar.2024.177205] [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: 08/13/2024] [Revised: 12/11/2024] [Accepted: 12/11/2024] [Indexed: 12/15/2024]
Abstract
The aberrant proliferation of fibroblast-like synoviocytes (FLS) significantly contributes to excessive synovial hyperplasia and joint deformity in rheumatoid arthritis (RA). It has been observed that the membrane iron transporter protein, ferroportin (FPN), is commonly downregulated in tumor cells, while its overexpression can inhibit tumor cell proliferation. However, limited studies have investigated the role of iron in the pathogenesis of RA. In this study, we examined the functional relevance of FPN in RA. The expression of FPN in RA tissue specimens and primary cells was assessed using western blotting and RT-PCR. An adjuvant-induced arthritis (AIA) rat model was established to further validate the expression level of FPN. Phenotypic analysis of FLS cell proliferation was performed via CCK-8, clonogenic formation, and cell scratch assays. The involvement of membrane iron transporter proteins was analyzed through RNAseq and reactive oxygen species (ROS) detection. The results demonstrated decreased expression of FPN in the synovial tissue of RA patients compared to the normal group. Overexpression of FPN can inhibit RA-FLS proliferation and migration by suppressing the PI3K/AKT pathway, and this effect is associated with the elevation of ROS levels. Our findings suggest that the downregulation of FPN may contribute to the pathogenesis of RA, indicating a potential role of iron dysregulation in this disease, and FPN regulates the proliferation and migration of FLS by promoting the levels of ROS in FLS as well as suppressing the PI3K/AKT signaling pathway. These results suggest that FPN could be a potential target for alleviating joint damage in RA.
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Affiliation(s)
- Weiting Shao
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China; School of Life and Science, Anhui Medical University, Ministry of Education, Hefei, China
| | - Fanxiao Liu
- Department of Orthopaedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Lin Zhu
- School of Life and Science, Anhui Medical University, Ministry of Education, Hefei, China
| | - Weiyi Qian
- School of Life and Science, Anhui Medical University, Ministry of Education, Hefei, China
| | - Qianqian Meng
- School of Life and Science, Anhui Medical University, Ministry of Education, Hefei, China
| | - Afei Zhang
- School of Life and Science, Anhui Medical University, Ministry of Education, Hefei, China
| | - Shuai Jin
- School of Life and Science, Anhui Medical University, Ministry of Education, Hefei, China
| | - Jingtao Lu
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China; School of Life and Science, Anhui Medical University, Ministry of Education, Hefei, China.
| | - Shuang G Yan
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
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Ni Q, Yang H, Rao H, Zhang L, Xiong M, Han X, Deng B, Wang L, Chen J, Shi Y. The role of the C5a-C5aR pathway in iron metabolism and gastric cancer progression. Front Immunol 2025; 15:1522181. [PMID: 39850877 PMCID: PMC11754390 DOI: 10.3389/fimmu.2024.1522181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 12/23/2024] [Indexed: 01/25/2025] Open
Abstract
Gastric cancer continues to be a leading global health concern, with current therapeutic approaches requiring significant improvement. While the disruption of iron metabolism in the advancement of gastric cancer has been well-documented, the underlying regulatory mechanisms remain largely unexplored. Additionally, the complement C5a-C5aR pathway has been identified as a crucial factor in gastric cancer development. The impact of the complement system on iron metabolism and its role in gastric cancer progression is an area warranting further investigation. Our research demonstrates that the C5a-C5aR pathway promotes gastric cancer progression by enhancing iron acquisition in tumor cells through two mechanisms. First, it drives macrophage polarization toward the M2 phenotype, which has a strong iron-release capability. Second, it increases the expression of LCN2, a high-affinity iron-binding protein critical for iron export from tumor-associated macrophages, by activating endoplasmic reticulum stress in these cells. Both mechanisms facilitate the transfer of iron from macrophages to cancer cells, thereby promoting tumor cell proliferation. This study aims to elucidate the connection between the complement C5a-C5aR pathway and iron metabolism within the tumor microenvironment. Our data suggest a pivotal role of the C5a-C5aR pathway in tumor iron management, indicating that targeting its regulatory mechanisms may pave the way for future iron-targeted therapeutic approaches in cancer treatment.
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Affiliation(s)
- Qinxue Ni
- The First Affiliated Hospital of Army Military Medical University, Department of General Surgery, Chongqing, China
| | - Hong Yang
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Hang Rao
- The First Affiliated Hospital of Army Military Medical University, Department of General Surgery, Chongqing, China
| | - Liyong Zhang
- The First Affiliated Hospital of Army Military Medical University, Department of General Surgery, Chongqing, China
| | - Mengyuan Xiong
- The First Affiliated Hospital of Army Military Medical University, Department of General Surgery, Chongqing, China
| | - Xiao Han
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Boshao Deng
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Lulu Wang
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Jian Chen
- Department of Immunology, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yan Shi
- The First Affiliated Hospital of Army Military Medical University, Department of General Surgery, Chongqing, China
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6
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Mao Y, Xia Z, Xia W, Jiang P. Metabolic reprogramming, sensing, and cancer therapy. Cell Rep 2024; 43:115064. [PMID: 39671294 DOI: 10.1016/j.celrep.2024.115064] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 10/30/2024] [Accepted: 11/21/2024] [Indexed: 12/15/2024] Open
Abstract
The metabolic reprogramming of tumor cells is a crucial strategy for their survival and proliferation, involving tissue- and condition-dependent remodeling of certain metabolic pathways. While it has become increasingly clear that tumor cells integrate extracellular and intracellular signals to adapt and proliferate, nutrient and metabolite sensing also exert direct or indirect influences, although the underlying mechanisms remain incompletely understood. Furthermore, metabolic changes not only support the rapid growth and dissemination of tumor cells but also promote immune evasion by metabolically "educating" immune cells in the tumor microenvironment (TME). Recent studies have highlighted the profound impact of metabolic reprogramming on the TME and the potential of targeting metabolic pathways as a therapeutic strategy, with several enzyme inhibitors showing promising results in clinical trials. Thus, understanding how tumor cells alter their metabolic pathways and metabolically remodel the TME to support their survival and proliferation may offer new strategies for metabolic therapy and immunotherapy.
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Affiliation(s)
- Youxiang Mao
- State Key Laboratory of Molecular Oncology, School of Life Sciences, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China
| | - Ziyan Xia
- State Key Laboratory of Molecular Oncology, School of Life Sciences, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China
| | - Wenjun Xia
- State Key Laboratory of Molecular Oncology, School of Life Sciences, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China
| | - Peng Jiang
- State Key Laboratory of Molecular Oncology, School of Life Sciences, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China.
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7
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Frascatani R, Colella M, Monteleone G. Hepcidin Is a Valuable Therapeutic Target for Colorectal Cancer. Cancers (Basel) 2024; 16:4068. [PMID: 39682254 DOI: 10.3390/cancers16234068] [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: 11/13/2024] [Revised: 11/28/2024] [Accepted: 12/03/2024] [Indexed: 12/18/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most frequent neoplasms and a major cause of cancer death worldwide. Despite recent advances in treatment approaches, the prognosis of advanced CRC remains poor, thus indicating the necessity of more effective treatments for CRC patients. CRC cells produce high levels of hepcidin, a peptide hormone that binds to the membrane-bound ferroportin and promotes its internalization and degradation, thus sequestering iron into the cancer cells with the downstream effect of enhancing tumor growth. Additionally, CRC cell-expressed hepcidin prolongs cell survival and, by targeting both CD8+ T cells and myeloid cells, restrains the induction of an efficient immune response against tumor antigens. The greatest expression of hepcidin is found in patients with metastatic CRC, and CRC patients with high hepcidin content have a worse survival rate than those with low hepcidin content. In the present article, we review the data supporting the prominent role of hepcidin in colon tumorigenesis and discuss how hepcidin inhibitors can help treat CRC patients in the metastatic setting with particular regard to the impact of hepcidin modulation on immunotherapeutic outcomes.
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Affiliation(s)
- Rachele Frascatani
- Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Marco Colella
- Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Giovanni Monteleone
- Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy
- Gastroenterology Unit, Fondazione Policlinico "Tor Vergata", 00133 Rome, Italy
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8
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Dwivedi M, Jindal D, Jose S, Hasan S, Nayak P. Elements in trace amount with a significant role in human physiology: a tumor pathophysiological and diagnostic aspects. J Drug Target 2024; 32:270-286. [PMID: 38251986 DOI: 10.1080/1061186x.2024.2309572] [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: 09/12/2023] [Accepted: 01/09/2024] [Indexed: 01/23/2024]
Abstract
Cancer has a devastating impact globally regardless of gender, age, and community, which continues its severity to the population due to the lack of efficient strategy for the cancer diagnosis and treatment. According to the World Health Organisation report, one out of six people dies due to this deadly cancer and we need effective strategies to regulate it. In this context, trace element has a very hidden and unexplored role and require more attention from investigators. The variation in concentration of trace elements was observed during comparative studies on a cancer patient and a healthy person making them an effective target for cancer regulation. The percentage of trace elements present in the human body depends on environmental exposure, food habits, and habitats and could be instrumental in the early diagnosis of cancer. In this review, we have conducted inclusive analytics on trace elements associated with the various types of cancers and explored the several methods involved in their analysis. Further, intricacies in the correlation of trace elements with prominent cancers like prostate cancer, breast cancer, and leukaemia are represented in this review. This comprehensive information on trace elements proposes their role during cancer and as biomarkers in cancer diagnosis.
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Affiliation(s)
- Manish Dwivedi
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow, India
- Research Cell, Amity University Uttar Pradesh, Lucknow, India
| | - Divya Jindal
- Department of Biotechnology, Center for Emerging Diseases, Jaypee Institute of Information Technology, Noida, India
| | - Sandra Jose
- MET's School of Engineering, Thrissur, India
| | - Saba Hasan
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow, India
| | - Pradeep Nayak
- Department of Physics, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, India
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Wei B, Liu W, Jin L, Huang Y, Cheng W, Fan H, Su S, Jin F, Zhang X, Yang Z, Liang S, Li L, Wu Y, Liu Y, Duan C, Li X. Hepcidin depending on astrocytic NEO1 ameliorates blood-brain barrier dysfunction after subarachnoid hemorrhage. Cell Death Dis 2024; 15:569. [PMID: 39107268 PMCID: PMC11303805 DOI: 10.1038/s41419-024-06909-x] [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: 04/05/2024] [Revised: 07/03/2024] [Accepted: 07/10/2024] [Indexed: 08/09/2024]
Abstract
Subarachnoid hemorrhage (SAH) significantly compromises the blood-brain barrier (BBB) and impairs patient recovery. This study elucidates the critical role of astrocytic Neogenin-1 (NEO1) in BBB integrity post-SAH and examines the regulatory effects of hepcidin on endothelial cell (EC) function amid NEO1-mediated disruptions in iron homeostasis. Proteomic analyses of cerebrospinal fluid (CSF) from SAH patients revealed a substantial decrease in NEO1 expression, identifying it as a key factor in BBB integrity. 111 CSF proteins were significantly reduced in early SAH stages (days 1-3), with NEO1 among the most significantly altered. This dysregulation was linked to poorer patient outcomes, as indicated by a negative correlation between NEO1 levels and Modified Rankin Scale scores six months post-SAH (R = -0.4743, P < 0.0001). Experimental models further highlighted the importance of NEO1: SAH model and NEO1GFAP-Cre mice exhibited exacerbated EC dysfunction and increased BBB permeability, evidenced by significant Evans Blue retention and dextran leakage in the parietal cortex, effects that were mitigated by hepcidin administration. Our findings highlight the complex interplay between astrocytic signaling and endothelial function in SAH pathophysiology. The loss of astrocytic NEO1 led to increased EC proliferation and altered BBB structure, as confirmed by transmission electron microscopy and immunostaining for PECAM-1, indicating heightened blood vessel density in the affected cortex. Hepcidin treatment effectively reversed the EC dysfunction and BBB disruption in both NEO1-cKO mice and the SAH model, highlighting its potential as a therapeutic agent to enhance recovery and improve prognosis following SAH.
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Affiliation(s)
- Boyang Wei
- Neurosurgery Center, Department of Cerebrovascular Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Wenchao Liu
- Neurosurgery Center, Department of Cerebrovascular Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Lei Jin
- Neurosurgery Center, Department of Cerebrovascular Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Yaxian Huang
- Neurosurgery Center, Department of Cerebrovascular Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Wenping Cheng
- Neurosurgery Center, Department of Cerebrovascular Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Haiyan Fan
- Neurosurgery Center, Department of Cerebrovascular Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Shixing Su
- Neurosurgery Center, Department of Cerebrovascular Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Fa Jin
- Neurosurgery Center, Department of Cerebrovascular Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Xin Zhang
- Neurosurgery Center, Department of Cerebrovascular Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Zeyu Yang
- School of Materials Science and Engineering, Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-sen University, Guangzhou, 510275, China
| | - Shuyin Liang
- Neurosurgery Center, Department of Cerebrovascular Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Longxiang Li
- Neurosurgery Center, Department of Cerebrovascular Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Yu Wu
- Neurosurgery Center, Department of Cerebrovascular Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
| | - Yanchao Liu
- Neurosurgery Center, Department of Cerebrovascular Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
| | - Chuanzhi Duan
- Neurosurgery Center, Department of Cerebrovascular Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
| | - Xifeng Li
- Neurosurgery Center, Department of Cerebrovascular Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
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Azur RAG, Olarte KCV, Ybañez WS, Ocampo AMM, Bagamasbad PD. CYB561 supports the neuroendocrine phenotype in castration-resistant prostate cancer. PLoS One 2024; 19:e0300413. [PMID: 38739593 PMCID: PMC11090301 DOI: 10.1371/journal.pone.0300413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 03/08/2024] [Indexed: 05/16/2024] Open
Abstract
Castration-resistant prostate cancer (CRPC) is associated with resistance to androgen deprivation therapy, and an increase in the population of neuroendocrine (NE) differentiated cells. It is hypothesized that NE differentiated cells secrete neuropeptides that support androgen-independent tumor growth and induce aggressiveness of adjacent proliferating tumor cells through a paracrine mechanism. The cytochrome b561 (CYB561) gene, which codes for a secretory vesicle transmembrane protein, is constitutively expressed in NE cells and highly expressed in CRPC. CYB561 is involved in the α-amidation-dependent activation of neuropeptides, and contributes to regulating iron metabolism which is often dysregulated in cancer. These findings led us to hypothesize that CYB561 may be a key player in the NE differentiation process that drives the progression and maintenance of the highly aggressive NE phenotype in CRPC. In our study, we found that CYB561 expression is upregulated in metastatic and NE prostate cancer (NEPC) tumors and cell lines compared to normal prostate epithelia, and that its expression is independent of androgen regulation. Knockdown of CYB561 in androgen-deprived LNCaP cells dampened NE differentiation potential and transdifferentiation-induced increase in iron levels. In NEPC PC-3 cells, depletion of CYB561 reduced the secretion of growth-promoting factors, lowered intracellular ferrous iron concentration, and mitigated the highly aggressive nature of these cells in complementary assays for cancer hallmarks. These findings demonstrate the role of CYB561 in facilitating transdifferentiation and maintenance of NE phenotype in CRPC through its involvement in neuropeptide biosynthesis and iron metabolism pathways.
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Affiliation(s)
- Romie Angelo G. Azur
- National Institute of Molecular Biology and Biotechnology, University of the Philippines Diliman, Quezon City, Philippines
| | - Kevin Christian V. Olarte
- National Institute of Molecular Biology and Biotechnology, University of the Philippines Diliman, Quezon City, Philippines
| | - Weand S. Ybañez
- National Institute of Molecular Biology and Biotechnology, University of the Philippines Diliman, Quezon City, Philippines
| | - Alessandria Maeve M. Ocampo
- National Institute of Molecular Biology and Biotechnology, University of the Philippines Diliman, Quezon City, Philippines
| | - Pia D. Bagamasbad
- National Institute of Molecular Biology and Biotechnology, University of the Philippines Diliman, Quezon City, Philippines
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11
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Feng J, Wang ZX, Bin JL, Chen YX, Ma J, Deng JH, Huang XW, Zhou J, Lu GD. Pharmacological approaches for targeting lysosomes to induce ferroptotic cell death in cancer. Cancer Lett 2024; 587:216728. [PMID: 38431036 DOI: 10.1016/j.canlet.2024.216728] [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: 11/30/2023] [Revised: 01/25/2024] [Accepted: 02/10/2024] [Indexed: 03/05/2024]
Abstract
Lysosomes are crucial organelles responsible for the degradation of cytosolic materials and bulky organelles, thereby facilitating nutrient recycling and cell survival. However, lysosome also acts as an executioner of cell death, including ferroptosis, a distinctive form of regulated cell death that hinges on iron-dependent phospholipid peroxidation. The initiation of ferroptosis necessitates three key components: substrates (membrane phospholipids enriched with polyunsaturated fatty acids), triggers (redox-active irons), and compromised defence mechanisms (GPX4-dependent and -independent antioxidant systems). Notably, iron assumes a pivotal role in ferroptotic cell death, particularly in the context of cancer, where iron and oncogenic signaling pathways reciprocally reinforce each other. Given the lysosomes' central role in iron metabolism, various strategies have been devised to harness lysosome-mediated iron metabolism to induce ferroptosis. These include the re-mobilization of iron from intracellular storage sites such as ferritin complex and mitochondria through ferritinophagy and mitophagy, respectively. Additionally, transcriptional regulation of lysosomal and autophagy genes by TFEB enhances lysosomal function. Moreover, the induction of lysosomal iron overload can lead to lysosomal membrane permeabilization and subsequent cell death. Extensive screening and individually studies have explored pharmacological interventions using clinically available drugs and phytochemical agents. Furthermore, a drug delivery system involving ferritin-coated nanoparticles has been specifically tailored to target cancer cells overexpressing TFRC. With the rapid advancements in understandings the mechanistic underpinnings of ferroptosis and iron metabolism, it is increasingly evident that lysosomes represent a promising target for inducing ferroptosis and combating cancer.
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Affiliation(s)
- Ji Feng
- School of Public Health, Fudan University, Shanghai, 200032, PR China; Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi Province, 530021, PR China
| | - Zi-Xuan Wang
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi Province, 530021, PR China; School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, PR China
| | - Jin-Lian Bin
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi Province, 530021, PR China
| | - Yong-Xin Chen
- Department of Physiology, School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi Province, 530021, PR China; Department of Physiology, School of Preclinical Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi Province, 530200, PR China
| | - Jing Ma
- Department of Physiology, School of Preclinical Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi Province, 530200, PR China
| | - Jing-Huan Deng
- Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, School of Public Health, Guangxi Medical University, Nanning, Guangxi, 530021, PR China
| | - Xiao-Wei Huang
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning, Guangxi Province, 530021, PR China
| | - Jing Zhou
- Department of Physiology, School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi Province, 530021, PR China.
| | - Guo-Dong Lu
- School of Public Health, Fudan University, Shanghai, 200032, PR China; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Guangxi Key Laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Nanning, Guangxi Province, 530021, PR China.
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12
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Zhang YY, Han Y, Li WN, Xu RH, Ju HQ. Tumor iron homeostasis and immune regulation. Trends Pharmacol Sci 2024; 45:145-156. [PMID: 38212195 DOI: 10.1016/j.tips.2023.12.003] [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: 11/30/2023] [Revised: 12/13/2023] [Accepted: 12/14/2023] [Indexed: 01/13/2024]
Abstract
Abnormal iron metabolism has long been regarded as a key metabolic hallmark of cancer. As a critical cofactor, iron contributes to tumor progression by participating in various processes such as mitochondrial electron transport, gene regulation, and DNA synthesis or repair. Although the role of iron in tumor cells has been widely studied, recent studies have uncovered the interplay of iron metabolism between tumor cells and immune cells, which may affect both innate and adaptive immune responses. In this review, we discuss the current understanding of the regulatory networks of iron metabolism between cancer cells and immune cells and how they contribute to antitumor immunity, and we analyze potential therapeutics targeting iron metabolism. Also, we highlight several key challenges and describe potential therapeutic approaches for future investigations.
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Affiliation(s)
- Yan-Yu Zhang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Sun Yat-sen University, Guangzhou 510060, P. R. China
| | - Yi Han
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Sun Yat-sen University, Guangzhou 510060, P. R. China
| | - Wen-Ning Li
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Sun Yat-sen University, Guangzhou 510060, P. R. China
| | - Rui-Hua Xu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Sun Yat-sen University, Guangzhou 510060, P. R. China.
| | - Huai-Qiang Ju
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Sun Yat-sen University, Guangzhou 510060, P. R. China.
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13
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Gong H, Li Z, Wu Z, Lian G, Su Z. Modulation of ferroptosis by non‑coding RNAs in cancers: Potential biomarkers for cancer diagnose and therapy. Pathol Res Pract 2024; 253:155042. [PMID: 38184963 DOI: 10.1016/j.prp.2023.155042] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/14/2023] [Accepted: 12/16/2023] [Indexed: 01/09/2024]
Abstract
Ferroptosis is a recently discovered cell programmed death. Extensive researches have indicated that ferroptosis plays an essential role in tumorigenesis, development, migration and chemotherapy drugs resistance, which makes it become a new target for tumor therapy. Non-coding RNAs (ncRNAs) are considered to control a wide range of cellular processes by modulating gene expression. Recent studies have indicated that ncRNAs regulate the process of ferroptosis via various pathway to affect the development of cancer. However, the regulation network remains ambiguous. In this review, we outlined the major metabolic processes of ferroptosis and concluded the relationship between ferroptosis-related ncRNAs and cancer progression. In addition, the prospect of ncRNAs being new therapeutic targets and early diagnosis biomarkers for cancer by regulating ferroptosis were presented, and the possible obstacles were also predicted. This could help in discovering novel cancer early diagnostic methods and therapeutic approaches.
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Affiliation(s)
- Huifang Gong
- Department of Biochemistry and Molecular Biology, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Zheng Li
- Department of Biochemistry and Molecular Biology, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Zhimin Wu
- Department of Biochemistry and Molecular Biology, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Gaojian Lian
- Department of Biochemistry and Molecular Biology, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
| | - Zehong Su
- Department of Biochemistry and Molecular Biology, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
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14
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Izumi Y, Kataoka H, Koshiba A, Ito F, Tanaka Y, Takaoka O, Maeda E, Okimura H, Sugahara T, Tarumi Y, Shimura K, Khan KN, Kusuki I, Mori T. Hepcidin as a key regulator of iron homeostasis triggers inflammatory features in the normal endometrium. Free Radic Biol Med 2023; 209:191-201. [PMID: 37884101 DOI: 10.1016/j.freeradbiomed.2023.10.402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 10/13/2023] [Accepted: 10/22/2023] [Indexed: 10/28/2023]
Abstract
Menstrual blood, containing high iron levels, can undergo retrograde transport into the abdominal cavity. Excess iron causes oxidative stress and inflammation. Iron metabolism is regulated by hepcidin, and serum hepcidin levels are increased in patients with endometriosis; however, the functions of hepcidin in normal endometrium remain unclear. We therefore aimed to examine hepcidin concentrations in patients with endometriosis and to determine if iron accumulation and hepcidin increased the production of reactive oxygen species (ROS) and inflammation in normal endometrial cells. We determined hepcidin levels in peritoneal fluid and menstrual blood from patients with and without endometriosis (25/16 and 15/15 patients, respectively). We also examined the effects of hepcidin on ferroportin expression, iron accumulation, and ROS generation in normal endometrial stromal cells (NESCs) from 20 women who underwent surgery for uterine leiomyoma, using immunohistochemistry and immunofluorescence analyses and analyzed its effect on the expression of inflammatory cytokines by real-time polymerase chain reaction. There was no significant difference in iron concentrations in menstrual blood or peritoneal fluid between women with and without endometriosis; however, women with endometriosis had significantly higher hepcidin levels in menstrual blood. Hepcidin reduced the expression of ferroportin in NESCs and promoted the accumulation of ferrous iron. Hepcidin plus ferrous iron increased the production of ROS and inflammatory cytokines compared with ferrous iron alone. These results indicate that women with endometriosis have high hepcidin levels in menstrual blood, leading to increased iron production, oxidative stress, and inflammation, which may, in turn, promote the development of endometriosis.
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Affiliation(s)
- Yuko Izumi
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan
| | - Hisashi Kataoka
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan.
| | - Akemi Koshiba
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan
| | - Fumitake Ito
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan
| | - Yukiko Tanaka
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan
| | - Osamu Takaoka
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan
| | - Eiko Maeda
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan
| | - Hiroyuki Okimura
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan
| | - Takuya Sugahara
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan
| | - Yosuke Tarumi
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan
| | - Koki Shimura
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan
| | - Khaleque N Khan
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan
| | - Izumi Kusuki
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan
| | - Taisuke Mori
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan
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15
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Bartolomé RA, Martín-Regalado Á, Pintado-Berninches L, Robles J, Ramírez-González MÁ, Boukich I, Sanchez-Gómez P, Balyasnikova IV, Casal JI. Schnurri-3 drives tumor growth and invasion in cancer cells expressing interleukin-13 receptor alpha 2. Cell Death Dis 2023; 14:742. [PMID: 37963919 PMCID: PMC10645886 DOI: 10.1038/s41419-023-06255-4] [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: 03/14/2023] [Revised: 10/23/2023] [Accepted: 10/30/2023] [Indexed: 11/16/2023]
Abstract
Interleukin 13 receptor alpha 2 (IL13Rα2) is a relevant therapeutic target in glioblastoma (GBM) and other tumors associated with tumor growth and invasion. In a previous study, we demonstrated that protein tyrosine phosphatase 1B (PTP1B) is a key mediator of the IL-13/IL13Rα2 signaling pathway. PTP1B regulates cancer cell invasion through Src activation. However, PTP1B/Src downstream signaling mechanisms that modulate the invasion process remain unclear. In the present research, we have characterized the PTP1B interactome and the PTP1B-associated phosphoproteome after IL-13 treatment, in different cellular contexts, using proteomic strategies. PTP1B was associated with proteins involved in signal transduction, vesicle transport, and with multiple proteins from the NF-κB signaling pathway, including Tenascin-C (TNC). PTP1B participated with NF-κB in TNC-mediated proliferation and invasion. Analysis of the phosphorylation patterns obtained after PTP1B activation with IL-13 showed increased phosphorylation of the transcription factor Schnurri-3 (SHN3), a reported competitor of NF-κB. SHN3 silencing caused a potent inhibition in cell invasion and proliferation, associated with a down-regulation of the Wnt/β-catenin pathway, an extensive decline of MMP9 expression and the subsequent inhibition of tumor growth and metastasis in mouse models. Regarding clinical value, high expression of SHN3 was associated with poor survival in GBM, showing a significant correlation with the classical and mesenchymal subtypes. In CRC, SHN3 expression showed a preferential association with the mesenchymal subtypes CMS4 and CRIS-B. Moreover, SHN3 expression strongly correlated with IL13Rα2 and MMP9-associated poor prognosis in different cancers. In conclusion, we have uncovered the participation of SNH3 in the IL-13/IL13Rα2/PTP1B pathway to promote tumor growth and invasion. These findings support a potential therapeutic value for SHN3.
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Affiliation(s)
- Rubén A Bartolomé
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.
| | - Ángela Martín-Regalado
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain
| | - Laura Pintado-Berninches
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain
- Universidad Autónoma de Madrid. Cantoblanco, Madrid, Spain
| | - Javier Robles
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain
- Protein Alternatives SL. Tres Cantos, Madrid, Spain
| | | | - Issam Boukich
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain
- Protein Alternatives SL. Tres Cantos, Madrid, Spain
| | - Pilar Sanchez-Gómez
- Unidad Funcional de Investigación en Enfermedades Crónicas. Instituto de Salud Carlos III, Madrid, Spain
| | - Irina V Balyasnikova
- Department of Neurological Surgery, Northwestern University, Chicago, IL, USA
- Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - J Ignacio Casal
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas (CIB-CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.
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16
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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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Nguyen NT, Jaramillo-Martinez V, Mathew M, Suresh VV, Sivaprakasam S, Bhutia YD, Ganapathy V. Sigma Receptors: Novel Regulators of Iron/Heme Homeostasis and Ferroptosis. Int J Mol Sci 2023; 24:14672. [PMID: 37834119 PMCID: PMC10572259 DOI: 10.3390/ijms241914672] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 09/13/2023] [Accepted: 09/20/2023] [Indexed: 10/15/2023] Open
Abstract
Sigma receptors are non-opiate/non-phencyclidine receptors that bind progesterone and/or heme and also several unrelated xenobiotics/chemicals. They reside in the plasma membrane and in the membranes of the endoplasmic reticulum, mitochondria, and nucleus. Until recently, the biology/pharmacology of these proteins focused primarily on their role in neuronal functions in the brain/retina. However, there have been recent developments in the field with the discovery of unexpected roles for these proteins in iron/heme homeostasis. Sigma receptor 1 (S1R) regulates the oxidative stress-related transcription factor NRF2 and protects against ferroptosis, an iron-induced cell death process. Sigma receptor 2 (S2R), which is structurally unrelated to S1R, complexes with progesterone receptor membrane components PGRMC1 and PGRMC2. S2R, PGRMC1, and PGRMC2, either independently or as protein-protein complexes, elicit a multitude of effects with a profound influence on iron/heme homeostasis. This includes the regulation of the secretion of the iron-regulatory hormone hepcidin, the modulation of the activity of mitochondrial ferrochelatase, which catalyzes iron incorporation into protoporphyrin IX to form heme, chaperoning heme to specific hemoproteins thereby influencing their biological activity and stability, and protection against ferroptosis. Consequently, S1R, S2R, PGRMC1, and PGRMC2 potentiate disease progression in hemochromatosis and cancer. These new discoveries usher this intriguing group of non-traditional progesterone receptors into an unchartered territory in biology and medicine.
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Affiliation(s)
| | | | | | | | | | | | - Vadivel Ganapathy
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; (N.T.N.); (V.J.-M.); (M.M.); (V.V.S.); (S.S.); (Y.D.B.)
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18
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Militaru FC, Militaru V, Crisan N, Bocsan IC, Udrea AA, Catana A, Kutasi E, Militaru MS. Molecular basis and therapeutic targets in prostate cancer: A comprehensive review. BIOMOLECULES & BIOMEDICINE 2023; 23:760-771. [PMID: 37021836 PMCID: PMC10494850 DOI: 10.17305/bb.2023.8782] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 03/29/2023] [Accepted: 03/29/2023] [Indexed: 04/07/2023]
Abstract
Prostate cancer is one of the most significant causes of morbidity and mortality in male patients. The incidence increases with age, and it is higher among African Americans. The occurrence of prostate cancer is associated with many risk factors, including genetic and hereditary predisposition. The most common genetic syndromes associated with prostate cancer risk are BRCA-associated hereditary breast and ovarian cancer (HBOC) and Lynch syndrome. Local-regional therapy, i.e., surgery is beneficial in early-stage prostate cancer management. Advanced and metastatic prostate cancers require systemic therapies, including hormonal inhibition, chemotherapy, and targeted agents. Most prostate cancers can be treated by targeting the androgen-receptor pathway and decreasing androgen production or binding to androgen receptors (AR). Castration-resistant prostate cancer (CRPC) usually involves the PI3K/AKT/mTOR pathway and requires targeted therapy. Specific molecular therapy can target mutated cell lines in which DNA defect repair is altered, caused by mutations of BRCA2, partner and localizer of BRCA2 (PALB2), and phosphatase and tensin homolog (PTEN) or the transmembrane protease serine 2-ERG (TMPRSS2-ERG) fusion. Most benefits were demonstrated in cyclin dependent-kinase 12 (CDK12) mutated cell lines when treated with anti-programmed cell death protein 1 (PD1) therapy. Therapies targeting p53 and AKT are the subject of ongoing clinical trials. Many genetic defects are listed as diagnostic, prognostic, and clinically actionable markers in prostate cancer. Androgen receptor splice variant 7 (AR-V7) is an important oncogenic driver and an early diagnostic and prognostic marker, as well as a therapeutic target in hormone-resistant CRPC. This review summarizes the pathophysiological mechanisms and available targeted therapies for prostate cancer.
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Affiliation(s)
- Florentina Claudia Militaru
- Department of Pharmacology, Toxicology and Clinical Pharmacology, University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Medisprof Cancer Center, Cluj-Napoca, Romania
| | - Valentin Militaru
- Medisprof Cancer Center, Cluj-Napoca, Romania
- Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Clinical County Hospital, Cluj-Napoca, Romania
| | - Nicolae Crisan
- Department of Urology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ioana Corina Bocsan
- Department of Pharmacology, Toxicology and Clinical Pharmacology, University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | | | - Andreea Catana
- Department of Molecular Sciences, Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Institute of Oncology I. Chiricuta, Cluj-Napoca, Romania
| | - Eniko Kutasi
- Department of Molecular Sciences, Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Mariela Sanda Militaru
- Department of Molecular Sciences, Medical Genetics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
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19
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Osmola M, Gierej B, Mleczko-Sanecka K, Jończy A, Ciepiela O, Kraj L, Ziarkiewicz-Wróblewska B, Basak GW. Anemia, Iron Deficiency, and Iron Regulators in Pancreatic Ductal Adenocarcinoma Patients: A Comprehensive Analysis. Curr Oncol 2023; 30:7722-7739. [PMID: 37623041 PMCID: PMC10453218 DOI: 10.3390/curroncol30080560] [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: 07/28/2023] [Revised: 08/14/2023] [Accepted: 08/16/2023] [Indexed: 08/26/2023] Open
Abstract
Anemia and iron deficiency (ID) are common complications in patients with pancreatic ductal adenocarcinoma (PDAC), but their underlying causes remain unclear. This study investigated the incidence and characteristics of anemia and micronutrient deficiencies in PDAC patients before initiating chemotherapy. A total of 103 PDAC patients were included, comprising 67 in the palliative and 36 in the adjuvant groups. The overall incidence of anemia was 42.7% (n = 44), with comparable rates in both groups. Normocytic and normochromic anemia were predominant, with mild and moderate cases observed in 32% and 10.7% of the cohort, respectively. ID was evident in 51.4% of patients, with absolute ID more frequent in the adjuvant than in the palliative group (19.4% vs. 13.4%). Functional ID occurred more often in the palliative than in the adjuvant group (41.8% vs. 25%). Vitamin B12 and folate deficiency occurred in <5% (n = 5) of patients. Furthermore, 8.7% (n = 9) of patients had chronic kidney disease and anemia. To elucidate mechanisms of iron deficiency, the study explored the expression of iron regulators (hepcidin (HEP), ferroportin (FPN), and ZIP14 protein) and mitochondrial mass in PDAC tissue with immunohistochemical (IHC) staining and Perl's Prussian blue to detect iron deposits on available tumor samples (n = 56). ZIP14 expression was significantly higher in less advanced tumors (p = 0.01) and correlated with mitochondrial mass (p < 0.001), potentially indicating its role in local iron homeostasis. However, no significant impact of tissue iron regulators on patient survival was observed. Perl's Prussian blue staining revealed iron deposits within macrophages, but not in pancreatic duct cells. Furthermore, the GEPIA database was used to compare mRNA expression of iron regulators (HEP, FPN, and ZIP14) and other genes encoding iron transport and storage, including Transferrin Receptor Protein 1 (TfR1) and both ferritin chain subunits (FTH and FTL), in PDAC and normal pancreatic samples. FPN, TfR1, FTH, and FTL showed higher expression in tumor tissues, indicating increased iron usage by cancer. ZIP14 expression was higher in the pancreas than in PDAC and was correlated with FPN expression. The study highlights the importance of baseline iron status assessment in managing PDAC patients due to the high incidence of anemia and iron deficiency. Furthermore, ZIP14, in addition to HEP and FPN, may play a crucial role in local iron homeostasis in PDAC patients, providing valuable insights into the underlying mechanisms of iron dysregulation.
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Affiliation(s)
- Malgorzata Osmola
- Department of Hematology, Transplantation, and Internal Medicine, University Clinical Centre, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Beata Gierej
- Department of Pathology, University Clinical Centre, Medical University of Warsaw, 02-097 Warsaw, Poland; (B.G.)
- Department of Pathology and Laboratory Medicine, Maria Skłodowska-Curie National Oncology Research Institute, 02-781 Warsaw, Poland
| | | | - Aneta Jończy
- International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland
| | - Olga Ciepiela
- Department of Laboratory Medicine, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Leszek Kraj
- Department of Oncology, University Clinical Centre, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Bogna Ziarkiewicz-Wróblewska
- Department of Pathology, University Clinical Centre, Medical University of Warsaw, 02-097 Warsaw, Poland; (B.G.)
| | - Grzegorz Władysław Basak
- Department of Hematology, Transplantation, and Internal Medicine, University Clinical Centre, Medical University of Warsaw, 02-097 Warsaw, Poland
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Wu H, Dong H, Ren S, Chen J, Zhang Y, Dai M, Wu Y, Zhang X. Exploration of novel clusters and prognostic value of immune‑related signatures and identify HAMP as hub gene in colorectal cancer. Oncol Lett 2023; 26:360. [PMID: 37545621 PMCID: PMC10398624 DOI: 10.3892/ol.2023.13946] [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: 02/02/2023] [Accepted: 05/31/2023] [Indexed: 08/08/2023] Open
Abstract
Immune checkpoint inhibitors currently serve an important role in prolonging patients' overall survival. However, the prognostic signatures of immune checkpoint inhibitors in colorectal cancer (CRC) remain uncertain and more knowledge on the genetic characteristics of colorectal cancer is needed. Patients with CRC from The Cancer Genome Atlas were classified into high-immunity group and low-immunity group based on median scores from single-sample gene set enrichment analysis using the GSVA package. We explored immune status by immune scores, stromal scores and tumor purity scores in ESTIMATE package and surveyed the difference of immune cells distribution with CIBERSORT package. Eighteen genes were selected using the LASSO Cox regression method and a prognostic risk model was constructed. Compared with patients in the low-risk group, those in the high-risk group had a significantly shorter survival time. For assessment of the prognostic validity of the risk model, receiver operating characteristic curves with areas under the curve of 0.769, 0.774 and 0.771 for 1, 3 and 5 years respectively. Differences in molecular mechanisms between high- and low-risk groups were analyzed using the clusterProfiler package. Tumor Immune Dysfunction and Exclusion data were downloaded and analyzed. The top 5 enriched pathways in the high-risk group involved 'calcium signaling', 'dilated cardiomyopathy', 'extracellular matrix receptor interaction', 'hypertrophic cardiomyopathy' and 'neuroactive ligand receptor interaction'. HAMP was identified as a hub gene, which was highly expressed in tumor samples. The results of the present study indicate that the prognostic model based on both immune-related genes and HAMP has the potential to support personalized treatment.
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Affiliation(s)
- Hongyuan Wu
- Department of Radiation Oncology, Affiliated Dongguan People's Hospital of Southern Medical University, Dongguan, Guangdong 523009, P.R. China
- Dongguan Key Laboratory of Precision Diagnosis and Treatment for Tumors, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital of Southern Medical University, Dongguan, Guangdong 523009, P.R. China
| | - Heling Dong
- School of Sports Education, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Shaofang Ren
- State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Jianxin Chen
- Department of General Surgery, Affiliated Dongguan People's Hospital of Southern Medical University, Dongguan, Guangdong 523009, P.R. China
| | - Yan Zhang
- Department of Radiation Oncology, Affiliated Dongguan People's Hospital of Southern Medical University, Dongguan, Guangdong 523009, P.R. China
| | - Meng Dai
- Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Yinfen Wu
- Department of Oncology, Affiliated Dongguan People's Hospital of Southern Medical University, Dongguan, Guangdong 523009, P.R. China
| | - Xuefang Zhang
- Department of Radiation Oncology, Affiliated Dongguan People's Hospital of Southern Medical University, Dongguan, Guangdong 523009, P.R. China
- Dongguan Key Laboratory of Precision Diagnosis and Treatment for Tumors, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital of Southern Medical University, Dongguan, Guangdong 523009, P.R. China
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21
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Formica V, Riondino S, Morelli C, Guerriero S, D'Amore F, Di Grazia A, Del Vecchio Blanco G, Sica G, Arkenau HT, Monteleone G, Roselli M. HIF2α, Hepcidin and their crosstalk as tumour-promoting signalling. Br J Cancer 2023; 129:222-236. [PMID: 37081189 PMCID: PMC10338631 DOI: 10.1038/s41416-023-02266-2] [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: 10/20/2022] [Revised: 03/25/2023] [Accepted: 03/30/2023] [Indexed: 04/22/2023] Open
Abstract
Not all aspects of the disruption of iron homeostasis in cancer have been fully elucidated. Iron accumulation in cancer cells is frequent for many solid tumours, and this is often accompanied by the contemporary rise of two key iron regulators, HIF2α and Hepcidin. This scenario is different from what happens under physiological conditions, where Hepcidin parallels systemic iron concentrations while HIF2α levels are inversely associated to Hepcidin. The present review highlights the increasing body of evidence for the pro-tumoral effect of HIF2α and Hepcidin, discusses the possible imbalance in HIF2α, Hepcidin and iron homeostasis during cancer, and explores therapeutic options relying on these pathways as anticancer strategies.
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Affiliation(s)
- Vincenzo Formica
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy.
| | - Silvia Riondino
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
| | - Cristina Morelli
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
- PhD Program in Systems and Experimental Medicine (XXXV cycle), University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy
| | - Simona Guerriero
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
| | - Federica D'Amore
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
| | - Antonio Di Grazia
- Gastroenterology Unit, Department of Systems Medicine, University of Rome Tor Vergata, 00133, Rome, Italy
| | | | - Giuseppe Sica
- Department of Surgery, University of Rome Tor Vergata, Rome, Italy
| | | | - Giovanni Monteleone
- Gastroenterology Unit, Department of Systems Medicine, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Mario Roselli
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
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22
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Crescenzi E, Leonardi A, Pacifico F. Iron Metabolism in Cancer and Senescence: A Cellular Perspective. BIOLOGY 2023; 12:989. [PMID: 37508419 PMCID: PMC10376531 DOI: 10.3390/biology12070989] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/06/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023]
Abstract
Iron participates in a number of biological processes and plays a crucial role in cellular homeostasis. Alterations in iron metabolism are considered hallmarks of cancer and drivers of aggressive behaviors, such as uncontrolled proliferation, resistance to apoptosis, enhanced metastatic ability, increased cell plasticity and stemness. Furthermore, a dysregulated iron metabolism has been associated with the development of an adverse tumor microenvironment. Alterations in iron metabolism have been described in cellular senescence and in aging. For instance, iron has been shown to accumulate in aged tissues and in age-related diseases. Furthermore, in vitro studies demonstrate increases in iron content in both replicative and stress-induced senescent cells. However, the role, the mechanisms of regulation and dysregulation and the effects of iron metabolism on senescence remain significantly less characterized. In this review, we first provide an overview of iron metabolism and iron regulatory proteins. Then, we summarize alterations in iron homeostasis in cancer and senescence from a cellular point of view.
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Affiliation(s)
- Elvira Crescenzi
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale, CNR, Via S. Pansini, 5, 80131 Naples, Italy
| | - Antonio Leonardi
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, "Federico II" University of Naples, Via S. Pansini, 5, 80131 Naples, Italy
| | - Francesco Pacifico
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale, CNR, Via S. Pansini, 5, 80131 Naples, Italy
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23
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Charlebois E, Pantopoulos K. Nutritional Aspects of Iron in Health and Disease. Nutrients 2023; 15:2441. [PMID: 37299408 PMCID: PMC10254751 DOI: 10.3390/nu15112441] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 05/16/2023] [Accepted: 05/17/2023] [Indexed: 06/12/2023] Open
Abstract
Dietary iron assimilation is critical for health and essential to prevent iron-deficient states and related comorbidities, such as anemia. The bioavailability of iron is generally low, while its absorption and metabolism are tightly controlled to satisfy metabolic needs and prevent toxicity of excessive iron accumulation. Iron entry into the bloodstream is limited by hepcidin, the iron regulatory hormone. Hepcidin deficiency due to loss-of-function mutations in upstream gene regulators causes hereditary hemochromatosis, an endocrine disorder of iron overload characterized by chronic hyperabsorption of dietary iron, with deleterious clinical complications if untreated. The impact of high dietary iron intake and elevated body iron stores in the general population is not well understood. Herein, we summarize epidemiological data suggesting that a high intake of heme iron, which is abundant in meat products, poses a risk factor for metabolic syndrome pathologies, cardiovascular diseases, and some cancers. We discuss the clinical relevance and potential limitations of data from cohort studies, as well as the need to establish causality and elucidate molecular mechanisms.
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Affiliation(s)
- Edouard Charlebois
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada;
- Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada
| | - Kostas Pantopoulos
- Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada;
- Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada
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24
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D W, L G, T Z, W X, L Y, Z X, Z W, L G, H Y. Study of iron metabolism based on T2* mapping sequences in PI-RADS 3 prostate lesions. Front Oncol 2023; 13:1185057. [PMID: 37274247 PMCID: PMC10232975 DOI: 10.3389/fonc.2023.1185057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 05/09/2023] [Indexed: 06/06/2023] Open
Abstract
Introduction Prostate cancer is one of the most common malignant tumors in Chinese men, which is rich in iron metabolic activity and is closely related to all stages of prostate cancer progression. Since the current diagnostic methods are insufficient, we aimed to evaluate the value of quantitative T2 star values from the T2* mapping sequences in multiparametric magnetic resonance imaging (mpMRI) in the diagnosis and grading of PI-RADS 3 prostate cancer (PCa). Methods We prospectively enrolled patients with PCa or benign prostatic hyperplasia (BPH) admitted to our hospital from January 2021 to November 2022. Imaging indicators, including the T2* value and apparent diffusion coefficient (ADC) value, were collected, and enzyme-linked immunosorbent assays (ELISAs) were used to measure the levels of proteins involved in iron metabolism in the patients. ROC curves were drawn to explore whether the T2* value could be used for the diagnosis and grading of PCa. Results We found that three iron metabolism indexes, ferritin, hepcidin, and the ferric ion (Fe), and the T2* value were significantly different between the PCa group and BPH group and between the low International Society of Urology Pathology (ISUP) group (ISUP ≤ 2) and the high ISUP group (ISUP>2). Additionally, there was a significant correlation between the levels of these three indicators and the T2* value. Further ROC analysis showed that the levels of iron metabolism-related indexes and T2* values performed well in diagnosing and grading PCa. Discussion The T2* value has good value in detecting and predicting the grade of prostate cancer and can reflect the iron metabolism of the tumor, which could provide a foundation for the diagnosis and grading of PCa in the future.
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Affiliation(s)
- Wenhao D
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Guangzheng L
- Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhen T
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xuedong W
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yonggang L
- Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xuefeng Z
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Weijie Z
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Gang L
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yuhua H
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, China
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25
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Liang J, Liao Y, Wang P, Yang K, Wang Y, Wang K, Zhong B, Zhou D, Cao Q, Li J, Zhao Y, Jiang N. Ferroptosis landscape in prostate cancer from molecular and metabolic perspective. Cell Death Discov 2023; 9:128. [PMID: 37061523 PMCID: PMC10105735 DOI: 10.1038/s41420-023-01430-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/04/2023] [Accepted: 04/06/2023] [Indexed: 04/17/2023] Open
Abstract
Prostate cancer is a major disease that threatens men's health. Its rapid progression, easy metastasis, and late castration resistance have brought obstacles to treatment. It is necessary to find new effective anticancer methods. Ferroptosis is a novel iron-dependent programmed cell death that plays a role in various cancers. Understanding how ferroptosis is regulated in prostate cancer will help us to use it as a new way to kill cancer cells. In this review, we summarize the regulation and role of ferroptosis in prostate cancer and the relationship with AR from the perspective of metabolism and molecular pathways. We also discuss the feasibility of ferroptosis in prostate cancer treatment and describe current limitations and prospects, providing a reference for future research and clinical application of ferroptosis.
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Affiliation(s)
- Jiaming Liang
- Tianjin institute of Urology, The Second Hospital of Tianjin Medical University, 300211, Tianjin, China
| | - Yihao Liao
- Tianjin institute of Urology, The Second Hospital of Tianjin Medical University, 300211, Tianjin, China
| | - Pu Wang
- Tianjin institute of Urology, The Second Hospital of Tianjin Medical University, 300211, Tianjin, China
| | - Kun Yang
- School of Future Technology, Xi'an Jiaotong University, 710049, Xi'an, Shaanxi, China
| | - Youzhi Wang
- Tianjin institute of Urology, The Second Hospital of Tianjin Medical University, 300211, Tianjin, China
| | - Keke Wang
- Department of Urology, Tangdu Hospital, The Air Force Military Medical University, Xi'an, Shaanxi, China
| | - Boqiang Zhong
- Tianjin institute of Urology, The Second Hospital of Tianjin Medical University, 300211, Tianjin, China
| | - Diansheng Zhou
- Tianjin institute of Urology, The Second Hospital of Tianjin Medical University, 300211, Tianjin, China
| | - Qian Cao
- Tianjin institute of Urology, The Second Hospital of Tianjin Medical University, 300211, Tianjin, China
| | - Junbo Li
- Tianjin institute of Urology, The Second Hospital of Tianjin Medical University, 300211, Tianjin, China
| | - Yang Zhao
- Department of Radiology, Tianjin Medical University Second Hospital, Tianjin, China
| | - Ning Jiang
- Tianjin institute of Urology, The Second Hospital of Tianjin Medical University, 300211, Tianjin, China.
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26
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Gonciarz RL, Sakhamuri S, Hooshdaran N, Kumar G, Kim H, Evans MJ, Renslo AR. Elevated labile iron in castration-resistant prostate cancer is targetable with ferrous iron-activatable antiandrogen therapy. Eur J Med Chem 2023; 249:115110. [PMID: 36708680 PMCID: PMC10210592 DOI: 10.1016/j.ejmech.2023.115110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 01/05/2023] [Accepted: 01/07/2023] [Indexed: 01/15/2023]
Abstract
Clinical responses to second generation androgen signaling inhibitors (e.g., enzalutamide) in metastatic castration-resistant prostate cancer (mCRPC) are variable and transient, and are associated with dose limiting toxicities, including rare but severe CNS effects. We hypothesized that changes to iron metabolism coincident with more advanced disease might be leveraged for tumor-selective delivery of antiandrogen therapy. Using the recently described chemical probes SiRhoNox and 18F-TRX in mCRPC models, we found elevated Fe2+ to be a common feature of mCRPC in vitro and in vivo. We next synthesized ferrous-iron activatable drug conjugates of second and third-generation antiandrogens and found these conjugates possessed comparable or enhanced antiproliferative activity across mCRPC cell line models. Mouse pharmacokinetic studies showed that these prototype antiandrogen conjugates are stable in vivo and limited exposure to conjugate or free antiandrogen in the brain. Our results reveal elevated Fe2+ to be a feature of mCRPC that might be leveraged to improve the tolerability and efficacy of antiandrogen therapy.
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Affiliation(s)
- Ryan L Gonciarz
- Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, 94158, United States
| | - Sasank Sakhamuri
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, 94158, United States
| | - Nima Hooshdaran
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, 94158, United States
| | - Garima Kumar
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, 94158, United States
| | - Hyunjung Kim
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, 94158, United States
| | - Michael J Evans
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, 94158, United States; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, 94158, United States.
| | - Adam R Renslo
- Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, 94158, United States; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, 94158, United States.
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27
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Alcantara-Zapata DE, Thiersch M, Gonzales GF. Association of serum hepcidin with prostate-specific antigen levels in men from high Andean cities of Peru. Int J Health Sci (Qassim) 2023; 17:28-36. [PMID: 36891043 PMCID: PMC9986881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/10/2023] Open
Abstract
Objective The prostate-specific antigen (PSA) is the primary biomarker to diagnose prostate cancer. Hepcidin has been reported as an alternative for this diagnosis; however, it is unclear how PSA and hepcidin function at high altitude (HA). This study aims to assess the association between hepcidin with PSA in HA residents chronically exposed to hypobaric hypoxia. Methods We retrospectively examined data of 70 healthy males (aged 18-65-years-old) from four different altitudes cities in Peru: Lima (<150 m), Huancayo (2380 m), Puno (3800 m), and Cerro de Pasco (4320 m). Serum hepcidin, testosterone, and PSA were analyzed by chemiluminescence immunoassay. HA parameters (hemoglobin [Hb], pulse oxygen saturation [SpO2], and chronic mountain sickness [CMS] score) were also included in the study. Bivariate analyses and a multivariate linear mixed model were used to evaluate the association between hepcidin and PSA, adjusted by HA parameters, age, and body mass index (BMI). Results Cases of excessive erythrocytosis (EE) (Hb >21 g/dL) were observed in the three highest cities. Hepcidin was positively correlated with Hb, CMS score, and BMI (P ≤ 0.05). Hepcidin was higher in Huancayo with respect to Puno, while PSA was lower in Cerro de Pasco in regard to Puno and Lima (P ≤ 0.05). Neither hepcidin nor PSA was increased by altitude in each city (P > 0.05). We did not find an association between hepcidin and PSA, even adjusted by age, BMI, Hb, and SpO2 (P ≤ 0.05). Conclusion These findings showed no association between hepcidin and PSA levels in healthy residents at HA.
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Affiliation(s)
- Diana E. Alcantara-Zapata
- Endocrinology and Reproduction Laboratory, Research and Development Laboratories (LID), Faculty of Sciences and Philosophy, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Markus Thiersch
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Gustavo F. Gonzales
- Endocrinology and Reproduction Laboratory, Research and Development Laboratories (LID), Faculty of Sciences and Philosophy, Universidad Peruana Cayetano Heredia, Lima, Peru
- High Altitude Research Institute, Universidad Peruana Cayetano Heredia, Lima, Peru
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28
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Scaramellini N, Fischer D, Agarvas AR, Motta I, Muckenthaler MU, Mertens C. Interpreting Iron Homeostasis in Congenital and Acquired Disorders. Pharmaceuticals (Basel) 2023; 16:ph16030329. [PMID: 36986429 PMCID: PMC10054723 DOI: 10.3390/ph16030329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 02/13/2023] [Accepted: 02/17/2023] [Indexed: 02/25/2023] Open
Abstract
Mammalian cells require iron to satisfy their metabolic needs and to accomplish specialized functions, such as hematopoiesis, mitochondrial biogenesis, energy metabolism, or oxygen transport. Iron homeostasis is balanced by the interplay of proteins responsible for iron import, storage, and export. A misbalance of iron homeostasis may cause either iron deficiencies or iron overload diseases. The clinical work-up of iron dysregulation is highly important, as severe symptoms and pathologies may arise. Treating iron overload or iron deficiency is important to avoid cellular damage and severe symptoms and improve patient outcomes. The impressive progress made in the past years in understanding mechanisms that maintain iron homeostasis has already changed clinical practice for treating iron-related diseases and is expected to improve patient management even further in the future.
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Affiliation(s)
- Natalia Scaramellini
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milano, Italy
- Unit of Medicine and Metabolic Disease, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Dania Fischer
- Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany
| | - Anand R. Agarvas
- Center for Translational Biomedical Iron Research, Department of Pediatric Oncology, Immunology, and Hematology, University of Heidelberg, INF 350, 69120 Heidelberg, Germany
| | - Irene Motta
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milano, Italy
- Unit of Medicine and Metabolic Disease, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Martina U. Muckenthaler
- Center for Translational Biomedical Iron Research, Department of Pediatric Oncology, Immunology, and Hematology, University of Heidelberg, INF 350, 69120 Heidelberg, Germany
- Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Side, 69120 Heidelberg, Germany
| | - Christina Mertens
- Center for Translational Biomedical Iron Research, Department of Pediatric Oncology, Immunology, and Hematology, University of Heidelberg, INF 350, 69120 Heidelberg, Germany
- Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany
- Correspondence: ; Tel.: +49-6221564582; Fax: +49-6221564580
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29
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Azemin WA, Alias N, Ali AM, Shamsir MS. Structural and functional characterisation of HepTH1-5 peptide as a potential hepcidin replacement. J Biomol Struct Dyn 2023; 41:681-704. [PMID: 34870559 DOI: 10.1080/07391102.2021.2011415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Hepcidin is a principal regulator of iron homeostasis and its dysregulation has been recognised as a causative factor in cancers and iron disorders. The strategy of manipulating the presence of hepcidin peptide has been used for cancer treatment. However, this has demonstrated poor efficiency and has been short-lived in patients. Many studies reported using minihepcidin therapy as an alternative way to treat hepcidin dysregulation, but this was only applied to non-cancer patients. Highly conserved fish hepcidin protein, HepTH1-5, was investigated to determine its potential use in developing a hepcidin replacement for human hepcidin (Hepc25) and as a therapeutic agent by targeting the tumour suppressor protein, p53, through structure-function analysis. The authors found that HepTH1-5 is stably bound to ferroportin, compared to Hepc25, by triggering the ferroportin internalisation via Lys42 and Lys270 ubiquitination, in a similar manner to the Hepc25 activity. Moreover, the residues Ile24 and Gly24, along with copper and zinc ligands, interacted with similar residues, Lys24 and Asp1 of Hepc25, respectively, showing that those molecules are crucial to the hepcidin replacement strategy. HepTH1-5 interacts with p53 and activates its function through phosphorylation. This finding shows that HepTH1-5 might be involved in the apoptosis signalling pathway upon a DNA damage response. This study will be very helpful for understanding the mechanism of the hepcidin replacement and providing insights into the HepTH1-5 peptide as a new target for hepcidin and cancer therapeutics.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Wan-Atirah Azemin
- School of Agriculture Science and Biotechnology, Faculty of Bioresources and Food Industry, Universiti Sultan Zainal Abidin, Besut, Terengganu, Malaysia.,Bioinformatics Research Group (BIRG), Department of Biosciences, Faculty of Science, Universiti Teknologi Malaysia, Skudai, Johor, Malaysia
| | - Nadiawati Alias
- School of Agriculture Science and Biotechnology, Faculty of Bioresources and Food Industry, Universiti Sultan Zainal Abidin, Besut, Terengganu, Malaysia
| | - Abdul Manaf Ali
- School of Agriculture Science and Biotechnology, Faculty of Bioresources and Food Industry, Universiti Sultan Zainal Abidin, Besut, Terengganu, Malaysia
| | - Mohd Shahir Shamsir
- Bioinformatics Research Group (BIRG), Department of Biosciences, Faculty of Science, Universiti Teknologi Malaysia, Skudai, Johor, Malaysia.,Faculty of Applied Sciences and Technology, Universiti Tun Hussein Onn Malaysia, Pagoh Higher Education Hub, Muar, Johor, Malaysia
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30
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Wang D. Progress in the study of ferroptosis in cancer treatment: State-of-the-Art. Chem Biol Interact 2023; 371:110348. [PMID: 36646403 DOI: 10.1016/j.cbi.2023.110348] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 01/04/2023] [Accepted: 01/06/2023] [Indexed: 01/15/2023]
Abstract
As a regulatory cell death mode defined in recent years, Ferroptosis is mainly characterized by increased intracellular free iron and the accumulation of lipid peroxides. Ferroptosis is closely related to iron ion metabolism, lipid metabolism, and amino acid metabolism. Cancer is the second leading cause of death worldwide, and effective removal of tumour cells while protecting normal cells is the key to tumour treatment. The continuous development and refinement of molecular mechanisms related to ferroptosis have shown promising applications in tumour therapy. There is increasing evidence that triggering ferroptosis in tumour cells is expected to be a new therapeutic strategy for tumour treatment.
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Affiliation(s)
- Dong Wang
- First Teaching Hospital, Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300193, China; Graduate School of Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
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31
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Belvin BR, Lewis JP. Ferroportin depletes iron needed for cell cycle progression in head and neck squamous cell carcinoma. Front Oncol 2023; 12:1025434. [PMID: 36698390 PMCID: PMC9868905 DOI: 10.3389/fonc.2022.1025434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 11/16/2022] [Indexed: 01/12/2023] Open
Abstract
Introduction Ferroportin (FPN), the only identified eukaryotic iron efflux channel, plays an important role in iron homeostasis and is downregulated in many cancers. To determine if iron related pathways are important for Head and Neck Squamous Cell Carcinoma (HNSCC) progression and proliferation, we utilize a model of FPN over-expression to simulate iron depletion and probe associated molecular pathways. Methods The state of iron related proteins and ferroptosis sensitivity was assessed in a panel of metastatic HNSCC cell lines. Stable, inducible expression of FPN was confirmed in the metastatic HNSCC lines HN12 and JHU-022 as well as the non-transformed normal oral keratinocyte (NOK) cell line and the effect of FPN mediated iron depletion was assessed in these cell lines. Results HNSCC cells are sensitive to iron chelation and ferroptosis, but the non-transformed NOK cell line is not. We found that FPN expression inhibits HNSCC cell proliferation and colony formation but NOK cells are unaffected. Inhibition of cell proliferation is rescued by the addition of hepcidin. Decreases in proliferation are due to the disruption of iron homeostasis via loss of labile iron caused by elevated FPN levels. This in turn protects HNSCC cells from ferroptotic cell death. Expression of FPN induces DNA damage, activates p21, and reduces levels of cyclin proteins thereby inhibiting cell cycle progression of HNSCC cells, arresting cells in the S-phase. Induction of FPN severely inhibits Edu incorporation and increased β-galactosidase activity, indicating cells have entered senescence. Finally, in an oral orthotopic mouse xenograft model, FPN induction yields a significant decrease in tumor growth. Conclusions Our results indicate that iron plays a role in HNSCC cell proliferation and growth and is important for cell cycle progression. Iron based interventional strategies such as ferroptosis or iron chelation may have potential therapeutic benefits in advanced HNSCC.
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Affiliation(s)
- Benjamin Ross Belvin
- Philips Institute for Oral Health Research, School of Dentistry, Richmond, VA, United States
| | - Janina P. Lewis
- Philips Institute for Oral Health Research, School of Dentistry, Richmond, VA, United States,Department of Biochemistry and Molecular Biology, School of Medicine, Richmond, VA, United States,Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States,*Correspondence: Janina P. Lewis,
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Lin F, Tuffour A, Hao G, Peprah FA, Huang A, Zhou Y, Zhang H. Distinctive modulation of hepcidin in cancer and its therapeutic relevance. Front Oncol 2023; 13:1141603. [PMID: 36895478 PMCID: PMC9989193 DOI: 10.3389/fonc.2023.1141603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 02/08/2023] [Indexed: 02/23/2023] Open
Abstract
Hepcidin, a short peptide synthesized primarily by hepatocytes in response to increased body iron and inflammation, is a crucial iron-regulating factor. Hepcidin regulates intestinal iron absorption and releases iron from macrophages into plasma through a negative iron feedback mechanism. The discovery of hepcidin inspired a torrent of research into iron metabolism and related problems, which have radically altered our understanding of human diseases caused by an excess of iron, an iron deficiency, or an iron disparity. It is critical to decipher how tumor cells manage hepcidin expression for their metabolic requirements because iron is necessary for cell survival, particularly for highly active cells like tumor cells. Studies show that tumor and non-tumor cells express and control hepcidin differently. These variations should be explored to produce potential novel cancer treatments. The ability to regulate hepcidin expression to deprive cancer cells of iron may be a new weapon against cancer cells.
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Affiliation(s)
- Feng Lin
- Key Laboratory of Healthy Freshwater Aquaculture, Ministry of Agriculture, Zhejiang Institute of Freshwater Fisheries, Huzhou, China
| | - Alex Tuffour
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China.,State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Guijie Hao
- Key Laboratory of Healthy Freshwater Aquaculture, Ministry of Agriculture, Zhejiang Institute of Freshwater Fisheries, Huzhou, China
| | | | - Aixia Huang
- Key Laboratory of Healthy Freshwater Aquaculture, Ministry of Agriculture, Zhejiang Institute of Freshwater Fisheries, Huzhou, China
| | - Yang Zhou
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Haiqi Zhang
- Key Laboratory of Healthy Freshwater Aquaculture, Ministry of Agriculture, Zhejiang Institute of Freshwater Fisheries, Huzhou, China
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33
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Qiu H, Gu G, Zuo E, Cheng X. Tumoral Overexpression of Hepcidin is Associated with Poor Prognosis of Patients with Clear Cell Renal Cell Carcinoma. Cancer Invest 2023; 41:84-92. [PMID: 36205556 DOI: 10.1080/07357907.2022.2133775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
This study aimed to investigate the prognostic value of tumoral HAMP expression in patients with clear cell renal cell carcinoma (ccRCC). In a TCGA dataset, we found that HAMP mRNA expression was increased in ccRCC tumors compared with normal controls. Tumoral HAMP mRNA expression was positively correlated with clinical stage, tumor grade, and TNM stages. Patients with high HAMP expression had poorer overall survival than those with low HAMP expression. Tumoral HAMP mRNA level independently predicted the survival of patients. HAMP protein expression was increased in real-world ccRCC tumors compared with those in paired, adjacent noncancerous tissue and was positively correlates with tumor grading. These results suggest HAMP as a potential prognostic factor for ccRCC patients.
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Affiliation(s)
- Huizhu Qiu
- Department of Hematology and Oncology, Soochow University Affiliated Taicang Hospital (The First People's Hospital of Taicang), Jiangsu, China
| | - Guojian Gu
- Department of Hematology and Oncology, Soochow University Affiliated Taicang Hospital (The First People's Hospital of Taicang), Jiangsu, China
| | - Erdong Zuo
- Department of Hematology and Oncology, Soochow University Affiliated Taicang Hospital (The First People's Hospital of Taicang), Jiangsu, China
| | - Xu Cheng
- Department of Hematology and Oncology, Soochow University Affiliated Taicang Hospital (The First People's Hospital of Taicang), Jiangsu, China
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34
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Tang Y, Ge S, Zheng X, Zheng J. High Hepcidin expression predicts poor prognosis in patients with clear cell renal cell carcinoma. Diagn Pathol 2022; 17:100. [PMID: 36585741 PMCID: PMC9805116 DOI: 10.1186/s13000-022-01274-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 12/19/2022] [Indexed: 01/01/2023] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is a growing public health challenge worldwide. Hepcidin antimicrobial peptide (HAMP) is differentially expressed in various tumors. However, the roles and functions of HAMP in ccRCC remain unclear. In the present study, we integrated systematic bioinformatics approaches to investigate the roles and functions of HAMP and its association with immune cell infiltration in ccRCC. Compared with paracancerous tissue, HAMP expression was significantly upregulated in ccRCC patients. Meanwhile, we found good diagnostic performance of HAMP for ccRCC patients and its close associations with the clinicopathological features of ccRCC patients. In addition, we found that HAMP is closely related to multiple immune pathways and positively correlated with various immune cells. HAMP was a significant independent predictor for ccRCC. High expression of HAMP was associated with worse clinical prognosis and more immune cell infiltration in ccRCC patients. HAMP may offer potential as a biomarker to predict prognosis and the clinical treatment outcome of ccRCC patients.
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Affiliation(s)
- Yuting Tang
- grid.412540.60000 0001 2372 7462Department of Rehabilitation, Municipal Hospital of Traditional Chinese Medicine, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200071 People’s Republic of China
| | - Shengdong Ge
- grid.284723.80000 0000 8877 7471Department of Urology, The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Southern Medical University, Guangzhou, China
| | - Xiao Zheng
- grid.412540.60000 0001 2372 7462Department of Rehabilitation, Municipal Hospital of Traditional Chinese Medicine, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200071 People’s Republic of China
| | - Jiejiao Zheng
- grid.413597.d0000 0004 1757 8802Department of Rehabilitation, HuaDong Hospital, FuDan University, Shanghai, 200040 People’s Republic of China
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35
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Huang J, Liu W, Song S, Li JC, Gan K, Shen C, Holzbeierlein J, Li B. The iron-modulating hormone hepcidin is upregulated and associated with poor survival outcomes in renal clear cell carcinoma. Front Pharmacol 2022; 13:1080055. [PMID: 36532749 PMCID: PMC9757070 DOI: 10.3389/fphar.2022.1080055] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 11/16/2022] [Indexed: 08/30/2023] Open
Abstract
Background: Reliable biomarkers are rare for renal cell carcinoma (RCC) treatment selection. We aimed to discover novel biomarkers for precision medicine. The iron-regulating hormone hepcidin (HAMP) was reportedly increased in RCC patient sera and tissues. However, its potential implication as a prognostic biomarker remains exclusive. Methods: Multiple RNA-seq and cDNA microarray datasets were utilized to analyze gene expression profiles. Hepcidin protein expression was assessed using an ELISA assay in cell culture models. Comparisons of gene expression profiles and patient survival outcomes were conducted using the R package bioinformatics software. Results: Five (HAMP, HBS, ISCA2, STEAP2, and STEAP3) out of 71 iron-modulating genes exhibited consistent changes along with tumor stage, lymph node invasion, distal metastasis, tumor cell grade, progression-free interval, overall survival, and disease-specific survival. Of which HAMP upregulation exerted as a superior factor (AUC = 0.911) over the other four genes in distinguishing ccRCC tissue from normal renal tissue. HAMP upregulation was tightly associated with its promoter hypomethylation and immune checkpoint factors (PDCD1, LAG3, TIGIT, and CTLA4). Interleukin-34 (IL34) treatment strongly enhanced hepcidin expression in renal cancer Caki-1 cells. Patients with higher levels of HAMP expression experienced worse survival outcomes. Conclusion: These data suggest that HAMP upregulation is a potent prognostic factor of poor survival outcomes and a novel immunotherapeutic biomarker for ccRCC patients.
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Affiliation(s)
- Jian Huang
- Pathological Diagnosis and Research Center, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Wang Liu
- Department of Urology, The University of Kansas Medical Center, Kansas, KS, United States
| | - Shiqi Song
- Pathological Diagnosis and Research Center, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jean C. Li
- Department of Urology, The University of Kansas Medical Center, Kansas, KS, United States
| | - Kaimei Gan
- Pathological Diagnosis and Research Center, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Chunxiao Shen
- Pathological Diagnosis and Research Center, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jeffrey Holzbeierlein
- Department of Urology, The University of Kansas Medical Center, Kansas, KS, United States
| | - Benyi Li
- Department of Urology, The University of Kansas Medical Center, Kansas, KS, United States
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36
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Xie H, Wang L, Tang Y, Zhao M, Wang Z, Liu M, Zhao Q, Zhou J, Wu Y. Functional analysis of differently expressed ferroptosis-related genes in patients with mitral valve prolapse. Front Genet 2022; 13:1062212. [PMID: 36523770 PMCID: PMC9745071 DOI: 10.3389/fgene.2022.1062212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 11/18/2022] [Indexed: 01/06/2025] Open
Abstract
Background: The prevalence of mitral valve prolapse (MVP) in heart valvular diseases is globally increasing. However, the understanding of its etiology and pathogenesis is limited. So far, the relationship between ferroptosis-related genes and long non-coding RNAs (lncRNAs) in MVP remains unexplored. This study investigates the potential pathogenesis of ferroptosis-related genes in MVP and provides a therapeutic target for the disease. Methods: Blood samples from patients with MVP and healthy volunteers were collected for transcriptomic sequencing to analyze the expression of ferroptosis-related differentially expressed genes (DEGs) and differentially expressed long non-coding RNAs (DElncRNAs Co-expression network of ferroptosis-related DEGs and DElncRNAs. Furthermore, this work conducted GO and KEGG enrichment analyses. Results: CDKN2A, SLC1A4, ATF3, and other core genes related to the mitral valve prolapse were screened out. CDKN2A, SLC1A4, and ATF3 genes were at the core position of the network, regulated by numerous lncRNAs. Notably, these genes are primarily involved in the extracellular region and p53 signaling pathway. Conclusion: In summary, CDKN2A, SLC1A4, and ATF3 regulate the pathophysiological process of MVP and are potential therapeutic targets.
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Affiliation(s)
| | | | | | | | | | | | | | - Jingxin Zhou
- Department of Cardiovascular Surgery, Nanjing Medical University First Affiliated Hospital, Nanjing, China
| | - Yanhu Wu
- Department of Cardiovascular Surgery, Nanjing Medical University First Affiliated Hospital, Nanjing, China
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37
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Di Grazia A, Di Fusco D, Franzè E, Colella M, Strimpakos G, Salvatori S, Formica V, Laudisi F, Maresca C, Colantoni A, Ortenzi A, Stolfi C, Monteleone I, Monteleone G. Hepcidin Upregulation in Colorectal Cancer Associates with Accumulation of Regulatory Macrophages and Epithelial-Mesenchymal Transition and Correlates with Progression of the Disease. Cancers (Basel) 2022; 14:5294. [PMID: 36358713 PMCID: PMC9658525 DOI: 10.3390/cancers14215294] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/24/2022] [Accepted: 10/26/2022] [Indexed: 08/30/2023] Open
Abstract
Advanced, metastatic colorectal cancer (CRC) is associated with high rate of mortality because of its poor responsiveness to chemotherapy/immunotherapy. Recent studies have shown that hepcidin, a peptide hormone produced mainly by hepatocytes, is expressed by and enhances the growth of tumor cells. We here assessed whether hepcidin expression helps identify subsets of CRC with advanced and aggressive course. By integrating results of in vitro/ex vivo studies with data of bioinformatics databases, we initially showed that hepcidin RNA and protein expression was more pronounced in tissue samples taken from the tumor area, as compared to the macroscopically unaffected, adjacent, colonic mucosa of CRC patients. The induction of hepcidin in the colonic epithelial cell line HCEC-1ct by interleukin (IL)-6, IL-21 and IL-23 occurred via a Stat3-dependent mechanism and, in primary CRC cells, hepcidin co-localized with active Stat3. In CRC tissue, hepcidin content correlated mainly with macrophage accumulation and IL-10 and CD206 expression, two markers of regulatory macrophages. Consistently, both IL-10 and CD206 were up-regulated by hepcidin in blood mononuclear cells. The highest levels of hepcidin were found in metastatic CRC and survival analysis showed that high expression of hepcidin associated with poor prognosis. Moreover, hepcidin expression correlated with markers of epithelial-to-mesenchymal transition and the silencing of hepcidin in CRC cells reduced epithelial-to-mesenchymal transition markers. These findings indicate that hepcidin is markedly induced in the advanced stages of CRC and suggest that it could serve as a prognostic biomarker in CRC.
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Affiliation(s)
- Antonio Di Grazia
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
| | - Davide Di Fusco
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
| | - Eleonora Franzè
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
| | - Marco Colella
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
| | - Georgios Strimpakos
- Institute of Biochemistry and Cell Biology (IBBC), National Council of Research (CNR), 00146 Rome, Italy
| | - Silvia Salvatori
- Gastroenterology Unit, Fondazione Policlinico “Tor Vergata”, 00133 Rome, Italy
| | - Vincenzo Formica
- Medical Oncology Unit, Fondazione Policlinico “Tor Vergata”, 00133 Rome, Italy
| | - Federica Laudisi
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
| | - Claudia Maresca
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
| | - Alfredo Colantoni
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
| | - Angela Ortenzi
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
| | - Carmine Stolfi
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
| | - Ivan Monteleone
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, 00133 Rome, Italy
| | - Giovanni Monteleone
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
- Gastroenterology Unit, Fondazione Policlinico “Tor Vergata”, 00133 Rome, Italy
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Tong X, Zhu C, Liu L, Huang M, Xu J, Chen X, Zou J. Role of Sostdc1 in skeletal biology and cancer. Front Physiol 2022; 13:1029646. [PMID: 36338475 PMCID: PMC9633957 DOI: 10.3389/fphys.2022.1029646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Accepted: 10/05/2022] [Indexed: 11/13/2022] Open
Abstract
Sclerostin domain-containing protein-1 (Sostdc1) is a member of the sclerostin family and encodes a secreted 28–32 kDa protein with a cystine knot-like domain and two N-linked glycosylation sites. Sostdc1 functions as an antagonist to bone morphogenetic protein (BMP), mediating BMP signaling. It also interacts with LRP6, mediating LRP6 and Wnt signaling, thus regulating cellular proliferation, differentiation, and programmed cell death. Sostdc1 plays various roles in the skin, intestines, brain, lungs, kidneys, and vasculature. Deletion of Sostdc1 gene in mice resulted in supernumerary teeth and improved the loss of renal function in Alport syndrome. In the skeletal system, Sostdc1 is essential for bone metabolism, bone density maintenance, and fracture healing. Recently, Sostdc1 has been found to be closely related to the development and progression of multiple cancer types, including breast, renal, gastric, and thyroid cancers. This article summarises the role of Sostdc1 in skeletal biology and related cancers to provide a theoretical basis for the treatment of related diseases.
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Affiliation(s)
- Xiaoyang Tong
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Chenyu Zhu
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Lifei Liu
- Department of Rehabilitation, The People’s Hospital of Liaoning Province, Shenyang, China
| | - Mei Huang
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Jiake Xu
- School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
| | - Xi Chen
- School of Sports Science, Wenzhou Medical University, Wenzhou, China
- *Correspondence: Xi Chen, ; Jun Zou,
| | - Jun Zou
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
- *Correspondence: Xi Chen, ; Jun Zou,
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QU L, HE X, TANG Q, FAN X, LIU J, LIN A. Iron metabolism, ferroptosis, and lncRNA in cancer: knowns and unknowns. J Zhejiang Univ Sci B 2022; 23:844-862. [PMID: 36226538 PMCID: PMC9561407 DOI: 10.1631/jzus.b2200194] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Cancer cells undergo substantial metabolic alterations to sustain increased energy supply and uncontrolled proliferation. As an essential trace element, iron is vital for many biological processes. Evidence has revealed that cancer cells deploy various mechanisms to elevate the cellular iron concentration to accelerate proliferation. Ferroptosis, a form of cell death caused by iron-catalyzed excessive peroxidation of polyunsaturated fatty acids (PUFAs), is a promising therapeutic target for therapy-resistant cancers. Previous studies have reported that long noncoding RNA (lncRNA) is a group of critical regulators involved in modulating cell metabolism, proliferation, apoptosis, and ferroptosis. In this review, we summarize the associations among iron metabolism, ferroptosis, and ferroptosis-related lncRNA in tumorigenesis. This information will help deepen understanding of the role of lncRNA in iron metabolism and raise the possibility of targeting lncRNA and ferroptosis in cancer combination therapy.
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Affiliation(s)
- Lei QU
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou310058, China,Cancer Center, Zhejiang University, Hangzhou310058, China,Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou310058, China
| | - Xinyu HE
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou310058, China,Cancer Center, Zhejiang University, Hangzhou310058, China,Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou310058, China
| | - Qian TANG
- Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining314400, China,Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou310006, China,College of Medicine and Veterinary Medicine, the University of Edinburgh, EdinburghEH16 4SB, UK,Biomedical and Health Translational Research Center of Zhejiang Province, Haining314400, China
| | - Xiao FAN
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou310058, China,Cancer Center, Zhejiang University, Hangzhou310058, China,Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou310058, China
| | - Jian LIU
- Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Haining314400, China,Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou310006, China,College of Medicine and Veterinary Medicine, the University of Edinburgh, EdinburghEH16 4SB, UK,Biomedical and Health Translational Research Center of Zhejiang Province, Haining314400, China,Jian LIU,
| | - Aifu LIN
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou310058, China,Cancer Center, Zhejiang University, Hangzhou310058, China,Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou310058, China,Breast Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310003, China,International School of Medicine, International Institutes of Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu322000, China,ZJU-QILU Joint Research Institute, Hangzhou310058, China,Aifu LIN,
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40
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Zhou Z, Wu J, Yang Y, Gao P, Wang L, Wu Z. Hepcidin as a prognostic biomarker in clear cell renal cell carcinoma. Am J Cancer Res 2022; 12:4120-4139. [PMID: 36225649 PMCID: PMC9548002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 08/22/2022] [Indexed: 06/16/2023] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is a common malignancy of urologic neoplasms. Hepcidin is a pivotal modulator of iron metabolism involved in human cancers; however, the biological significance of hepcidin in ccRCC remains to be fully understood. Therefore, in this study, we evaluated the expression profiles of hepcidin in ccRCC from several public databases and found that hepcidin expression was upregulated in ccRCC, which was further validated in ccRCC cell lines, clinical samples, and tissue microarray (TMA) quantitative real-time PCR and immunohistochemistry. In addition, we found that the expression level of hepcidin was correlated with the age, T stage and pathologic stage of patients. Furthermore, hepcidin promoter methylation was significantly associated with the worse poor clinical parameters of ccRCC patients, and hepcidin was an independent prognostic factor. Mechanistically, enrichment analysis revealed that hepcidin participated in the immune-related and metabolism-related pathways. Hepcidin was positively correlated with not only immune infiltration and immune checkpoints but also tumor mutation burden and cytotoxic T lymphocyte. Finally, we validated the positive correlation of hepcidin with the marker of macrophage (CD68) in the TMA. Our findings provide insights into understanding the function and its underlying mechanism of hepcidin in ccRCC and suggest that hepcidin might serve as a potential predictive biomarker of response to immunotherapy and the prognosis of patients with ccRCC.
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Affiliation(s)
- Zijian Zhou
- Department of Urology, Huashan Hospital, Fudan UniversityShanghai 200040, PR China
- Institute of Urology, Fudan UniversityShanghai 200040, PR China
| | - Jiajin Wu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029, PR China
| | - Yuanyuan Yang
- Department of Urology, Huashan Hospital, Fudan UniversityShanghai 200040, PR China
- Institute of Urology, Fudan UniversityShanghai 200040, PR China
| | - Peng Gao
- Department of Urology, Huashan Hospital, Fudan UniversityShanghai 200040, PR China
- Institute of Urology, Fudan UniversityShanghai 200040, PR China
| | - Lujia Wang
- Department of Urology, Huashan Hospital, Fudan UniversityShanghai 200040, PR China
- Institute of Urology, Fudan UniversityShanghai 200040, PR China
| | - Zhong Wu
- Department of Urology, Huashan Hospital, Fudan UniversityShanghai 200040, PR China
- Institute of Urology, Fudan UniversityShanghai 200040, PR China
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41
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Soh J, Lim ZX, Lim EH, Kennedy BK, Goh J. Ironing out exercise on immuno-oncological outcomes. J Immunother Cancer 2022; 10:jitc-2021-002976. [PMID: 36180069 PMCID: PMC9528609 DOI: 10.1136/jitc-2021-002976] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/06/2022] [Indexed: 12/02/2022] Open
Abstract
Despite accumulating evidence that supports the beneficial effects of physical exercise in inhibiting cancer progression, whether exercise modulates its effects through systemic and cellular changes in iron metabolism and immune-tumor crosstalk is unknown. Cancer cells have greater metabolic requirements than normal cells, with their survival and proliferation depending largely on iron bioavailability. Although iron is an essential mineral for mitogenesis, it also participates in a form of iron-dependent programmed cell death termed ferroptosis. In this short hypothesis paper, we speculate that modulating iron bioavailability, transport and metabolism with regular exercise can have significant implications for tumor and stromal cells in the tumor microenvironment, by affecting multiple tumor-autonomous and stromal cell responses.
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Affiliation(s)
- Janjira Soh
- Centre for Healthy Longevity, National University Health System (NUHS), Singapore.,Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore
| | - Zi Xiang Lim
- Centre for Healthy Longevity, National University Health System (NUHS), Singapore.,Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore
| | - Elaine Hsuen Lim
- Division of Medical Oncology, National Cancer Centre Singapore (NCCS), Singapore
| | - Brian K Kennedy
- Centre for Healthy Longevity, National University Health System (NUHS), Singapore.,Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.,Singapore Institute for Clinical Sciences (SICS), Agency for Science, Technology & Research (A*STAR), Singapore
| | - Jorming Goh
- Centre for Healthy Longevity, National University Health System (NUHS), Singapore .,Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore.,Division of Medical Oncology, National Cancer Centre Singapore (NCCS), Singapore.,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore
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42
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Ali FT, Soliman RM, Hassan NS, Ibrahim AM, El-Gizawy MM, Mandoh AAY, Ibrahim EA. Sensitivity and specificity of microRNA-204, CA125, and CA19.9 as biomarkers for diagnosis of ovarian cancer. PLoS One 2022; 17:e0272308. [PMID: 35921382 PMCID: PMC9348731 DOI: 10.1371/journal.pone.0272308] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 07/18/2022] [Indexed: 11/28/2022] Open
Abstract
Background Ovarian cancer is usually detected at later stages and no effective screening approach, has been identified. Therefore, sensitive and specific biomarkers for detecting ovarian cancer are urgently needed. Objective This study aimed to investigate the efficacy of six biomarkers for the early clinical diagnosis of ovarian cancer. Subjects & methods The study included 120 patients (benign ovarian tumors and early and late ovarian carcinoma) and 30 control healthy volunteers. MiRNA-204, CA125, CA19.9, hepcidin, microfibril-associated glycoprotein 2, and ferroportin levels were determined in all patients and control volunteers. Results The combined area under the receiver operating characteristic curves for miRNA-204, CA125, and CA19.9 were 0.938, 1.000, and 0.998 for benign tumors and early and late ovarian carcinomas, respectively. The sensitivities of miRNA-204, CA125, and CA19.9 were 98.04%, 100.00%, and 96.19% and the specificities were 58.33%, 62.50%, and 57.78%, respectively. Conclusion The positive predictivity of miRNA-204, CA125, and CA19.9 for ovarian cancer is high (59.57%, 58.24%, and 61.67%, respectively). Thus, the combination of these three biomarkers is a good diagnostic tool for ovarian cancer.
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Affiliation(s)
- Fahmy T. Ali
- Faculty of Science, Department of Biochemistry, Ain Shams University, Cairo, Egypt
| | - Reham M. Soliman
- Faculty of Science, Department of Biochemistry, Ain Shams University, Cairo, Egypt
| | - Nahla S. Hassan
- Faculty of Science, Department of Biochemistry, Ain Shams University, Cairo, Egypt
- * E-mail:
| | - Ahmed M. Ibrahim
- Faculty of Medicine, Department of Medicine, Ain Shams University, Cairo, Egypt
| | - Mayada M. El-Gizawy
- Medical Physiology Department, Medical Division, National Research Center, Giza, Egypt
| | - Abd Allah Y. Mandoh
- Department of Molecular Biology and Cytogenics, Armed Forces Central Laboratory and Blood Bank, Cairo, Egypt
| | - Ehab A. Ibrahim
- Faculty of Science, Department of Biochemistry, Ain Shams University, Cairo, Egypt
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ARPC1A is regulated by STAT3 to inhibit ferroptosis and promote prostate cancer progression. Hum Cell 2022; 35:1591-1601. [DOI: 10.1007/s13577-022-00754-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 07/15/2022] [Indexed: 11/04/2022]
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Cui Z, Fu Y, Yang Z, Gao Z, Feng H, Zhou M, Zhang L, Chen C. Comprehensive Analysis of a Ferroptosis Pattern and Associated Prognostic Signature in Acute Myeloid Leukemia. Front Pharmacol 2022; 13:866325. [PMID: 35656299 PMCID: PMC9152364 DOI: 10.3389/fphar.2022.866325] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 04/19/2022] [Indexed: 11/24/2022] Open
Abstract
Ferroptosis is a widespread form of programmed cell death. The environment of cancer cells makes them vulnerable to ferroptosis, including AML cells, yet the specific association between ferroptosis and AML outcome is little known. In this study, we utilized ferroptosis-related genes to distinguish two subtypes in TCGA cohort, which were subsequently validated in independent AML cohorts. The subtypes were linked with tumor-related immunological abnormalities, mutation landscape and pathway dysregulation, and clinical outcome. Further, we developed a 13-gene prognostic model for AML from DEG analysis in the two subtypes. A risk score was calculated for each patient, and then the overall group was stratified into high- and low-risk groups; the higher risk score correlated with short survival. The model was validated in both independent AML cohorts and pan-cancer cohorts, which demonstrated robustness and extended the usage of the model. A nomogram was constructed that integrated risk score, FLT3-ITD, TP53, and RUNX1 mutations, and age. This model had the additional value of discriminating the sensitivity of several chemotherapeutic drugs and ferroptosis inducers in the two risk groups, which increased the translational value of this model as a potential tool in clinical management. Through integrated analysis of ferroptosis pattern and its related model, our work shed new light on the relationship between ferroptosis and AML, which may facilitate clinical application and therapeutics.
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Affiliation(s)
- Zelong Cui
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yue Fu
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zongcheng Yang
- Center of Stomatology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Zhenxing Gao
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Huimin Feng
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Minran Zhou
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Lu Zhang
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chunyan Chen
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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45
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Wang X, Shi Q, Gong P, Zhou C, Cao Y. An Integrated Systematic Analysis and the Clinical Significance of Hepcidin in Common Malignancies of the Male Genitourinary System. Front Genet 2022; 13:771344. [PMID: 35646093 PMCID: PMC9133565 DOI: 10.3389/fgene.2022.771344] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 04/04/2022] [Indexed: 12/28/2022] Open
Abstract
Tumors of the male genitourinary system are of great concern to the health of men worldwide. Although emerging experiment-based evidence indicates an association between hepcidin and such cancers, an integrated analysis is still lacking. For this reason, in this study, we determined the underlying oncogenic functions of hepcidin in common male genitourinary system tumors, including bladder urothelial carcinoma (BLCA), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), prostate adenocarcinoma (PRAD), and testicular germ cell tumors (TGCT) according to the data from The Cancer Genome Atlas. We found that hepcidin was highly expressed in kidney and testicular cancers. Meanwhile, the expression level of hepcidin was distinctly associated with the prognosis and immune cell infiltration in male patients with certain genitourinary system cancers, especially in KIRC. Elevated hepcidin levels also present as a risk factor in male genitourinary system tumors. Moreover, enrichment analyses revealed that some of the principal associated signaling pathways involving hepcidin and its related genes are identified as tumorigenesis-related. Immunofluorescence staining confirmed the conclusion of our immune infiltration analysis in KIRC tissue. In this study, for the first time, we provided evidence for the oncogenic function of hepcidin in different types of male genitourinary system tumors.
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Affiliation(s)
- Xiaogang Wang
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Qianqian Shi
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Pengfeng Gong
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Cuixing Zhou
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Yunjie Cao
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, China
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46
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Jiang H, Muir RK, Gonciarz RL, Olshen AB, Yeh I, Hann BC, Zhao N, Wang YH, Behr SC, Korkola JE, Evans MJ, Collisson EA, Renslo AR. Ferrous iron-activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors. J Exp Med 2022; 219:e20210739. [PMID: 35262628 PMCID: PMC8916116 DOI: 10.1084/jem.20210739] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 08/02/2021] [Accepted: 11/01/2021] [Indexed: 12/13/2022] Open
Abstract
KRAS mutations drive a quarter of cancer mortality, and most are undruggable. Several inhibitors of the MAPK pathway are FDA approved but poorly tolerated at the doses needed to adequately extinguish RAS/RAF/MAPK signaling in the tumor cell. We found that oncogenic KRAS signaling induced ferrous iron (Fe2+) accumulation early in and throughout mutant KRAS-mediated transformation. We converted an FDA-approved MEK inhibitor into a ferrous iron-activatable drug conjugate (FeADC) and achieved potent MAPK blockade in tumor cells while sparing normal tissues. This innovation allowed sustainable, effective treatment of tumor-bearing animals, with tumor-selective drug activation, producing superior systemic tolerability. Ferrous iron accumulation is an exploitable feature of KRAS transformation, and FeADCs hold promise for improving the treatment of KRAS-driven solid tumors.
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Affiliation(s)
- Honglin Jiang
- Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA
| | - Ryan K. Muir
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA
| | - Ryan L. Gonciarz
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA
| | - Adam B. Olshen
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA
| | - Iwei Yeh
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA
- Departments of Pathology and Dermatology, University of California, San Francisco, San Francisco, CA
| | - Byron C. Hann
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA
| | - Ning Zhao
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA
| | - Yung-hua Wang
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA
| | - Spencer C. Behr
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA
| | - James E. Korkola
- Center for Spatial Systems Biomedicine, Oregon Health & Sciences University, Portland, OR
| | - Michael J. Evans
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA
| | - Eric A. Collisson
- Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA
| | - Adam R. Renslo
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA
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Salmon Protein Hydrolysate Potentiates the Growth Inhibitory Effect of Bicalutamide on Human Prostate Cancer Cell Lines LNCaP and PC3 by Modulating Iron Homeostasis. Mar Drugs 2022; 20:md20040228. [PMID: 35447901 PMCID: PMC9032914 DOI: 10.3390/md20040228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 03/16/2022] [Accepted: 03/25/2022] [Indexed: 11/30/2022] Open
Abstract
Prostate cancer is a common cause of cancer death in men. In advanced stages of prostate cancer, androgen deprivation therapy (ADT) is initiated. Despite ADT, prostate cancers invariably progress to become androgen independent. A growing body of evidence implicates iron dysmetabolism in prostate cancer progression. A bioactive peptide-rich salmon protein hydrolysate (SPH) has previously been demonstrated to modulate iron homeostatic mechanisms. In the present study, the anticancer effect of SPH and bicalutamide co-treatment on LNCaP and PC3 prostate cancer cell proliferation was investigated. Our results found that SPH potentiates the anti-proliferative effect of bicalutamide in a dose-dependent manner for both cell lines. In the presence of 160 µg/mL SPH, co-treatment with 1.0 µM bicalutamide decreased LNCaP cells’ relative colony survival from 25% (1.0 µM bicalutamide monotreatment) to 2% after culturing for 12 days. For PC3 cells, the relative colony survival diminished from 52% (10.0 µM bicalutamide) to 32% at an SPH concentration of 160 µg/mL. Gene expression profiling, employing quantitative real-time PCR, revealed that the inhibitory effects were related to significant FTH1 up-regulation with a concomitant TFRC down-regulation. In conclusion, our results provide in vitro evidence that SPH potentiates the growth inhibitory effect of bicalutamide on prostate cancer cells by modulating iron homeostasis mechanisms.
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48
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Rana S, Prabhakar N. Iron disorders and hepcidin. Clin Chim Acta 2021; 523:454-468. [PMID: 34755647 DOI: 10.1016/j.cca.2021.10.032] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 10/22/2021] [Accepted: 10/26/2021] [Indexed: 12/13/2022]
Abstract
Iron is an essential element due to its role in a wide variety of physiological processes. Iron homeostasis is crucial to prevent iron overload disorders as well as iron deficiency anemia. The liver synthesized peptide hormone hepcidin is a master regulator of systemic iron metabolism. Given its role in overall health, measurement of hepcidin can be used as a predictive marker in disease states. In addition, hepcidin-targeting drugs appear beneficial as therapeutic agents. This review emphasizes recent development on analytical techniques (immunochemical, mass spectrometry and biosensors) and therapeutic approaches (hepcidin agonists, stimulators and antagonists). These insights highlight hepcidin as a potential biomarker as well as an aid in the development of new drugs for iron disorders.
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Affiliation(s)
- Shilpa Rana
- Department of Biochemistry, Sector-25, Panjab University, Chandigarh 160014, India
| | - Nirmal Prabhakar
- Department of Biochemistry, Sector-25, Panjab University, Chandigarh 160014, India.
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49
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Guo Q, Li L, Hou S, Yuan Z, Li C, Zhang W, Zheng L, Li X. The Role of Iron in Cancer Progression. Front Oncol 2021; 11:778492. [PMID: 34858857 PMCID: PMC8631356 DOI: 10.3389/fonc.2021.778492] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 10/15/2021] [Indexed: 01/19/2023] Open
Abstract
Iron is an essential trace element for the human body, and its deficiency or excess can induce a variety of biological processes. Plenty of evidences have shown that iron metabolism is closely related to the occurrence and development of tumors. In addition, iron plays an important role in cell death, which is very important for the development of potential strategies for tumor treatment. Here, we reviewed the latest research about iron metabolism disorders in various types of tumors, the functions and properties of iron in ferroptosis and ferritinophagy, and new opportunities for iron-based on treatment methods for tumors, providing more information regarding the prevention and treatment of tumors.
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Affiliation(s)
- Qianqian Guo
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Liwen Li
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Shanshan Hou
- Department of Pharmacy, Zhejiang Pharmaceutical College, Ningbo, China
| | - Ziqiao Yuan
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Chenhui Li
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Wenzhou Zhang
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiaoman Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
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50
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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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