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Gao YF, Yang YJ, Qin JB, Yu MY, Hu SW, Zhang HF, Lin FH, Hu HY, Fang MJ, Zeng JZ. Design, synthesis, and biological evaluation of quinolinyl-ureido-phenyl-hydrazide derivatives and quinolinyl-hydrazide derivatives as anticancer agents targeting Nur77-mediated ferroptosis. Eur J Med Chem 2025; 291:117559. [PMID: 40215561 DOI: 10.1016/j.ejmech.2025.117559] [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: 01/29/2025] [Revised: 03/11/2025] [Accepted: 03/21/2025] [Indexed: 05/03/2025]
Abstract
In the recent decade, targeting ferroptosis for cancer therapy has attracted remarkable attention. Interestingly, the transcriptional regulator Nur77, a promising therapeutic target in cancer, has been recently identified as a crucial regulator of ferroptosis. However, no ferroptosis inducer targeting Nur77 has been reported currently. In this study, we built upon our prior research on Nur77 modulator 4-PQBH to design and synthesize four series of new compounds, with the objective of developing novel Nur77-mediated ferroptosis inducers. Among them, compound 8f exhibited the most potency against the tested cancer cell lines, including human estrogen positive breast cancer and triple-negative breast cancer cell lines, while displaying lower toxicity towards human normal cell lines HaCaT and MCF-10A (IC50> 50 μM). Furthermore, 8f demonstrated superior Nur77-binding activity in comparison to the reference compound Csn-B, and it has the capacity to activate the Nur77-driven luciferase activity and increase the protein level of Nur77. Remarkably, 8f induced an increase in the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and lipid peroxidation, concurrently with a reduction in the expression of GPX4 protein, culminating in the induction of ferroptosis in a Nur77-dependent manner. In vivo, 8f treatment has been observed to significantly suppress MCF7 xenograft tumor growth. Consequently, a novel ferroptosis inducer targeting Nur77 (8f) is first reported as a potent anti-EPBC agent, providing may serve as a promising lead for further drug development targeting Nur77-mediated ferroptosis.
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Affiliation(s)
- Yan-Fang Gao
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China
| | - Yi-Jing Yang
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China
| | - Jing-Bo Qin
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong-Hong Kong-Macao University Joint Laboratory of the Interventional Medicine Foundation of Guangdong Province, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, China
| | - Ming-Yue Yu
- Xingzhi College, Zhejiang Normal University, Lanxi, 321004, China; College of Chemistry and Bioengineering, Yichun, 336000, China
| | - Sheng-Wei Hu
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China
| | - Hao-Fan Zhang
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China
| | - Fan-Hong Lin
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China
| | - Hong-Yu Hu
- Xingzhi College, Zhejiang Normal University, Lanxi, 321004, China.
| | - Mei-Juan Fang
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China.
| | - Jin-Zhang Zeng
- State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China.
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Rabiu L, Zhang P, Liu Z, Tang Y, Gidado KI, Ibrahim A, Saliu MA, Tariq HK, Wan X, Xu S, Xu Z, Zhang G. TIPE2 deficiency amplifies inflammation and immune dysregulation in MASH through modulating hepatic lipid metabolism and immune cell function. Inflamm Res 2025; 74:65. [PMID: 40244311 DOI: 10.1007/s00011-025-02031-6] [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: 12/24/2024] [Revised: 03/20/2025] [Accepted: 04/01/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND Metabolic Dysfunction-Associated Steatohepatitis (MASH) affects nearly 25% of the global population, yet there are no effective pharmacological treatments. Tumor necrosis factor α-induced protein 8-like 2 (TIPE2) is expressed in various immune cells and is crucial for regulating both innate and adaptive immune responses. However, its role in MASH development and the underlying mechanisms remain unclear. METHOD In this study, the role of TIPE2 in MASH was investigated using TIPE2 knockout (KO) mice and human hepatic LO2 cells. Immune cell infiltration, cytokine levels, and gene expression were analyzed. Techniques included flow cytometry for immune cell profiling, cytokine analysis, RNA sequencing, and quantitative PCR (qPCR) for validating gene expression changes. RESULTS TIPE2 was identified as a key regulator in MASH, influencing immune modulation and metabolic processes. TIPE2 KO mice exhibited increased infiltration and activation of natural killer (NK) cells, M1 macrophages, and myeloid-derived suppressor cells (MDSCs), along with elevated pro-inflammatory cytokines such as IFN-gamma, TNF-alpha, IL- 1 beta, and IL- 6. MDSCs from TIPE2 KO mice demonstrated enhanced PD-L1 expression, contributing to chronic liver inflammation through T cell suppression. RNA sequencing revealed that TIPE2 overexpression in human hepatic LO2 cells upregulated genes associated with amino acid biosynthesis, carbon metabolism, lipid regulation, glycolysis, and gluconeogenesis. These findings were supported by qPCR analyses of liver samples from mice, confirming TIPE2's role in maintaining lipid homeostasis and modulating immune responses. CONCLUSION The study highlights the pivotal role of TIPE2 in immune regulation and its influence on immune cell activation and inflammatory responses, which are critical in MASH progression. By exploring TIPE2-mediated immune regulation and its impact on the interplay between immune cell dynamics and liver metabolism, this research underscores TIPE2's central role in linking immune dysfunction to metabolic disturbances in MASH.
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Affiliation(s)
- Lawan Rabiu
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China
- University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Pengchao Zhang
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China
- University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Zhongming Liu
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China
| | - Yexiao Tang
- Cancer Center, Shenzhen Guangming District People's Hospital, Shenzhen, 518106, PR China
| | - Khalid I Gidado
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China
- University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Abdulrahman Ibrahim
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China
- University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Muhammad A Saliu
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China
- University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Hafiza Kashaf Tariq
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China
- University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Xiaochun Wan
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China
- University of Chinese Academy of Sciences, Beijing, 100049, PR China
| | - Shu Xu
- Cancer Center, Shenzhen Guangming District People's Hospital, Shenzhen, 518106, PR China.
| | - Zhiming Xu
- Cancer Center, Shenzhen Guangming District People's Hospital, Shenzhen, 518106, PR China.
| | - Guizhong Zhang
- Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, PR China.
- University of Chinese Academy of Sciences, Beijing, 100049, PR China.
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Yang G, Qian B, He L, Zhang C, Wang J, Qian X, Wang Y. Application prospects of ferroptosis in colorectal cancer. Cancer Cell Int 2025; 25:59. [PMID: 39984914 PMCID: PMC11846473 DOI: 10.1186/s12935-025-03641-0] [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: 01/10/2024] [Accepted: 01/07/2025] [Indexed: 02/23/2025] Open
Abstract
Colorectal cancer (CRC) is a serious threat to human health with the third morbidity and the second cancer-related mortality worldwide. It is urgent to explore more effective strategy for CRC because of the acquired treatment resistance from the non-surgical conventional therapies, including radiation, chemotherapy, targeted therapy and immunotherapy. Ferroptosis is a novel form of programmed cell death characterized by iron-dependent lipid peroxidation species (ROS) accumulation and has been identified as a promising target for cancer treatment, especially for those with treatment resistance. In this review, we mainly summarize the recent studies on the influence and regulation of ferroptosis by which (including gut microbiota) modulating the metabolism of iron, amino acid and lipid. Thus this analysis may provide potential targets for inducing CRC ferroptosis and shed lights on the future application of ferroptosis in CRC.
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Affiliation(s)
- Gen Yang
- Department of Pathology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Boning Qian
- Department of Pathology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Liya He
- Department of Pathology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Chi Zhang
- Department of Pathology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Jianqiang Wang
- Department of Pathology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, Henan, China
| | - Xinlai Qian
- Department of Pathology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, Henan, China.
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
- Henan Provincial Key Laboratory of Molecular Oncologic Pathology, Xinxiang, Henan, China.
| | - Yongxia Wang
- Department of Pathology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, Henan, China.
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
- Henan Provincial Key Laboratory of Molecular Oncologic Pathology, Xinxiang, Henan, China.
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Safari MH, Rahimzadeh P, Alaei E, Alimohammadi M, Esfandiari N, Daneshi S, Malgard N, Farahani N, Taheriazam A, Hashemi M. Targeting ferroptosis in gastrointestinal tumors: Interplay of iron-dependent cell death and autophagy. Mol Cell Probes 2025; 79:102013. [PMID: 39837469 DOI: 10.1016/j.mcp.2025.102013] [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: 11/22/2024] [Revised: 01/06/2025] [Accepted: 01/18/2025] [Indexed: 01/23/2025]
Abstract
Ferroptosis is a regulated cell death mechanism distinct from apoptosis, autophagy, and necroptosis, marked by iron accumulation and lipid peroxidation. Since its identification in 2012, it has developed into a potential therapeutic target, especially concerning GI disorders like PC, HCC, GC, and CRC. This interest arises from the distinctive role of ferroptosis in the progression of diseases, presenting a new avenue for treatment where existing therapies fall short. Recent studies emphasize the promise of focusing on ferroptosis to fight GI cancers, showcasing its unique pathophysiological mechanisms compared to other types of cell death. By comprehending how ferroptosis aids in the onset and advancement of GI diseases, scientists aim to discover novel drug targets and treatment approaches. Investigating ferroptosis in gastrointestinal disorders reveals exciting possibilities for novel therapies, potentially revolutionizing cancer treatment and providing renewed hope for individuals affected by these tumors.
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Affiliation(s)
- Mohamad Hosein Safari
- Department of Internal Medicine, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Elmira Alaei
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mina Alimohammadi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Negin Esfandiari
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Salman Daneshi
- Department of Public Health, School of Health, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Neda Malgard
- Department of Internal Medicine, Firoozgar Hospital, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Najma Farahani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Taha SR, Karimi M, Mahdavi B, Yousefi Tehrani M, Bemani A, Kabirian S, Mohammadi J, Jabbari S, Hushmand M, Mokhtar A, Pourhanifeh MH. Crosstalk between non-coding RNAs and programmed cell death in colorectal cancer: implications for targeted therapy. Epigenetics Chromatin 2025; 18:3. [PMID: 39810224 PMCID: PMC11734566 DOI: 10.1186/s13072-024-00560-8] [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: 09/17/2024] [Accepted: 11/13/2024] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) remains one of the most common causes of cancer-related mortality worldwide. Its progression is influenced by complex interactions involving genetic, epigenetic, and environmental factors. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have been identified as key regulators of gene expression, affecting diverse biological processes, notably programmed cell death (PCD). OBJECTIVE This review aims to explore the relationship between ncRNAs and PCD in CRC, focusing on how ncRNAs influence cancer cell survival, proliferation, and treatment resistance. METHODS A comprehensive literature analysis was conducted to examine recent findings on the role of ncRNAs in modulating various PCD mechanisms, including apoptosis, autophagy, necroptosis, and pyroptosis, and their impact on CRC development and therapeutic response. RESULTS ncRNAs were found to significantly regulate PCD pathways, impacting tumor growth, metastasis, and treatment sensitivity in CRC. Their influence on these pathways highlights the potential of ncRNAs as biomarkers for early CRC detection and as targets for innovative therapeutic interventions. CONCLUSION Understanding the involvement of ncRNAs in PCD regulation offers new insights into CRC biology. The targeted modulation of ncRNA-PCD interactions presents promising avenues for personalized cancer treatment, which may improve patient outcomes by enhancing therapeutic effectiveness and reducing resistance.
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Affiliation(s)
- Seyed Reza Taha
- Department of Pathology and Immunology, Washington University School of Medicine, St. LouisWashington, MO, USA
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mehdi Karimi
- Faculty of Medicine, Bogomolets National Medical University (NMU), Kiev, Ukraine.
| | - Bahar Mahdavi
- Department of Molecular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | | | - Ali Bemani
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Shahriar Kabirian
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Javad Mohammadi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Sina Jabbari
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Meysam Hushmand
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Alireza Mokhtar
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Hossein Pourhanifeh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
- PAKAN Institute, Tehran, Iran.
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Xia W, Lv Y, Zou Y, Kang Z, Li Z, Tian J, Zhou H, Su W, Zhong J. The role of ferroptosis in colorectal cancer and its potential synergy with immunotherapy. Front Immunol 2025; 15:1526749. [PMID: 39850905 PMCID: PMC11754392 DOI: 10.3389/fimmu.2024.1526749] [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: 11/12/2024] [Accepted: 12/20/2024] [Indexed: 01/25/2025] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent and deadly malignancies worldwide. Recently, ferroptosis, a novel form of regulated cell death characterized by iron dependency and lipid peroxidation, has garnered significant attention from researchers. The mechanisms underlying ferroptosis, including intracellular iron levels, lipid peroxidation, and antioxidant system regulation, offer new insights into cancer treatment strategies. This study aims to explore the emerging role of ferroptosis in the context of immunotherapy for CRC, highlighting its potential mechanisms and clinical applications. We employed a comprehensive review of current literature to elucidate the biological mechanisms of ferroptosis, its relationship with CRC, and the interplay between ferroptosis and immunotherapy. Ferroptosis reshapes the tumor microenvironment (TME) by regulating intracellular iron levels, lipid metabolism, and antioxidant systems, significantly enhancing the efficacy of immune checkpoint inhibitors (ICIs). Meanwhile, traditional Chinese medicine therapies promote antitumor immunity by modulating the TME and inducing ferroptosis. Additionally, advances in nanotechnology have facilitated precise therapy by enabling targeted delivery of ferroptosis inducers or immunomodulators, transforming "cold" tumors into "hot" tumors and further boosting ICI efficacy. This study comprehensively reviews the latest developments in ferroptosis, immunotherapy, traditional Chinese medicine, and nanotechnology in CRC, highlighting the importance of ferroptosis-related biomarkers and novel inducers for personalized treatment. In summary, ferroptosis offers a promising strategy to overcome CRC therapy resistance and enhance immunotherapy efficacy, warranting further investigation and translational application.
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Affiliation(s)
- Wenhua Xia
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Yuanhao Lv
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Yan Zou
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Zhanting Kang
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Zhaoyi Li
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Jiaqi Tian
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Hongyan Zhou
- Xinxiang Key Laboratory of Precision Diagnosis and Treatment for Colorectal Cancer, Xinxiang First People’s Hospital, Xinxiang, China
| | - Wei Su
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
- Xinxiang Engineering Technology Research Center of Digestive Tumor Molecular Diagnosis, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Jiateng Zhong
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
- Xinxiang Key Laboratory of Precision Diagnosis and Treatment for Colorectal Cancer, Xinxiang First People’s Hospital, Xinxiang, China
- Xinxiang Engineering Technology Research Center of Digestive Tumor Molecular Diagnosis, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
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Li Y, Liu C, Fang B, Chen X, Wang K, Xin H, Wang K, Yang SM. Ferroptosis, a therapeutic target for cardiovascular diseases, neurodegenerative diseases and cancer. J Transl Med 2024; 22:1137. [PMID: 39710702 DOI: 10.1186/s12967-024-05881-6] [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: 09/02/2024] [Accepted: 11/13/2024] [Indexed: 12/24/2024] Open
Abstract
The identification of ferroptosis represents a pivotal advancement in the field of cell death research, revealing an entirely novel mechanism of cellular demise and offering new insights into the initiation, progression, and therapeutic management of various diseases. Ferroptosis is predominantly induced by intracellular iron accumulation, lipid peroxidation, or impairments in the antioxidant defense system, culminating in membrane rupture and consequent cell death. Studies have associated ferroptosis with a wide range of diseases, and by enhancing our comprehension of its underlying mechanisms, we can formulate innovative therapeutic strategies, thereby providing renewed hope for patients.
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Affiliation(s)
- Yinghui Li
- Department of Cardiovascular Surgery, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
| | - Cuiyun Liu
- Department of Cardiovascular Surgery, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
| | - Bo Fang
- Department of Cardiovascular Surgery, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
| | - Xinzhe Chen
- Department of Cardiovascular Surgery, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
| | - Kai Wang
- Department of Cardiovascular Surgery, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
| | - Hui Xin
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, 266021, China.
| | - Kun Wang
- Department of Cardiovascular Surgery, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China.
| | - Su-Min Yang
- Department of Cardiovascular Surgery, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China.
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Fang C, Tu H, Li R, Bi D, Shu G. Bronchopulmonary dysplasia: analysis and validation of ferroptosis-related diagnostic biomarkers and immune cell infiltration features. Pediatr Res 2024; 96:1673-1680. [PMID: 38760473 DOI: 10.1038/s41390-024-03249-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 04/07/2024] [Accepted: 04/16/2024] [Indexed: 05/19/2024]
Abstract
BACKGROUND Early and precise diagnosis of bronchopulmonary dysplasia (BPD) is essential to improve the prognosis of preterm infants with BPD. Studying ferroptosis-related genes for diagnostic markers of BPD was the objective of this study. METHODS Using the GEO database and the FerrDb database, we obtained the GSE32472 dataset and screened the ferroptosis-related differentially expressed mRNAs (FRDE-mRNAs). By using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG), possible biological functions and pathways were identified for FRDE-mRNAs. Three machine learning algorithms (LASSO, SVM-RFE, Random Forest) were used to recognize hub genes, as well as CIBERSORT for exploring the immune landscape of BPD and controls. Functional predictions for hub genes were made using single-gene gene set enrichment analysis (GSEA). RESULTS Twenty three FRDE-mRNAs were obtained and were mainly involved in autophagy, fatty acid metabolism and ferroptosis. The four hub genes (LPIN1, ACADSB, WIPI1 and SLC7A11) screened were utilized to construct a diagnostic nomogram. The receiver operating characteristic (ROC) curves and calibration curves demonstrateld that the nomogram exhibited good predictive performance. Eight types of immune cell markers differed significantly between BPD and controls. CONCLUSION We developed a diagnostic model for BPD, which could facilitate the early diagnosis and timely intervention of BPD. IMPACT The role of ferroptosis in bronchopulmonary dysplasia is rarely reported. The ferroptosis-related genes (LPIN1, ACADSB, WIPI1 and SLC7A11) we identified could serve as early diagnostic biomarkers for BPD. Immune cell infiltration features in BPD and signaling pathways associated with marker genes give new insight into the disease process and provide a basis for further research.
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Affiliation(s)
| | - Haixia Tu
- School of Medicine, Yangzhou University, Yangzhou, China
| | - Rong Li
- Dalian Medical University, Dalian, China
| | - Dengqin Bi
- School of Medicine, Yangzhou University, Yangzhou, China
| | - Guihua Shu
- School of Medicine, Yangzhou University, Yangzhou, China.
- Department of Neonatology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, China.
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Feng Y, Liu CH, Yang J, Zhang H, Li L, Yang Q, Gan W, Yang Z, Gong P, Fu C, Qian G, Li D. Integrative analysis of non12-hydroxylated bile acid revealed the suppressed molecular map of alternative pathway in nonalcoholic steatohepatitis mice. FASEB J 2024; 38:e70167. [PMID: 39556333 DOI: 10.1096/fj.202401630r] [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: 07/17/2024] [Revised: 10/17/2024] [Accepted: 10/28/2024] [Indexed: 11/19/2024]
Abstract
Bile acids (BAs) are significantly altered in the liver and serum of patients with nonalcoholic steatohepatitis (NASH). However, the underlying mechanisms of these changes, particularly BA alternative pathways (BAP) responsible for non12-OH BAs, remain unclear. RNA-seq data were initially analyzed to reveal the changes of gene expression in NASH patients. Targeted metabolomics were conducted on plasma from NASH mice induced by high-fat or western diet with CCl4 for 10-24 weeks. Liver tissues were examined using proteomics, RT-qPCR, and western blotting. An integrated approach was then employed to analyze protein interactions and network correlations. Analysis of RNA-seq data revealed the inhibition of CYP7B1 in NASH patients, indicating the dysregulation of BAP. In NASH mouse models, dysregulation of BA circulation was observed by increased plasma total BA (TBA) levels and decreased liver TBA, with liver swelling and histopathological changes. Targeted metabolomics revealed suppressed levels of non12-OH BAs, which inversely correlated with increased liver injury markers. The reduced mRNA and protein expression of Fxr and upregulation of Lxr signaling in livers suggested the suppressed BAP was modulated by Fxr-Lxr signaling. Moreover, BAP interactions predominantly implicated multiple metabolism disruptions, involving 7 hub proteins (Hk1, Acadsb, Pklr, Insr, Ldlr, Cyp27a1, and Cyp7b1), offering promising therapeutic targets for NASH. We presented the metabolic and proteomic map of BAP and its regulatory network in NASH progression. Therapeutic targeting of BAP or its co-regulatory proteins holds promise for NASH treatment and metabolic syndrome management.
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Affiliation(s)
- Yanruyu Feng
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
- Ninth People's Hospital of Zhengzhou, Zhengzhou, China
| | - Chang-Hai Liu
- Center of Infectious Diseases, Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Jingtao Yang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - He Zhang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Lian Li
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Qian Yang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Wei Gan
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Zi Yang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Puyang Gong
- College of Pharmacy, Southwest Minzu University, Chengdu, China
| | - Chunmei Fu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Guangsheng Qian
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Dapeng Li
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
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10
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Chi ZC. Progress in research of ferroptosis in gastrointestinal tumors. Shijie Huaren Xiaohua Zazhi 2024; 32:699-715. [DOI: 10.11569/wcjd.v32.i10.699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/04/2024] [Accepted: 09/19/2024] [Indexed: 10/28/2024] Open
Abstract
Ferroptosis is a non-apoptotic and oxidation-damaged regulated cell death caused by iron accumulation, lipid peroxidation, and subsequent plasma membrane rupture. Ferroptosis is the main cause of tissue damage caused by iron overload and lipid peroxidation. With the deepening of the research in recent years, the understanding of the occurrence and treatment of tumors has made a major breakthrough, which brings new strategies for anti-cancer treatment. This paper reviews the relationship between ferroptosis and gastrointestinal tumors, the research of ferroptosis in cancer prevention and treatment, and the role of ferroptosis in the prevention and treatment of gastrointestinal tumors.
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Affiliation(s)
- Zhao-Chun Chi
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao 266011, Shandong Province, China
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11
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Ru Q, Li Y, Chen L, Wu Y, Min J, Wang F. Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects. Signal Transduct Target Ther 2024; 9:271. [PMID: 39396974 PMCID: PMC11486532 DOI: 10.1038/s41392-024-01969-z] [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: 03/27/2024] [Revised: 08/08/2024] [Accepted: 09/02/2024] [Indexed: 10/15/2024] Open
Abstract
Iron, an essential mineral in the body, is involved in numerous physiological processes, making the maintenance of iron homeostasis crucial for overall health. Both iron overload and deficiency can cause various disorders and human diseases. Ferroptosis, a form of cell death dependent on iron, is characterized by the extensive peroxidation of lipids. Unlike other kinds of classical unprogrammed cell death, ferroptosis is primarily linked to disruptions in iron metabolism, lipid peroxidation, and antioxidant system imbalance. Ferroptosis is regulated through transcription, translation, and post-translational modifications, which affect cellular sensitivity to ferroptosis. Over the past decade or so, numerous diseases have been linked to ferroptosis as part of their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous system diseases, cardiovascular diseases, and musculoskeletal diseases. Ferroptosis-related proteins have become attractive targets for many major human diseases that are currently incurable, and some ferroptosis regulators have shown therapeutic effects in clinical trials although further validation of their clinical potential is needed. Therefore, in-depth analysis of ferroptosis and its potential molecular mechanisms in human diseases may offer additional strategies for clinical prevention and treatment. In this review, we discuss the physiological significance of iron homeostasis in the body, the potential contribution of ferroptosis to the etiology and development of human diseases, along with the evidence supporting targeting ferroptosis as a therapeutic approach. Importantly, we evaluate recent potential therapeutic targets and promising interventions, providing guidance for future targeted treatment therapies against human diseases.
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Affiliation(s)
- Qin Ru
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Yusheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Lin Chen
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China
| | - Yuxiang Wu
- Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China.
| | - Junxia Min
- The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
| | - Fudi Wang
- The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China.
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12
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Yan L, Shi J, Zhu J. Cellular and molecular events in colorectal cancer: biological mechanisms, cell death pathways, drug resistance and signalling network interactions. Discov Oncol 2024; 15:294. [PMID: 39031216 PMCID: PMC11265098 DOI: 10.1007/s12672-024-01163-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 07/15/2024] [Indexed: 07/22/2024] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, affecting millions each year. It emerges from the colon or rectum, parts of the digestive system, and is closely linked to both genetic and environmental factors. In CRC, genetic mutations such as APC, KRAS, and TP53, along with epigenetic changes like DNA methylation and histone modifications, play crucial roles in tumor development and treatment responses. This paper delves into the complex biological underpinnings of CRC, highlighting the pivotal roles of genetic alterations, cell death pathways, and the intricate network of signaling interactions that contribute to the disease's progression. It explores the dysregulation of apoptosis, autophagy, and other cell death mechanisms, underscoring the aberrant activation of these pathways in CRC. Additionally, the paper examines how mutations in key molecular pathways, including Wnt, EGFR/MAPK, and PI3K, fuel CRC development, and how these alterations can serve as both diagnostic and prognostic markers. The dual function of autophagy in CRC, acting as a tumor suppressor or promoter depending on the context, is also scrutinized. Through a comprehensive analysis of cellular and molecular events, this research aims to deepen our understanding of CRC and pave the way for more effective diagnostics, prognostics, and therapeutic strategies.
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Affiliation(s)
- Lei Yan
- Medical Department, The Central Hospital of Shaoyang Affiliated to University of South China, Shaoyang, China
| | - Jia Shi
- Department of Obstetrics and Gynecology, The Central Hospital of Shaoyang Affiliated to University of South China, Shaoyang, China
| | - Jiazuo Zhu
- Department of Oncology, Xuancheng City Central Hospital, No. 117 Tong Road, Xuancheng, Anhui, China.
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13
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Khan F, Pandey P, Verma M, Ramniwas S, Lee D, Moon S, Park MN, Upadhyay TK, Kim B. Emerging trends of phytochemicals as ferroptosis modulators in cancer therapy. Biomed Pharmacother 2024; 173:116363. [PMID: 38479184 DOI: 10.1016/j.biopha.2024.116363] [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: 12/27/2023] [Revised: 02/24/2024] [Accepted: 02/27/2024] [Indexed: 03/27/2024] Open
Abstract
Ferroptosis, a novel form of regulated cell death characterized by dependence on iron and lipid peroxidation, has been implicated in a wide range of clinical conditions including neurological diseases, cardiovascular disorders, acute kidney failure, and various types of cancer. Therefore, it is critical to suppress cancer progression and proliferation. Ferroptosis can be triggered in cancer cells and some normal cells by synthetic substances, such as erastin, Ras-selective lethal small molecule-3, or clinical pharmaceuticals. Natural bioactive compounds are traditional drug discovery tools, and some have been therapeutically used as dietary additives or pharmaceutical agents against various malignancies. The fact that natural products have multiple targets and minimal side effects has led to notable advances in anticancer research. Research has indicated that ferroptosis can also be induced by natural compounds during cancer treatment. In this review, we focused on the most recent developments in emerging molecular processes and the significance of ferroptosis in cancer. To provide new perspectives on the future development of ferroptosis-related anticancer medications, we also provide a summary of the implications of natural phytochemicals in triggering ferroptosis through ROS production and ferritinophagy induction in a variety of malignancies.
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Affiliation(s)
- Fahad Khan
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, India
| | - Pratibha Pandey
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, India.
| | - Meenakshi Verma
- University Centre for Research and Development, Chandigarh University, Gharuan, Mohali, Punjab 140413, India; Department of Chemistry, University Institute of Sciences, Chandigarh University, Gharuan, Mohali, Punjab 140413, India
| | - Seema Ramniwas
- University Centre for Research and Development, Chandigarh University, Gharuan, Mohali, Punjab 140413, India
| | - Dain Lee
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemun-gu, Seoul 02447, the Republic of Korea
| | - Seungjoon Moon
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemun-gu, Seoul 02447, the Republic of Korea; Chansol Hospital of Korean Medicine, 290, Buheung-ro, Bupyeong-gu, Incheon 21390, the Republic of Korea
| | - Moon Nyeo Park
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemun-gu, Seoul 02447, the Republic of Korea
| | - Tarun Kumar Upadhyay
- Department of Biotechnology, Parul Institute of Applied Sciences and Research and Development Cell, Parul University, Vadodara 391760, India
| | - Bonglee Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemun-gu, Seoul 02447, the Republic of Korea.
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14
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Estêvão D, da Cruz-Ribeiro M, Cardoso AP, Costa ÂM, Oliveira MJ, Duarte TL, da Cruz TB. Iron metabolism in colorectal cancer: a balancing act. Cell Oncol (Dordr) 2023; 46:1545-1558. [PMID: 37273145 DOI: 10.1007/s13402-023-00828-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/04/2023] [Indexed: 06/06/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second deadliest malignancy worldwide. Current dietary habits are associated with increased levels of iron and heme, both of which increase the risk of developing CRC. The harmful effects of iron overload are related to the induction of iron-mediated pro-tumorigenic pathways, including carcinogenesis and hyperproliferation. On the other hand, iron deficiency may also promote CRC development and progression by contributing to genome instability, therapy resistance, and diminished immune responses. In addition to the relevance of systemic iron levels, iron-regulatory mechanisms in the tumor microenvironment are also believed to play a significant role in CRC and to influence disease outcome. Furthermore, CRC cells are more prone to escape iron-dependent cell death (ferroptosis) than non-malignant cells due to the constitutive activation of antioxidant genes expression. There is wide evidence that inhibition of ferroptosis may contribute to the resistance of CRC to established chemotherapeutic regimens. As such, ferroptosis inducers represent promising therapeutic drugs for CRC. CONCLUSIONS AND PERSPECTIVES This review addresses the complex role of iron in CRC, particularly in what concerns the consequences of iron excess or deprivation in tumor development and progression. We also dissect the regulation of cellular iron metabolism in the CRC microenvironment and emphasize the role of hypoxia and of oxidative stress (e.g. ferroptosis) in CRC. Finally, we underline some iron-related players as potential therapeutic targets against CRC malignancy.
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Affiliation(s)
- Diogo Estêvão
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
- Laboratory of Experimental Cancer Research, Department of Human Structure and Repair, Cancer Research Institute, Ghent University, Ghent, Belgium
| | - Miguel da Cruz-Ribeiro
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal
| | - Ana P Cardoso
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
| | - Ângela M Costa
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
| | - Maria J Oliveira
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
- FMUP - Faculty of Medicine, Pathology Department, University of Porto, Porto, Portugal
| | - Tiago L Duarte
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
| | - Tânia B da Cruz
- i3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal.
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15
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Li Q, Liu H, Jin Y, Yu Y, Wang Y, Wu D, Guo Y, Xi L, Ye D, Pan Y, Zhang X, Li J. Analysis of a new therapeutic target and construction of a prognostic model for breast cancer based on ferroptosis genes. Comput Biol Med 2023; 165:107370. [PMID: 37643511 DOI: 10.1016/j.compbiomed.2023.107370] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 07/09/2023] [Accepted: 08/12/2023] [Indexed: 08/31/2023]
Abstract
Breast cancer, which is the most common malignant tumor among women worldwide and an important cause of death in women. The existing prognostic model for patients with breast cancer is not accurate as breast cancer is resistant to commonly used antitumor drugs. Ferroptosis is a novel mechanism of programmed cell death that depends on iron accumulation and lipid peroxidation. Various studies have confirmed the role of ferroptosis in tumor regulation and ferroptosis is now considered to play an important role in breast cancer development. At present, the association between breast cancer prognosis and ferroptosis-related gene expression remains unclear. Further exploration of this research area may optimize the evaluation and prediction of prognosis of patients with breast cancer and finding of new therapeutic targets. In this study, clinical factors and the expression of multiple genes were evaluated in breast cancer samples from the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database database. Eleven prognostication-related genes (TP63, IFNG, MT3, ANO6, FLT3, PTGS2, SLC1A4, JUN, SLC7A5, CHAC1, and TF) were identified from differentially expressed genes to construct a survival prediction model, which showed a good prediction ability. KEGG pathway analysis revealed that immune-related pathways were the primary pathways. ssGSEA analysis showed significant differences in the distribution of certain immune-related cell subsets, such as CD8+T cells and B cells, and in the expression of multiple immune genes, including type II IFN response and APC coinhibition. In addition, 10 immune targets related to ferroptosis in breast cancer were found: CD276, CD80, HHLA2, LILRA2, NCR3LG1, NECTIN3, PVR, SLAMF9,TNFSF4, and BTN1A1. Using TCGA, new ferroptosis genes related to breast cancer prognosis were identified, a new reliable and accurate prognosis model was developed, and 10 new potential therapeutic targets different from the traditional targeted drugs were identified to provide a reference for improving the poor prognosis of patients with breast cancer.
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Affiliation(s)
- Qi Li
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.
| | - Hengchen Liu
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Zhejiang Provincial Clinical Research Center for Cancer, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.
| | - Yun Jin
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.
| | - Yuanquan Yu
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.
| | - Yihang Wang
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.
| | - Di Wu
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.
| | - Yinghao Guo
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.
| | - Longfu Xi
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.
| | - Dan Ye
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.
| | - Yanzhi Pan
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.
| | - Xiaoxiao Zhang
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.
| | - Jiangtao Li
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China; Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, China.
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Zhu X, Li S. Ferroptosis, Necroptosis, and Pyroptosis in Gastrointestinal Cancers: The Chief Culprits of Tumor Progression and Drug Resistance. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2300824. [PMID: 37436087 PMCID: PMC10502844 DOI: 10.1002/advs.202300824] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 06/29/2023] [Indexed: 07/13/2023]
Abstract
In recent years, the incidence of gastrointestinal cancers is increasing, particularly in the younger population. Effective treatment is crucial for improving patients' survival outcomes. Programmed cell death, regulated by various genes, plays a fundamental role in the growth and development of organisms. It is also critical for maintaining tissue and organ homeostasis and takes part in multiple pathological processes. In addition to apoptosis, there are other types of programmed cell death, such as ferroptosis, necroptosis, and pyroptosis, which can induce severe inflammatory responses. Notably, besides apoptosis, ferroptosis, necroptosis, and pyroptosis also contribute to the occurrence and development of gastrointestinal cancers. This review aims to provide a comprehensive summary on the biological roles and molecular mechanisms of ferroptosis, necroptosis, and pyroptosis, as well as their regulators in gastrointestinal cancers and hope to open up new paths for tumor targeted therapy in the near future.
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Affiliation(s)
- Xudong Zhu
- Department of General SurgeryCancer Hospital of Dalian University of TechnologyCancer Hospital of China Medical UniversityLiaoning Cancer Hospital and InstituteShenyangLiaoning Province110042China
| | - Shenglong Li
- Second Ward of Bone and Soft Tissue Tumor SurgeryCancer Hospital of Dalian University of TechnologyCancer Hospital of China Medical UniversityLiaoning Cancer Hospital and InstituteShenyangLiaoning Province110042China
- The Liaoning Provincial Key Laboratory of Interdisciplinary Research on Gastrointestinal Tumor Combining Medicine with EngineeringShenyangLiaoning Province110042China
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17
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Yoo SS, Do SK, Choi JE, Kang HG, Hong MJ, Lee JH, Lee WK, Do YW, Lee EB, Park JE, Choi SH, Seo H, Lee YH, Lee J, Lee SY, Cha SI, Kim CH, Park JY. Lipid Metabolism Pathway Genes and Lung Cancer: ACADSB rs12220683G>C Is Associated with Better Survival Outcome in Patients with Non-Small Cell Lung Cancer. Oncology 2023; 102:67-75. [PMID: 37527640 DOI: 10.1159/000533156] [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: 02/23/2023] [Accepted: 07/14/2023] [Indexed: 08/03/2023]
Abstract
INTRODUCTION Altered lipid metabolism has been reported to be associated with prognosis in multiple cancers. This study aimed to investigate the association of polymorphisms in lipid metabolism pathway genes with survival outcomes in patients with surgically resected non-small cell lung cancer (NSCLC). METHODS In total, 744 patients with surgically resected NSCLC (380 in the discovery cohort and 364 in the validation cohort) were included in this study. The association between 176 polymorphisms of lipid metabolism pathway genes and the clinical outcomes of NSCLC patients was analyzed. RESULTS Among the polymorphisms investigated, ACADSB rs10902859G>A was associated with significantly better overall survival (OS) in the discovery, validation, and combined cohorts. ACADSB rs10902859G>A was located in the repressed region and had strong linkage disequilibrium (D' = 1.00 and r2 = 0.94), with rs12220683G>C located in the H3K4me3 peak region, which indicates the presence of active promoters. ACADSB rs12220683G>C was also associated with better OS in the discovery, validation, and combined cohorts (in a dominant model; adjusted hazard ratio [aHR] = 0.53, 95% confidence interval [CI] = 0.30-0.94, p = 0.03; aHR = 0.37, 95% CI = 0.15-0.89, p = 0.03; and aHR = 0.47, 95% CI = 0.29-0.75, p = 0.002, respectively). In vitro luciferase assay demonstrated that the promoter activity of ACADSB was significantly increased in the rs12220683 variant C allele compared with that in the wild G allele (p = 3 × 10-5). CONCLUSION These results suggest that ACADSB rs12220683G>C increases promoter activity and that increased ACADSB expression may result in better OS in patients with surgically resected NSCLC.
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Affiliation(s)
- Seung Soo Yoo
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Sook Kyung Do
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
- Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Jin Eun Choi
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
- Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Hyo-Gyoung Kang
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
- Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Mi Jeong Hong
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
- Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Jang Hyuck Lee
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
- Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Won Kee Lee
- Medical Research Collaboration Center in Kyungpook National University Hospital and School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Young Woo Do
- Department of Thoracic Surgery, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Eung Bae Lee
- Department of Thoracic Surgery, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Ji Eun Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Sun Ha Choi
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Hyewon Seo
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Yong Hoon Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Jaehee Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Shin Yup Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Seung Ick Cha
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Chang Ho Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Jae Yong Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
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Chen Z, Wang W, Abdul Razak SR, Han T, Ahmad NH, Li X. Ferroptosis as a potential target for cancer therapy. Cell Death Dis 2023; 14:460. [PMID: 37488128 PMCID: PMC10366218 DOI: 10.1038/s41419-023-05930-w] [Citation(s) in RCA: 93] [Impact Index Per Article: 46.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 05/24/2023] [Accepted: 06/23/2023] [Indexed: 07/26/2023]
Abstract
Ferroptosis is a recently discovered essential type of cell death that is mainly characterized by iron overload and lipid peroxidation. Emerging evidence suggests that ferroptosis is a double-edged sword in human cancer. However, the precise underlying molecular mechanisms and their differential roles in tumorigenesis are unclear. Therefore, in this review, we summarize and briefly present the key pathways of ferroptosis, paying special attention to the regulation of ferroptosis as well as its dual role as an oncogenic and as a tumor suppressor event in various human cancers. Moreover, multiple pharmacological ferroptosis activators are summarized, and the prospect of targeting ferroptosis in cancer therapy is further elucidated.
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Affiliation(s)
- Zhen Chen
- Department of Gastroenterology, the Third Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Tumor Molecular Therapy Medicine, Xinxiang, 453003, Henan Province, China
- Department of Biomedical Science, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam 13200, Kepala Batas, Pulau Pinang, Malaysia
- Xinxiang Key Laboratory for Molecular Therapy of Cancer, Xinxiang Medical University, Xinxiang, 453003, Henan Province, P. R. China
| | - Weilong Wang
- Department of Gastroenterology, the Third Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Tumor Molecular Therapy Medicine, Xinxiang, 453003, Henan Province, China
- Department of Biomedical Science, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam 13200, Kepala Batas, Pulau Pinang, Malaysia
- Xinxiang Key Laboratory for Molecular Therapy of Cancer, Xinxiang Medical University, Xinxiang, 453003, Henan Province, P. R. China
| | - Siti Razila Abdul Razak
- Department of Biomedical Science, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam 13200, Kepala Batas, Pulau Pinang, Malaysia
| | - Tao Han
- Department of Gastroenterology, the Third Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Tumor Molecular Therapy Medicine, Xinxiang, 453003, Henan Province, China
- Xinxiang Key Laboratory for Molecular Therapy of Cancer, Xinxiang Medical University, Xinxiang, 453003, Henan Province, P. R. China
- Institutes of Health Central Plains, Xinxiang Medical University, Xinxiang, 453003, Henan Province, P. R. China
| | - Nor Hazwani Ahmad
- Department of Biomedical Science, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam 13200, Kepala Batas, Pulau Pinang, Malaysia.
| | - Xiumin Li
- Department of Gastroenterology, the Third Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Tumor Molecular Therapy Medicine, Xinxiang, 453003, Henan Province, China.
- Xinxiang Key Laboratory for Molecular Therapy of Cancer, Xinxiang Medical University, Xinxiang, 453003, Henan Province, P. R. China.
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Yu Z, Zhan Y, Guo Y, He D. Better prediction of clinical outcome in clear cell renal cell carcinoma based on a 6 metabolism-related gene signature. Sci Rep 2023; 13:11490. [PMID: 37460577 DOI: 10.1038/s41598-023-38380-7] [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: 05/22/2023] [Accepted: 07/07/2023] [Indexed: 07/20/2023] Open
Abstract
It has been reported that metabolic disorders participate in the formation and progression of clear cell renal cell carcinoma (ccRCC). However, the predictive value of metabolism-related genes (MRGs) in clinical outcome of ccRCC is still largely unknown. Herein, a novel metabolism-related signature was generated to assess the effect of MRGs on the prognosis of ccRCC patients. Important module MRGs were selected by differentially expressed analysis and WGCNA. Subsequently, the hub MRGs were screened via univariate cox regression as well as LASSO regression. A new metabolism-related signature of 6 hub MRGs (PAFAH2, ACADSB, ACADM, HADH, PYCR1 and ITPKA) was constructed, with a good prognostic prediction ability in the TCGA cohort. The prediction accuracy of this signature was further confirmed in both GSE22541 and FAHWMU cohort. Interestingly, this MRG risk signature was highly correlated with tumor mutation burden and immune infiltration in ccRCC. Notably, lower PAFAH2, a member of 6 MRGs, was found in ccRCC. Knockdown of PAFAH2 contributed to renal cancer cell proliferation and migration. Collectively, a 6-MRG prognostic risk signature is generated to estimate the prognostic status of ccRCC patients, providing a novel insight in the prognosis prediction and treatment of ccRCC.
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Affiliation(s)
- Zhixian Yu
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yating Zhan
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yong Guo
- Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Dalin He
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, China.
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Huang W, Yang F, Zhang Y, Fang Q, Lai Y, Lan Y. A Newly Established Cuproptosis-Related Gene Signature for Predicting Prognosis and Immune Infiltration in Uveal Melanoma. Int J Mol Sci 2023; 24:11358. [PMID: 37511120 PMCID: PMC10379443 DOI: 10.3390/ijms241411358] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/03/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
Uveal melanoma (UVM) is the most common primary ocular malignancy in adults and involves several types of regulated cell death. Cuproptosis is a novel method of regulating cell death by binding lipoylated TCA cycle proteins. There is still no research on the relationship between cuproptosis-related genes (CRGs) and UVM. Here, we aimed to develop a prognostic CRG signature for UVM. After a prognostic CRG signature was constructed, we determined the relationship between the signature and immune infiltration, bioinformatics analysis and experimental validation. Finally, a prognostic cuproptosis-related three-gene (CRTG) signature was constructed, which comprised ORAI2, ACADSB and SLC47A1. The risk score of the CRTG signature was negatively correlated with the overall survival (OS) and progression-free survival (PFS) of patients, which revealed strong predictive ability and its independent prognostic value. In addition, we found that the risk score was negative for chromosomes 3 and 6p, and positive for 8q, and high-risk UVM patients showed an increase in protumor immune infiltrates and a high expression of immune checkpoints. Finally, experimental validation verified that the migratory ability of MUM-2B cells was suppressed by the knockdown of the identified genes in vitro. We constructed a CRTG signature that is helpful in predicting prognosis and guiding treatment for patients with UVM.
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Affiliation(s)
- Wei Huang
- Department of Ophthalmology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; (W.H.)
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Fan Yang
- Department of Ophthalmology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; (W.H.)
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Center for Reproductive Genetics and Reproductive Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Yichi Zhang
- Department of Ophthalmology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; (W.H.)
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Qianqi Fang
- Department of Ophthalmology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; (W.H.)
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Yitao Lai
- Department of Ophthalmology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; (W.H.)
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Yuqing Lan
- Department of Ophthalmology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; (W.H.)
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
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21
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Zhang R, Chen J, Wang S, Zhang W, Zheng Q, Cai R. Ferroptosis in Cancer Progression. Cells 2023; 12:1820. [PMID: 37508485 PMCID: PMC10378139 DOI: 10.3390/cells12141820] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/01/2023] [Accepted: 07/08/2023] [Indexed: 07/30/2023] Open
Abstract
Ferroptosis is a newly discovered iron-dependent form of regulated cell death driven by phospholipid peroxidation and associated with processes including iron overload, lipid peroxidation, and dysfunction of cellular antioxidant systems. Ferroptosis is found to be closely related to many diseases, including cancer at every stage. Epithelial-mesenchymal transition (EMT) in malignant tumors that originate from epithelia promotes cancer-cell migration, invasion, and metastasis by disrupting cell-cell and cell-cell matrix junctions, cell polarity, etc. Recent studies have shown that ferroptosis appears to share multiple initiators and overlapping pathways with EMT in cancers and identify ferroptosis as a potential predictor of various cancer grades and prognoses. Cancer metastasis involves multiple steps, including local invasion of cancer cells, intravasation, survival in circulation, arrest at a distant organ site, extravasation and adaptation to foreign tissue microenvironments, angiogenesis, and the formation of "premetastatic niche". Numerous studies have revealed that ferroptosis is closely associated with cancer metastasis. From the cellular perspective, ferroptosis has been implicated in the regulation of cancer metastasis. From the molecular perspective, the signaling pathways activated during the two events interweave. This review briefly introduces the mechanisms of ferroptosis and discusses how ferroptosis is involved in cancer progression, including EMT, cancer angiogenesis, invasion, and metastasis.
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Affiliation(s)
- Rongyu Zhang
- Department of Biochemistry & Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jinghong Chen
- Department of Biochemistry & Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Saiyang Wang
- Department of Biochemistry & Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Wenlong Zhang
- Department of Biochemistry & Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Quan Zheng
- Center for Singl-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Rong Cai
- Department of Biochemistry & Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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Yan H, Talty R, Aladelokun O, Bosenberg M, Johnson CH. Ferroptosis in colorectal cancer: a future target? Br J Cancer 2023; 128:1439-1451. [PMID: 36703079 PMCID: PMC10070248 DOI: 10.1038/s41416-023-02149-6] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 01/05/2023] [Accepted: 01/10/2023] [Indexed: 01/27/2023] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer deaths worldwide and is characterised by frequently mutated genes, such as APC, TP53, KRAS and BRAF. The current treatment options of chemotherapy, radiation therapy and surgery are met with challenges such as cancer recurrence, drug resistance, and overt toxicity. CRC therapies exert their efficacy against cancer cells by activating biological pathways that contribute to various forms of regulated cell death (RCD). In 2012, ferroptosis was discovered as an iron-dependent and lipid peroxide-driven form of RCD. Recent studies suggest that therapies which target ferroptosis are promising treatment strategies for CRC. However, a greater understanding of the mechanisms of ferroptosis initiation, propagation, and resistance in CRC is needed. This review provides an overview of recent research in ferroptosis and its potential role as a therapeutic target in CRC. We also propose future research directions that could help to enhance our understanding of ferroptosis in CRC.
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Affiliation(s)
- Hong Yan
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, 06510, USA
| | - Ronan Talty
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
| | - Oladimeji Aladelokun
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, 06510, USA
| | - Marcus Bosenberg
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
- Department of Dermatology, Yale School of Medicine, New Haven, CT, USA
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
| | - Caroline H Johnson
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, 06510, USA.
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23
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Lin D, Hu B, Zhu S, Wu Y. Exploring a ferroptosis and oxidative stress-based prognostic model for clear cell renal cell carcinoma. Front Oncol 2023; 13:1131473. [PMID: 37064095 PMCID: PMC10098013 DOI: 10.3389/fonc.2023.1131473] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Accepted: 03/20/2023] [Indexed: 04/01/2023] Open
Abstract
BackgroundFerroptosis is a newly defined cell death process triggered by increased iron load and tremendous lipid reactive oxygen species (ROS). Oxidative stress-related ferroptosis is of great important to the occurrence and progression of clear cell renal cell carcinoma (ccRCC), which is particularly susceptibility to ferroptosis agonist. Therefore, exploring the molecular features of ferroptosis and oxidative stress might guide the clinical treatment and prognosis prediction for ccRCC patients.MethodsThe differentially expressed ferroptosis and oxidative stress-associated genes (FPTOSs) between normal renal and ccRCC tissues were identified based on The Cancer Genome Atlas (TCGA) database, and those with prognostic significances were applied to develop a prognostic model and a risk scoring system (FPTOS_score). The clinical parameter, miRNA regulation, tumor mutation burden (TMB), immune cell infiltration, immunotherapy response, and drug susceptibility between two FPTOS-based risk stratifications were determined.ResultsWe have identified 5 prognosis-associated FPTOSs (ACADSB, CDCA3, CHAC1, MYCN, and TFAP2A), and developed a reliable FPTOS_socre system to distinguish patients into low- and high-risk groups. The findings implied that patients from the high-risk group performed poor prognoses, even after stratified analysis of various clinical parameters. A total of 30 miRNA-FPTOS regulatory pairs were recognized to identify the possible molecular mechanisms. Meanwhile, patients from the high-risk group exhibited higher TMB levels than those from the low-risk groups, and the predominant mutated driver genes were VHL, PBRM1 and TTN in both groups. The main infiltrating immune cells of high- and low-risk groups were CD8+ T cells and resting mast cells, respectively, and patients from the high-risk groups showed preferable drug responsiveness to anti-PD-1 immunotherapy. Eventually, potential sensitive drugs (cisplatin, BI-D1870, and docetaxel) and their enrichment pathways were identified to guide the treatment of ccRCC patients with high-risk.ConclusionOur study comprehensively analyzed the expression profiles of FPTOSs and constructed a scoring system with considerable prognostic value, which would supply novel insights into the personalized treatment strategies and prognostic evaluation of ccRCC patient.
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Affiliation(s)
- Dongxu Lin
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Bintao Hu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shiqing Zhu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yue Wu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- *Correspondence: Yue Wu,
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24
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Zhang R, Kang R, Tang D. Ferroptosis in gastrointestinal cancer: From mechanisms to implications. Cancer Lett 2023; 561:216147. [PMID: 36965540 DOI: 10.1016/j.canlet.2023.216147] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/16/2023] [Accepted: 03/22/2023] [Indexed: 03/27/2023]
Abstract
Ferroptosis is a form of regulated cell death that is initiated by excessive lipid peroxidation that results in plasma membrane damage and the release of damage-associated molecular patterns. In recent years, ferroptosis has gained significant attention in cancer research due to its unique mechanism compared to other forms of regulated cell death, especially caspase-dependent apoptotic cell death. Gastrointestinal (GI) cancer encompasses malignancies that arise in the digestive tract, including the stomach, intestines, pancreas, colon, liver, rectum, anus, and biliary system. These cancers are a global health concern, with high incidence and mortality rates. Despite advances in medical treatments, drug resistance caused by defects in apoptotic pathways remains a persistent challenge in the management of GI cancer. Hence, exploring the role of ferroptosis in GI cancers may lead to more efficacious treatment strategies. In this review, we provide a comprehensive overview of the core mechanism of ferroptosis and discuss its function, regulation, and implications in the context of GI cancers.
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Affiliation(s)
- Ruoxi Zhang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
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25
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Song YQ, Yan XD, Wang Y, Wang ZZ, Mao XL, Ye LP, Li SW. Role of ferroptosis in colorectal cancer. World J Gastrointest Oncol 2023; 15:225-239. [PMID: 36908317 PMCID: PMC9994046 DOI: 10.4251/wjgo.v15.i2.225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/15/2022] [Accepted: 01/09/2023] [Indexed: 02/14/2023] Open
Abstract
Colorectal cancer (CRC) is the second deadliest cancer and the third-most common malignancy in the world. Surgery, chemotherapy, and targeted therapy have been widely used to treat CRC, but some patients still develop resistance to these treatments. Ferroptosis is a novel non-apoptotic form of cell death. It is an iron-dependent non-apoptotic cell death characterized by the accumulation of lipid reactive oxygen species and has been suggested to play a role in reversing resistance to anticancer drugs. This review summarizes recent advances in the prognostic role of ferroptosis in CRC and the mechanism of action in CRC.
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Affiliation(s)
- Ya-Qi Song
- Taizhou Hospital of Zhejiang Province, Zhejiang University, Linhai 317000, Zhejiang Province, China
| | - Xiao-Dan Yan
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
| | - Yi Wang
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
| | - Zhen-Zhen Wang
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
| | - Xin-Li Mao
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
| | - Li-Ping Ye
- Taizhou Hospital of Zhejiang Province, Zhejiang University, Linhai 317000, Zhejiang Province, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
| | - Shao-Wei Li
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai 317000, Zhejiang Province, China
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Monocyte-Derived miRNA-1914-5p Attenuates IL-1β-Induced Monocyte Adhesion and Transmigration. Int J Mol Sci 2023; 24:ijms24032829. [PMID: 36769149 PMCID: PMC9917334 DOI: 10.3390/ijms24032829] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 01/24/2023] [Accepted: 01/27/2023] [Indexed: 02/05/2023] Open
Abstract
Atherosclerosis can lead to cardiovascular and cerebrovascular diseases. Atherosclerotic plaque formation is promoted by the accumulation of inflammatory cells. Therefore, modulating monocyte recruitment represents a potential therapeutic strategy. In an inflammatory state, the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) is upregulated in endothelial cells. We previously reported that miR-1914-5p in endothelial cells suppresses interleukin (IL)-1β-induced ICAM-1 expression and monocyte adhesion to endothelial cells. However, whether monocyte miR-1914-5p affects monocyte recruitment is unclear. In this study, IL-1β decreased miR-1914-5p expression in a human monocyte cell line. Moreover, miR-1914-5p inhibition enhanced adhesion to endothelial cells with the upregulation of macrophage-1 antigen (Mac-1), a counter-ligand to ICAM-1. Transmigration through the endothelial layer was also promoted with the upregulation of monocyte chemotactic protein-1 (MCP-1). Furthermore, a miR-1914-5p mimic suppressed IL-1β-induced monocyte adhesion and transmigration in monocytes with Mac-1 and MCP-1 downregulation. Further investigation of miR-1914-5p in monocytes could lead to the development of novel diagnostic markers and therapeutic strategies for atherosclerosis.
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27
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Yang L, Zhang Y, Zhang Y, Fan Z. Mechanism and application of ferroptosis in colorectal cancer. Biomed Pharmacother 2023; 158:114102. [PMID: 36528917 DOI: 10.1016/j.biopha.2022.114102] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 11/10/2022] [Accepted: 12/05/2022] [Indexed: 12/23/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common malignant tumor in the world. CRC has high morbidity and mortality rates and it is a serious threat to human health. Ferroptosis is a unique form of iron-dependent oxidative cell death that is usually accompanied by iron accumulation and lipid peroxidation. Ferroptosis has attracted worldwide attention since it was first proposed. It plays an important role in the development of a variety of diseases, such as tumors, ischemia/reperfusion injury, nervous system diseases, and kidney damage, and it may serve as a new therapeutic target. This article reviews the mechanism of ferroptosis and the possibility to target ferroptosis pathways in CRC, providing new ideas for the diagnosis and treatment of CRC.
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Affiliation(s)
- Liu Yang
- Department of General Surgery, The Third People's Hospital of Dalian, Dalian Medical University, Dalian, China; Department of Central Laboratory, The Third People's Hospital of Dalian, Dalian Medical University, Dalian, China; Liaoning Province Key Laboratory of Corneal and Ocular Surface Diseases Research, The Third People's Hospital of Dalian, Dalian, China
| | - Yewei Zhang
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - Yingyi Zhang
- Department of General Surgery, The Third People's Hospital of Dalian, Dalian Medical University, Dalian, China; Department of Central Laboratory, The Third People's Hospital of Dalian, Dalian Medical University, Dalian, China; Liaoning Province Key Laboratory of Corneal and Ocular Surface Diseases Research, The Third People's Hospital of Dalian, Dalian, China.
| | - Zhe Fan
- Department of General Surgery, The Third People's Hospital of Dalian, Dalian Medical University, Dalian, China; Department of Central Laboratory, The Third People's Hospital of Dalian, Dalian Medical University, Dalian, China; Liaoning Province Key Laboratory of Corneal and Ocular Surface Diseases Research, The Third People's Hospital of Dalian, Dalian, China.
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Insights on Ferroptosis and Colorectal Cancer: Progress and Updates. MOLECULES (BASEL, SWITZERLAND) 2022; 28:molecules28010243. [PMID: 36615434 PMCID: PMC9821926 DOI: 10.3390/molecules28010243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 12/25/2022] [Accepted: 12/25/2022] [Indexed: 12/29/2022]
Abstract
Patients with advanced-stage or treatment-resistant colorectal cancer (CRC) benefit less from traditional therapies; hence, new therapeutic strategies may help improve the treatment response and prognosis of these patients. Ferroptosis is an iron-dependent type of regulated cell death characterized by the accumulation of lipid reactive oxygen species (ROS), distinct from other types of regulated cell death. CRC cells, especially those with drug-resistant properties, are characterized by high iron levels and ROS. This indicates that the induction of ferroptosis in these cells may become a new therapeutic approach for CRC, particularly for eradicating CRC resistant to traditional therapies. Recent studies have demonstrated the mechanisms and pathways that trigger or inhibit ferroptosis in CRC, and many regulatory molecules and pathways have been identified. Here, we review the current research progress on the mechanism of ferroptosis, new molecules that mediate ferroptosis, including coding and non-coding RNA; novel inducers and inhibitors of ferroptosis, which are mainly small-molecule compounds; and newly designed nanoparticles that increase the sensitivity of cells to ferroptosis. Finally, the gene signatures and clusters that have predictive value on CRC are summarized.
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29
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Ping S, Gong R, Lei K, Qing G, Zhang G, Chen J. Development and validation of a ferroptosis-related lncRNAs signature to predict prognosis and microenvironment for melanoma. Discov Oncol 2022; 13:125. [PMID: 36371574 PMCID: PMC9653531 DOI: 10.1007/s12672-022-00581-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 10/25/2022] [Indexed: 11/13/2022] Open
Abstract
Ferroptosis plays an important role in cancer. However, studies about ferroptosis-related lncRNAs (FRLs) in skin cutaneous melanoma (SKCM) are scarce. Moreover, the relationship between prognostic FRLs and tumor microenvironment (TME) in melanoma remains unclear. This study investigates the potential prognostic value of FRLs and their association with TME in SKCM. The RNA-sequencing data of SKCM were downloaded from The Cancer Genome Atlas (TCGA) database. Melanoma patients were randomly divided into training and testing groups in a 1:1 ratio. A signature composed of 19 FRLs was developed by the least absolute shrinkage and selection operator (LASSO) regression analysis to divide patients into a low-risk group with a better prognosis and a high-risk group with a poor prognosis. Multivariate Cox regression analysis suggested that the risk score was an independent prognostic factor. The Area Under Curve (AUC) value of the risk score reached 0.768 in the training group and 0.770 in the testing group. Subsequent analysis proved that immune-related signaling pathways were significantly enriched in the low-risk group. The tumor immune cell infiltration analysis demonstrated that melanoma in the high-risk group tended to be immunologically "cold". We identified a novel FRLs signature which could accurately predict the prognosis of patients with melanoma.
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Affiliation(s)
- Shuai Ping
- Department of Gastroenterology, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, No. 1677 Wutaishan Road, Huangdao District, Qingdao, 266000 China
| | - Ruining Gong
- Department of Gastroenterology, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, No. 1677 Wutaishan Road, Huangdao District, Qingdao, 266000 China
| | - Ke Lei
- Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, No. 1677 Wutaishan Road, Huangdao District, Qingdao, 266000 China
| | - Gong Qing
- Department of Gastroenterology, Tumor Immunology and Cytotherapy, Medical Research Center, The Affiliated Hospital of Qingdao University, No. 1677 Wutaishan Road, Huangdao District, Qingdao, 266000 China
| | - Guangheng Zhang
- Department of Orthopaedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430077 China
| | - Jianghai Chen
- Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 Hubei China
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Menegatti J, Nakel J, Stepanov YK, Caban KM, Ludwig N, Nord R, Pfitzner T, Yazdani M, Vilimova M, Kehl T, Lenhof HP, Philipp SE, Meese E, Fröhlich T, Grässer FA, Hart M. Changes of Protein Expression after CRISPR/Cas9 Knockout of miRNA-142 in Cell Lines Derived from Diffuse Large B-Cell Lymphoma. Cancers (Basel) 2022; 14:cancers14205031. [PMID: 36291816 PMCID: PMC9600116 DOI: 10.3390/cancers14205031] [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: 09/15/2022] [Revised: 10/10/2022] [Accepted: 10/11/2022] [Indexed: 11/22/2022] Open
Abstract
Simple Summary The gene of the human tumor suppressive microRNA-142 (miR-142) carries mutations in about 20% of cases of diffuse large B-cell lymphoma (DLBCL). Because microRNAs post-transcriptionally regulate the protein expression of their cognate messenger RNA (mRNAs) targets, we determined the effect of miR-142 knockout on protein expression in two cell lines derived from DLBCL. We found a significant up-regulation of 52 proteins but also a down-regulation of 41 proteins upon miR-142 deletion. Knockout of a miRNA may be used to identify novel targets, and seed-sequence mutants of a miRNA unable to bind to their targets can be used to confirm potential novel targets. With this approach, we identify AKT1S1, CCNB1, LIMA1 and TFRC as novel targets of miR-142. As miR-142 is highly present in the miRNA processing RISC complexes, the deletion of this miRNA might result in its replacement by other miRNAs, thus introducing an additional layer of complexity regarding gene regulation. Abstract Background: As microRNA-142 (miR-142) is the only human microRNA gene where mutations have consistently been found in about 20% of all cases of diffuse large B-cell lymphoma (DLBCL), we wanted to determine the impact of miR-142 inactivation on protein expression of DLBCL cell lines. Methods: miR-142 was deleted by CRISPR/Cas9 knockout in cell lines from DLBCL. Results: By proteome analyses, miR-142 knockout resulted in a consistent up-regulation of 52 but also down-regulation of 41 proteins in GC-DLBCL lines BJAB and SUDHL4. Various mitochondrial ribosomal proteins were up-regulated in line with their pro-tumorigenic properties, while proteins necessary for MHC-I presentation were down-regulated in accordance with the finding that miR-142 knockout mice have a defective immune response. CFL2, CLIC4, STAU1, and TWF1 are known targets of miR-142, and we could additionally confirm AKT1S1, CCNB1, LIMA1, and TFRC as new targets of miR-142-3p or -5p. Conclusions: Seed-sequence mutants of miR-142 confirmed potential targets and novel targets of miRNAs can be identified in miRNA knockout cell lines. Due to the complex contribution of miRNAs within cellular regulatory networks, in particular when miRNAs highly present in RISC complexes are replaced by other miRNAs, primary effects on gene expression may be covered by secondary layers of regulation.
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Affiliation(s)
- Jennifer Menegatti
- Institute of Virology, Saarland University Medical School, 66421 Homburg, Germany
| | - Jacqueline Nakel
- Institute of Virology, Saarland University Medical School, 66421 Homburg, Germany
| | - Youli K. Stepanov
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Karolina M. Caban
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Nicole Ludwig
- Institute of Human Genetics, Saarland University, 66421 Homburg, Germany
| | - Ruth Nord
- Institute of Virology, Saarland University Medical School, 66421 Homburg, Germany
| | - Thomas Pfitzner
- Institute of Virology, Saarland University Medical School, 66421 Homburg, Germany
| | - Maryam Yazdani
- Institute of Virology, Saarland University Medical School, 66421 Homburg, Germany
| | - Monika Vilimova
- Institute of Virology, Saarland University Medical School, 66421 Homburg, Germany
| | - Tim Kehl
- Center for Bioinformatics, Saarland University, 66041 Saarbrücken, Germany
| | - Hans-Peter Lenhof
- Center for Bioinformatics, Saarland University, 66041 Saarbrücken, Germany
| | - Stephan E. Philipp
- Experimental and Clinical Pharmacology and Toxicology, Saarland University Medical School, 66421 Homburg, Germany
| | - Eckart Meese
- Institute of Human Genetics, Saarland University, 66421 Homburg, Germany
| | - Thomas Fröhlich
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-University Munich, 81377 Munich, Germany
| | - Friedrich A. Grässer
- Institute of Virology, Saarland University Medical School, 66421 Homburg, Germany
- Correspondence: (F.A.G.); (M.H.)
| | - Martin Hart
- Institute of Human Genetics, Saarland University, 66421 Homburg, Germany
- Correspondence: (F.A.G.); (M.H.)
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Wang Y, Xu Y, Zhang Y. A novel ferroptosis-related long noncoding RNA signature for relapse free survival prediction in patients with breast cancer. Medicine (Baltimore) 2022; 101:e29573. [PMID: 35945765 PMCID: PMC9351903 DOI: 10.1097/md.0000000000029573] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Ferroptosis is the process of cell death dependent on iron. Growing evidence suggests that ferroptosis plays vital roles in the biological process of many cancers. However, just a small number of ferroptosis-related lncRNAs have been explored in depth. Ferroptosis-related lncRNAs in breast cancer (BC) were identified by co-expression analysis based on The Cancer Genome Atlas database (TCGA). The whole set was divided into a training set and a test set with a 1:1 ratio. Univariate Cox regression and LASSO analyses were performed to establish a signature in the 3 sets. Kaplan-Meier analysis and receiver operating characteristic (ROC) for the 3 sets validated the effectiveness and robustness of the signature. Besides, we also explore the relationship between this and clinical characteristics, immune cell infiltration and tumor microenvironment. Meanwhile, the nomogram was drawn by screening indicators of independent recurrent prediction. Finally, we evaluated the relationships between the signature and tumor microenvironment. We identified 391 ferroptosis-related lncRNAs and constructed a 5 lncRNAs-based signature in the training, test, and whole sets, stratifying patients into high-risk and low-risk groups. According to survival analysis, patients in the high-risk groups had worse relapse free survival (RFS) compared to the low risk-groups. The ROC curves indicated that the recurrent signature had a promising predictive capability for BC patients. Moreover, an independent factors-based nomogram model could offer the quantitative prediction and net benefit for the recurrence of BC patients. Finally, the microenvironment, including tumor mutational burden (TMB), immune cell functions and immune checkpoints, showed big differences between the 2 groups. The 5 ferroptosis-related lncRNAs and their signature might be novel promising biomarkers and immunotherapy targets for patients with BC.
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Affiliation(s)
- Yuzhi Wang
- Department of Laboratory Medicine, People’s Hospital of Deyang City, Deyang, Sichuan, P. R. China
| | - Yunfei Xu
- Department of Laboratory Medicine, Chengdu Women’s and Children’s Central Hospital, Chengdu, Sichuan, P. R. China
| | - Yi Zhang
- Department of Blood Transfusion, People’s Hospital of Deyang City, Deyang, Sichuan, P. R. China
- *Correspondence: Yi Zhang, People’s Hospital of Deyang City, No. 173, Section 1, Taishan North Road, Deyang City, Sichuan 618000, China (e-mail: )
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Identification of Ferroptosis-Related lncRNA Pairs for Predicting the Prognosis of Head and Neck Squamous Cell Carcinoma. JOURNAL OF ONCOLOGY 2022; 2022:7602482. [PMID: 35909900 PMCID: PMC9328971 DOI: 10.1155/2022/7602482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 06/20/2022] [Indexed: 11/17/2022]
Abstract
Background Ferrogenesis was strongly associated with tumorigenesis and development, and activating the ferrogenic process was a novel regimen in treating cancer, especially conventional treatment-resistant cancers. The purpose of the article was to construct a ferroptosis-related long noncoding RNAs (FRlncRNAs) signature, regardless of expression levels to effectively predict prognosis and immunotherapeutic response for head and neck squamous cell carcinoma (HNSCC). Methods The RNA-seq data for HNSCC and corresponding clinical information were obtained in the TCGA database, and ferroptosis-related genes (FRGs) were extracted in the ferroptosis database. On this basis, differentially expressed FRlncRNAs (DEFRlncRNAs) pairs were identified through coexpression analysis, differential expression analysis, and a fresh pairing algorithm. Then, a risk assessment model was established with univariate Cox, LASSO, and multivariate Cox regression analysis. Finally, we evaluated the model from various aspects, including survival status, clinicopathological characteristics, infiltration status of immune cells, immune functions, chemotherapeutic sensitivity, immune checkpoint inhibitors (ICIs)-related molecules, and N6-methyladenosine (m6A) mRNA status. Result We established a signature of 11-DEFRlncRNA pairs related to the prognosis of HNSCC that had AUC values above 0.75 in the one-, three-, and five-year ROC curves, underscoring the high susceptibility and specifiability of predicting HNSCC prognosis. Survival rates were remarkably higher for the low-risk patients than for the high-risk patients, and the signature was significantly correlated with survival, clinical, T, and N stages. Finally, immune cell infiltration status, immune functions, chemotherapeutic sensitivity, and expression levels of ICIs-related and m6A-related molecules were statistically different among different groups. Conclusion Our study established a novel lncRNA signature, which is independent of specific expression levels, could predict patient prognosis, and might have promising clinical applications in HNCSS.
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Yuan X, Zhou Q, Zhang F, Zheng W, Liu H, Chen A, Tao Y. Identification of immunity- and ferroptosis-related genes for predicting the prognosis of serous ovarian cancer. Gene X 2022; 838:146701. [PMID: 35777713 DOI: 10.1016/j.gene.2022.146701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 06/13/2022] [Accepted: 06/24/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Serous ovarian cancer (SOC) is the most common type of ovarian cancer (OC), with bad outcomes. To improve the prognosis of SOC patients, a novel risk signature was developed by combining immunity- and ferroptosis-related genes. METHODS By means of comparing SOC tissues with normal tissues, we screened the differential expression of immunity-related genes (DE-IRGs) and ferroptosis-related genes(DE-FRGs) with the standards of |log2fold change| > 1 and false discovery rate (FDR) < 0.05. After obtaining the meaningful differentially expressed genes from immune and ferroptosis (DEGs), we established a prognostic risk signature by utilizing Cox regression analyses in TCGA training set, which was validated in TCGA testing set and GSE26712 dataset. Besides, the differential expression of immune-related markers, immunophenoscore (IPS), TIDE score,T cell dysfunction score and T cell exclusion score were also analyzed. We further verified the expression of target genes in ovarian tumor cells lines by QRT-PCR. RESULTS A risk signature constructed by totally four immunity- and ferroptosis-related DEGs (CXCL11, CX3CR1, FH, and DNAJB6) was developed, which distinguished the SOC patients as high-risk and low-risk groups. Patients in the high-risk group showed a lower overall survival (OS) than those in the low-risk group. Furthermore, the risk score was independent when analyzed with clinical augments, which was significantly associated with 13 KEGG signaling pathways. The gene signature showed favorable predictive performance according to Receiver operating characteristic (ROC) curves. Notably, the expression of immune-related markers or IPS indicated a negative connection with the risk score. SOC patients had a lower score of TIDE and T cell dysfunction than Whom had a higher score. Nonetheless, there were no significant differences in T cell exclusion scores between the two groups.Compared with normal ovarian cell line IOSE-80,QRT-PCR experiments exhibited that CXCL11, CX3CR1and FH were up-regulated in ovarian tumor cells lines(SK-OV-3,COC1,A2780),while DNAJB6 was down-regulated. CONCLUSION Four-biomarker signature formed by immunity- and ferroptosis-related genes may be clinically used as risk stratifcation tool in serous ovarian cancer,which can help further clinical decision-making regarding prognostic prediction,individualized treatment and follow-up scheduling.
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Affiliation(s)
- Xiaoqing Yuan
- Department of Gynecology and Obstetrics, The People's Hospital of China Three Gorges University, Hubei, China/The First Hospital Of Yichang.
| | - Quan Zhou
- Department of Gynecology and Obstetrics, The People's Hospital of China Three Gorges University, Hubei, China/The First Hospital Of Yichang
| | - Fan Zhang
- Department of Gynecology and Obstetrics, The People's Hospital of China Three Gorges University, Hubei, China/The First Hospital Of Yichang
| | - Wenfei Zheng
- Department of Gynecology and Obstetrics, The People's Hospital of China Three Gorges University, Hubei, China/The First Hospital Of Yichang
| | - Hui Liu
- Department of Gynecology and Obstetrics, The People's Hospital of China Three Gorges University, Hubei, China/The First Hospital Of Yichang
| | - Aihua Chen
- Department of Gynecology and Obstetrics, The People's Hospital of China Three Gorges University, Hubei, China/The First Hospital Of Yichang
| | - Yaling Tao
- Department of Gynecology and Obstetrics, The People's Hospital of China Three Gorges University, Hubei, China/The First Hospital Of Yichang
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Dang G, Li T, Yang D, Yang G, Du X, Yang J, Miao Y, Han L, Ma X, Song Y, Liu B, Li X, Wang X, Feng J. T lymphocyte-derived extracellular vesicles aggravate abdominal aortic aneurysm by promoting macrophage lipid peroxidation and migration via pyruvate kinase muscle isozyme 2. Redox Biol 2022; 50:102257. [PMID: 35149342 PMCID: PMC8842084 DOI: 10.1016/j.redox.2022.102257] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/22/2022] [Accepted: 01/31/2022] [Indexed: 01/08/2023] Open
Abstract
T lymphocyte and macrophage infiltration in the aortic wall is critical for abdominal aortic aneurysm (AAA). However, how T lymphocytes interact with macrophages in the pathogenesis of AAA remains largely uncharacterized. In an elastase-induced murine AAA model, we first found that the expression of pyruvate kinase muscle isozyme 2 (PKM2), the last rate-limiting enzyme in glycolysis, was increased in infiltrated T lymphocytes of vascular lesions. T lymphocyte-specific PKM2 deficiency in mice (LckCrePKM2fl/fl) or intraperitoneal administration of the sphingomyelinase inhibitor GW4869 caused a significant attenuation of the elastase-increased aortic diameter, AAA incidence, elastic fiber disruption, matrix metalloproteinases (MMPs) expression, and macrophage infiltration in the vascular adventitia compared with those in PKM2fl/fl mice. Mechanistically, extracellular vesicles (EVs) derived from PKM2-activated T lymphocytes elevated macrophage iron accumulation, lipid peroxidation, and migration in vitro, while macrophages treated with EVs from PKM2-null T lymphocytes or pretreated with the lipid peroxidation inhibitors ferrostatin-1 (Fer-1), liproxstatin-1 (Lip-1), or the iron chelating agent deferoxamine mesylate (DFOM) reversed these effects. In vascular lesions of elastase-induced LckCrePKM2fl/fl mice with AAA, the oxidant system weakened, with downregulated 4-hydroxynonenal (4-HNE) levels and strengthened antioxidant defense systems with upregulated glutathione peroxidase 4 (GPX4) and cystine/glutamate antiporter solute carrier family 7 member 11 (Slc7a11) expressions in macrophages. High-throughput metabolomics showed that EVs derived from PKM2-activated T lymphocytes contained increased levels of polyunsaturated fatty acid (PUFA)-containing phospholipids, which may provide abundant substrates for lipid peroxidation in target macrophages. More importantly, upregulated T lymphocyte PKM2 expression was also found in clinical AAA subjects, and EVs isolated from AAA patient plasma enhanced macrophage iron accumulation, lipid peroxidation, and migration ex vivo. Therefore, from cell-cell crosstalk and metabolic perspectives, the present study shows that PKM2-activated T lymphocyte-derived EVs may drive AAA progression by promoting macrophage redox imbalance and migration, and targeting the T lymphocyte-EV-macrophage axis may be a potential strategy for early warning and treating AAA.
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Affiliation(s)
- Guohui Dang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China
| | - Tianrun Li
- Department of Interventional Radiology and Vascular Surgery, Peking University Third Hospital, North Garden Road 49, Haidian District, Beijing 100191, China
| | - Dongmin Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China
| | - Guangxin Yang
- Department of Interventional Radiology and Vascular Surgery, Peking University Third Hospital, North Garden Road 49, Haidian District, Beijing 100191, China
| | - Xing Du
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China
| | - Juan Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China
| | - Yutong Miao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China
| | - Lulu Han
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China
| | - Xiaolong Ma
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China
| | - Yuwei Song
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China
| | - Bo Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China
| | - Xuan Li
- Department of Interventional Radiology and Vascular Surgery, Peking University Third Hospital, North Garden Road 49, Haidian District, Beijing 100191, China
| | - Xian Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China
| | - Juan Feng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China; Department of Interventional Radiology and Vascular Surgery, Peking University Third Hospital, North Garden Road 49, Haidian District, Beijing 100191, China; Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China.
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Wu Z, Lu Z, Li L, Ma M, Long F, Wu R, Huang L, Chou J, Yang K, Zhang Y, Li X, Hu G, Zhang Y, Lin C. Identification and Validation of Ferroptosis-Related LncRNA Signatures as a Novel Prognostic Model for Colon Cancer. Front Immunol 2022; 12:783362. [PMID: 35154072 PMCID: PMC8826443 DOI: 10.3389/fimmu.2021.783362] [Citation(s) in RCA: 87] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 12/28/2021] [Indexed: 12/13/2022] Open
Abstract
Background Ferroptosis is a newly defined form of programmed cell death that plays an important role in many cancers. However, ferroptosis-related lncRNAs (FRLs) involved in the regulation of colon cancer are not thoroughly understood. This study aimed to identify a prognostic FRL signature in colon cancer and explore its potential molecular function. Methods RNA-seq data and relevant clinical information were obtained from The Cancer Genome Atlas (TCGA) database, and a list of ferroptosis-related genes was extracted from the FerrDb website. Analysis of differentially expressed FRLs was performed using the 'limma' package in R software. By implementing coexpression analysis and univariate Cox analysis, we then identified prognostic FRLs. Using Cox regression analysis with the least absolute shrinkage and selection operator (LASSO) algorithm, we constructed a prognostic model based on 4 FRLs. We evaluated the prognostic power of this model using Kaplan-Meier (K-M) survival curve analysis and receiver operating characteristic (ROC) curve analysis. Moreover, the relationships between the signature and immune landscape, somatic mutation and drug sensitivity were explored. Finally, in vitro experiments were conducted to validate the functions of AP003555.1 and AC000584.1. Results A 4-FRL signature was constructed. Two risk groups were classified based on the risk score calculated by this signature. The signature-based risk score exhibited a more powerful capacity for survival prediction than traditional clinicopathological features in colon patients. Additionally, we observed a significant difference in immune cells, such as CD4+ and CD8+ T cells and macrophages, between the two groups. Moreover, the high-risk group exhibited lower IC50 values for certain chemotherapy drugs, such as cisplatin, docetaxel, bleomycin or axitinib. Finally, the in vitro experiments showed that ferroptosis processes were suppressed after AP003555.1 and AC000584.1 knockdown. Conclusion The proposed 4-FRL signature is a promising biomarker to predict clinical outcomes and therapeutic responses in colon cancer patients.
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Affiliation(s)
- Zhiwei Wu
- Department of Gastrointestinal Surgery, The Third XiangYa Hospital of Central South University, Changsha, China
| | - Zhixing Lu
- Department of Gastrointestinal Surgery, The Third XiangYa Hospital of Central South University, Changsha, China
| | - Liang Li
- Department of Gastrointestinal Surgery, The Third XiangYa Hospital of Central South University, Changsha, China
| | - Min Ma
- Department of Gastrointestinal Surgery, The Third XiangYa Hospital of Central South University, Changsha, China
| | - Fei Long
- Department of Gastrointestinal Surgery, The Third XiangYa Hospital of Central South University, Changsha, China
| | - Runliu Wu
- Department of Gastrointestinal Surgery, The Third XiangYa Hospital of Central South University, Changsha, China
| | - Lihua Huang
- School of Life Sciences, Central South University, Changsha, China
| | - Jing Chou
- Department of Gastrointestinal Surgery, The Third XiangYa Hospital of Central South University, Changsha, China
| | - Kaiyan Yang
- Department of Gastrointestinal Surgery, The Third XiangYa Hospital of Central South University, Changsha, China
| | - Yi Zhang
- Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Xiaorong Li
- Department of Gastrointestinal Surgery, The Third XiangYa Hospital of Central South University, Changsha, China
| | - Gui Hu
- Department of Gastrointestinal Surgery, The Third XiangYa Hospital of Central South University, Changsha, China
| | - Yi Zhang
- Department of Gastrointestinal Surgery, The Third XiangYa Hospital of Central South University, Changsha, China
| | - Changwei Lin
- Department of Gastrointestinal Surgery, The Third XiangYa Hospital of Central South University, Changsha, China
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Liu X, Zhang W, Wang H, Zhu L, Xu K. Decreased Expression of ACADSB Predicts Poor Prognosis in Clear Cell Renal Cell Carcinoma. Front Oncol 2022; 11:762629. [PMID: 35096573 PMCID: PMC8791850 DOI: 10.3389/fonc.2021.762629] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 12/20/2021] [Indexed: 12/30/2022] Open
Abstract
Background Previous reports have shown that short/branched chain acyl-CoA dehydrogenase (ACADSB) plays an important role in glioma, but its role in clear cell renal carcinoma (ccRCC) has not been reported. Methods The TIMER and UALCAN databases were used for pan-cancer analysis. RNA sequencing and microarray data of patients with ccRCC were downloaded from the Cancer Genome Atlas and Gene Expression Omnibus database. The differential expression of ACADSB in ccRCC and normal kidney tissues was tested. Correlations between ACADSB expression and clinicopathological parameters were assessed using the Wilcoxon test. The influences of ACADSB expression and clinicopathological parameters on overall survival were assessed using Cox proportional hazards models. Gene set enrichment analysis (GSEA) was performed to explore the associated gene sets enriched in different ACADSB expression phenotypes. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on genes with similar expression patterns to ACADSB. Correlations between ACADSB and ferroptosis-related genes were assessed using Spearman’s correlation analysis. Results Pan-cancer analysis revealed that ACADSB is down-regulated in multiple cancers, and decreased expression of ACADSB correlates with poor prognosis in certain types of cancer. Differential expression analyses revealed that ACADSB was down-regulated in ccRCC, indicating that ACADSB expression could be a single significant parameter to discriminate between normal and tumor tissues. Clinical association analysis indicated that decreased ACADSB expression was associated with high tumor stage and grade. The Cox regression model indicated that low ACADSB expression was an independent risk factor for the overall survival of patients with ccRCC. GSEA showed that 10 gene sets, including fatty acid (FA) metabolism, were differentially enriched in the ACADSB high expression phenotype. GO and KEGG pathway enrichment analysis revealed that ACADSB-related genes were significantly enriched in categories related to FA metabolism, branched-chain amino acid (BCAA) metabolism, and iron regulation. Spearman’s correlation analysis suggested that the expression of ACADSB was positively correlated with the expression of ferroptosis driver genes. Conclusions ACADSB showed good diagnostic and prognostic abilities for ccRCC. The downregulation of ACADSB might promote tumorigenesis and tumor progression by inhibiting FA catabolism, BCAA catabolism, and ferroptosis in ccRCC.
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Affiliation(s)
- Xianhui Liu
- Department of Urology, Peking University People's Hospital, Beijing, China
| | - Weiyu Zhang
- Department of Urology, Peking University People's Hospital, Beijing, China
| | - Huanrui Wang
- Peking University Applied Lithotripsy Institute, Peking University People's Hospital, Beijing, China
| | - Lin Zhu
- Department of Urology, Peking University People's Hospital, Beijing, China
| | - Kexin Xu
- Department of Urology, Peking University People's Hospital, Beijing, China
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Yang F, Sun SY, Wang S, Guo JT, Liu X, Ge N, Wang GX. Molecular regulatory mechanism of ferroptosis and its role in gastrointestinal oncology: Progress and updates. World J Gastrointest Oncol 2022; 14:1-18. [PMID: 35116100 PMCID: PMC8790407 DOI: 10.4251/wjgo.v14.i1.1] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 08/04/2021] [Accepted: 12/07/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) tumors, including liver, pancreatic, gastric, and colorectal cancers, have a high incidence rate and low survival rate due to the lack of effective therapeutic methods and frequent relapses. Surgery and postoperative chemoradiotherapy have largely reduced the fatality rates for most GI tumors, but these therapeutic approaches result in poor prognoses due to severe adverse reactions and the development of drug resistance. Recent studies have shown that ferroptosis plays an important role in the onset and progression of GI tumors. Ferroptosis is a new non-apoptotic form of cell death, which is iron-dependent, non-apoptotic cell death characterized by the accumulation of lipid reactive oxygen species (ROS). The activation of ferroptosis can lead to tumor cell death. Thus, regulating ferroptosis in tumor cells may become a new therapeutic approach for tumors, making it become a research hotspot. Current studies suggest that ferroptosis is mainly triggered by the accumulation of lipid ROS. Furthermore, several studies have indicated that ferroptosis may be a new approach for the treatment of GI tumors. Here, we review current research progress on the mechanism of ferroptosis, current inducers and inhibitors of ferroptosis, and the role of ferroptosis in GI tumors to propose new methods for the treatment of such tumors.
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Affiliation(s)
- Fan Yang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Si-Yu Sun
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Sheng Wang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Jin-Tao Guo
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Xiang Liu
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Nan Ge
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Guo-Xin Wang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
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Wang CX, Chen LH, Zhuang HB, Shi ZS, Chen ZC, Pan JP, Hong ZS. Auriculasin enhances ROS generation to regulate colorectal cancer cell apoptosis, ferroptosis, oxeiptosis, invasion and colony formation. Biochem Biophys Res Commun 2022; 587:99-106. [PMID: 34872005 DOI: 10.1016/j.bbrc.2021.11.101] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 11/29/2021] [Indexed: 12/25/2022]
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors in the digestive system, and Chinese herbal medicine plays an important role in tumor treatment. The in-depth study of auriculasin isolated from Flemingia philippinensis showed that auriculasin promoted reactive oxygen species (ROS) generation in a concentration-dependent manner; when ROS scavenger NAC was added, the effects of auriculasin in promoting ROS generation and inhibiting cell viability were blocked. Auriculasin induced CRC cell apoptosis, led to mitochondrial shrinkage, and increased the intracellular accumulation of Fe2+ and MDA. When auriculasin and NAC were added simultaneously, the levels of apoptosis, Fe2+ and MDA returned to the control group levels, indicating that auriculasin activated apoptosis and ferroptosis by inducing ROS generation. In addition, auriculasin promoted the expression of Keap1 and AIFM1, but significantly reduced the phosphorylation level of AIFM1, while NAC significantly blocked the regulation of Keap1 and AIFM1 by auriculasin, which indicates that auriculasin can also induce oxeiptosis through ROS. When Z-VAD-FMK, Ferrostatin-1, Keap1 siRNA, PGAM5 siRNA and AIFM1 siRNA were added respectively, the inhibitory effect of auriculasin on cell viability was significantly weakened, indicating that auriculasin inhibits cell viability by inducing apoptosis, ferroptosis and oxeiptosis. Auriculasin also inhibited the invasion and clone forming ability of CRC cells, while NAC blocked the above effects of auriculasin. Therefore, auriculasin can promote CRC cell apoptosis, ferroptosis and oxeiptosis by inducing ROS generation, thereby inhibiting cell viability, invasion and clone formation, indicating that auriculasin has a significant antitumor effect.
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Affiliation(s)
- Chun-Xiao Wang
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China
| | - Li-Hua Chen
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China
| | - Hai-Bin Zhuang
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China
| | - Ze-Sheng Shi
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China
| | - Zhi Chuan Chen
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China
| | - Jian-Peng Pan
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China
| | - Zhong-Shi Hong
- Department of General Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, China.
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Jia CL, Yang F, Li R. Prognostic Model Construction and Immune Microenvironment Analysis of Breast Cancer Based on Ferroptosis-Related lncRNAs. Int J Gen Med 2021; 14:9817-9831. [PMID: 34949938 PMCID: PMC8691199 DOI: 10.2147/ijgm.s342783] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 12/09/2021] [Indexed: 12/12/2022] Open
Abstract
Purpose To construct a prognostic model of breast cancer using ferroptosis-related lncRNAs and explore novel therapeutic targets. Materials and Methods A prognostic characteristic model based on differential expression of ferroptosis-related lncRNAs in breast cancer was established based on TCGA data. Results Eleven ferroptosis-related lncRNAs associated with breast cancer prognosis were identified. Kaplan–Meier analysis suggested that high-risk lncRNA signatures correspond to a poor prognosis. The AUC of the signature lncRNAs was 0.682, demonstrating that it is accurate in predicting BC prognosis. GSEA showed that ferroptosis-related lncRNAs in high-risk individuals are mainly enriched in cell cycle, cell adhesion and tumor pathways. Immunity and gene expression analysis revealed that APC co-inhibition, check-point, HLA, inflammation-promoting and T cell co-stimulation among others were significantly different between the high-and low-risk group. Three immune checkpoints were highly expressed in the high-risk group. Conclusion Ferroptosis-related lncRNAs can be used as a prognostic feature to construct a prognostic model of breast cancer, based on which early detection markers, therapeutic targets and anti-tumor immune microenvironment can be studied, and clinical treatment can also be instructive.
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Affiliation(s)
- Cong Li Jia
- Institute of Plastic Surgery, Weifang Medical College, Weifang, Shandong, People's Republic of China
| | - Fu Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Ruining Li
- Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, People's Republic of China
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Yang YB, Zhou JX, Qiu SH, He JS, Pan JH, Pan YL. Identification of a Novel Ferroptosis-Related Gene Prediction Model for Clinical Prognosis and Immunotherapy of Colorectal Cancer. DISEASE MARKERS 2021; 2021:4846683. [PMID: 34868393 PMCID: PMC8635899 DOI: 10.1155/2021/4846683] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Accepted: 11/03/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND Colorectal cancer (CRC) is the third most common malignancies worldwide. Ferroptosis is a programmed, iron-dependent cell death observed in cancer cells. However, the prognostic potential and immunotherapy biomarker potential of ferroptosis-related genes (FRGs) in CRC patients remains to be clarified. METHODS At first, we comprehensively analysed the different expression and prognosis of related FRGs in CRC patients based on TCGA cohort. The relationship between functional enrichment of these genes and immune microenvironment in CRC was investigated using the TCGA database. Prognostic model was constructed to determine the association between FRGs and the prognosis of CRC. Relative verification was done based on the GEO database. Meanwhile, the ceRNA network of FRGs in the model was also performed to explore the regulatory mechanisms. RESULTS Eight differentially expressed FRGs were associated with the prognosis of CRC patients. Patients from the TCGA database were classified into the A, B, and C FRG clusters with different features. And FRG scores were constructed to quantify the FRG pattern of individual patients with colorectal cancer. The CRC patients with higher FRG score showed worse survival outcomes, higher immune dysfunction, and lower response to immunotherapy. The prognostic model showed a high accuracy for predicting the OS of CRC. Finally, a ceRNA network was analysed to show the concrete regulation mechanisms of critical FRGs in CRC. CONCLUSIONS The FRG risk score prognostic model based on 8 FRGs exhibit superior predictive performance, providing a novel prognostic model with a high accuracy for CRC patients. Moreover, FRG score can be the potential biomarker of the response of immunotherapy for CRC.
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Affiliation(s)
- Ya-bing Yang
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Jia-xin Zhou
- International School, Jinan University, Guangzhou, Guangdong 510632, China
| | - Sheng-hui Qiu
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Jia-shuai He
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Jing-hua Pan
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Yun-long Pan
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
- MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan University, Guangzhou 510632, China
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Zhang S, Sun J, Gu M, Wang G, Wang X. Circular RNA: A promising new star for the diagnosis and treatment of colorectal cancer. Cancer Med 2021; 10:8725-8740. [PMID: 34796685 PMCID: PMC8683543 DOI: 10.1002/cam4.4398] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 09/18/2021] [Accepted: 10/19/2021] [Indexed: 12/11/2022] Open
Abstract
Background Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive tract. According to the research of circular RNAs in the CRC field, compared with linear RNAs, circular RNAs are a special type of noncoding RNA that are covalently closed circular structures, which have no 5' cap structure and 3' polyA tail and are not affected by RNA exonuclease and actinomycin D. Biological functions Notably, circular RNAs have a high degree of stability and potential effect on gene regulation. Meanwhile, circular RNAs are involved in the sponge action of microRNAs and mediate protein translation and direct binding, alternative splicing, and histone modification. Relationships with CRC Studies have shown that circular RNAs are related to the proliferation, invasion, recurrence, metastasis, ferroptosis, apoptosis, and chemotherapy resistance of CRC. Conclusions This article provides a brief review based on the source, structural characteristics, mechanisms, biological functions of circular RNAs, and the relationships between CRC.
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Affiliation(s)
- Shunhao Zhang
- Graduate School of Nantong University, Nantong, China
| | - Jing Sun
- Graduate School of Nantong University, Nantong, China
| | - Minqi Gu
- Graduate School of Nantong University, Nantong, China
| | - Guihua Wang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Xudong Wang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, China
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Development and validation of ferroptosis-related lncRNAs prognosis signatures in kidney renal clear cell carcinoma. Cancer Cell Int 2021; 21:591. [PMID: 34736453 PMCID: PMC8567554 DOI: 10.1186/s12935-021-02284-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 10/20/2021] [Indexed: 12/14/2022] Open
Abstract
Background Ferroptosis is a recently recognised new type of cell death which may be a potential target for cancer therapy. In the present study, we aimed to screen ferroptosis-related differentially expressed long non-coding RNAs as biomarkers to predict the outcome of kidney renal clear cell carcinoma. Methods RNAseq count data and corresponding clinical information were obtained from the Cancer Genome Atlas database. Lists of ferroptosis-related genes and long non-coding RNAs were obtained from the FerrDb and GENCODE databases, respectively. The candidate prognostic signatures were screened by Cox regression analyses and least absolute shrinkage and selection operator analyses. Results Three ferroptosis-related long non-coding RNAs (DUXAP8, LINC02609, and LUCAT1) were significantly correlated with the overall survival of kidney renal clear cell carcinoma independently. Kidney renal clear cell carcinoma patients with high-risk values displayed worse OS. Meanwhile, the expression of these three ferroptosis-related long non-coding RNAs and their risk scores were significantly correlated with clinicopathological features. Principal component analyses showed that patients with kidney renal clear cell carcinoma have differential risk values were well distinguished by the three ferroptosis-related long non-coding RNAs. Conclusions The present study suggests that the risk assessment model constructed by these three ferroptosis-related long non-coding RNAs could accurately predict the outcome of kidney renal clear cell carcinoma. We also provide a novel perspective for cancer prognosis screening. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02284-1.
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Wang R, Xing R, Su Q, Yin H, Wu D, Lv C, Yan Z. Knockdown of SFRS9 Inhibits Progression of Colorectal Cancer Through Triggering Ferroptosis Mediated by GPX4 Reduction. Front Oncol 2021; 11:683589. [PMID: 34336668 PMCID: PMC8322952 DOI: 10.3389/fonc.2021.683589] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 06/18/2021] [Indexed: 12/23/2022] Open
Abstract
Ferroptosis, a newly discovered form of programmed cell death characterized by lipid peroxidation, crafts a new perspective on cancer treatment. Serine and arginine rich splicing factor 9 (SFRS9) is frequently described as a proto-oncogene in cervical and bladder cancer. However, the role of SFRS9 in colorectal cancer (CRC) and whether SFRS9 exerts its function associated with ferroptosis is largely unknown. Herein, we found that the expression of SFRS9 mRNA and protein in the CRC tissues was obviously higher than that in the paracancerous tissues. Function assays revealed that SFRS9 overexpression (SFRS9-OE) significantly promoted cell viability, cell cycle progression and colony formation of CRC cells. While SFRS9 knockdown by shRNAs transfection inhibited these progressions. Furthermore, cell death and lipid peroxidation induced by ferroptosis inducers erastin and sorafenib were suppressed by SFRS9-OE. Bioinformatics analysis indicated that SFRS9 can bind to peroxidase 4 (GPX4) mRNA which is a central regulator of ferroptosis. Western blot showed that GPX4 protein expression was clearly elevated upon SFRS9-OE, while it was decreased in SFRS9-inhibited CRC cells. RNA immunoprecipitation experiment was carried out in HCT116 cells to confirm the binding of SFRS9 and GPX4 mRNA specifically. SiGPX4 transfection reversed the inhibitory effects of SFRS9-OE on the erastin and sorafenib-induced ferroptosis. Consistent with our in vitro observations, SFRS9 promoted the growth of tumors while SFRS9 knockdown significantly inhibited tumor growth in nude mice. In conclusion, SFRS9 represents an obstructive factor to ferroptosis by upregulating GPX4 protein expression, and knocking down SFRS9 might be an effective treatment for CRC.
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Affiliation(s)
- Rui Wang
- Department of Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, China
| | - Rui Xing
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qi Su
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Hongzhuan Yin
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Di Wu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Chi Lv
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhaopeng Yan
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
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Zhang K, Ping L, Du T, Liang G, Huang Y, Li Z, Deng R, Tang J. A Ferroptosis-Related lncRNAs Signature Predicts Prognosis and Immune Microenvironment for Breast Cancer. Front Mol Biosci 2021; 8:678877. [PMID: 34164433 PMCID: PMC8215711 DOI: 10.3389/fmolb.2021.678877] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 05/25/2021] [Indexed: 01/10/2023] Open
Abstract
Background: Ferroptosis, a regulated cell death which is driven by the iron-dependent peroxidation of lipids, plays an important role in cancer. However, studies about ferroptosis-related Long non-coding RNAs (lncRNAs) in breast cancer (BC) are limited. Besides, the prognostic role of ferroptosis-related lncRNAs and their relationship to immune microenvironment in breast cancer remain unclear. This study aimed to explore the potential prognostic value of ferroptosis-related lncRNAs and their relationship to immune microenvironment in breast cancer. Methods: RNA-sequencing data of female breast cancer patients were downloaded from TCGA database. 937 patients were randomly separated into training or validation cohort in 2:1 ratio. Ferroptosis-related lncRNAs were screened by Pearson correlation analysis with 239 reported ferroptosis-related genes. A ferroptosis-related lncRNAs signature was constructed with univariate and multivariate Cox regression analyses in the training cohort, and its prognostic value was further tested in the validation cohort. Results: An 8-ferroptosis-related-lncRNAs signature was developed by multivariate Cox regression analysis to divide patients into two risk groups. Patients in the high-risk group had worse prognosis than patients in the low-risk group. Multivariate Cox regression analysis showed the risk score was an independent prognostic indicator. Receiver operating characteristic curve (ROC) analysis proved the predictive accuracy of the signature. The area under time-dependent ROC curve (AUC) reached 0.853 at 1 year, 0.802 at 2 years, 0.740 at 5 years in the training cohort and 0.791 at 1 year, 0.778 at 2 years, 0.722 at 5 years in the validation cohort. Further analysis demonstrated that immune-related pathways were significantly enriched in the high-risk group. Analysis of the immune cell infiltration landscape showed that breast cancer in the high-risk group tended be immunologically “cold”. Conclusion: We identified a novel ferroptosis-related lncRNA signature which could precisely predict the prognosis of breast cancer patients. Ferroptosis-related lncRNAs may have a potential role in the process of anti-tumor immunity and serve as therapeutic targets for breast cancer.
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Affiliation(s)
- Kaiming Zhang
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Liqin Ping
- Department of Medical Oncology, State Key Laboratory of On cology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Tian Du
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Gehao Liang
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yun Huang
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Zhiling Li
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Rong Deng
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Jun Tang
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
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Ferroptosis-Related Gene Signature Promotes Ovarian Cancer by Influencing Immune Infiltration and Invasion. JOURNAL OF ONCOLOGY 2021; 2021:9915312. [PMID: 34135962 PMCID: PMC8175133 DOI: 10.1155/2021/9915312] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 05/10/2021] [Indexed: 12/12/2022]
Abstract
Ovarian cancer is a kind of gynecological malignancy with high mortality. Ferroptosis is a new type of iron-dependent cell death characterized by the formation of lipid peroxides and excessive accumulation of reactive oxygen species. Studies have shown that ferroptosis modulates tumor genesis, progression, and invasion, including ovarian cancer. Based on the mRNA expression data from TCGA, we construct a scoring system using consensus clustering analysis, univariate Cox regression analysis, and least absolute selection operator. Then, we systematically evaluate the relationship between score and clinical characteristics of ovarian cancer. The result from the prediction of biofunction pathways shows that score serves as an independent prognostic marker for ovarian cancer and affects tumor progression by modulating tumor metastasis. Moreover, immunocytes such as activated CD4 T cell, activated CD8 T cell, regulatory T cells, macrophage, and stromal cells, including adipocytes, epithelial cells, and fibroblast infiltrate more in the tumor microenvironment in a high-score group, indicating ferroptosis can also affect tumor immune landscape. Critically, four potentially sensitive drugs, including staurosporine, epothilone B, DMOG, and HG6-64-1 based on the scores, are predicted, and DMOG is recognized as a novel targeted drug for ovarian cancer. In general, we construct the scoring system based on ferroptosis-related genes that can predict the prognosis of ovarian cancer patients and propose that ferroptosis may affect ovarian cancer progression by mediating tumor metastasis and immune landscape. Novel drugs to target ovarian cancer are also predicted.
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Wang Y, Xia HB, Chen ZM, Meng L, Xu AM. Identification of a ferroptosis-related gene signature predictive model in colon cancer. World J Surg Oncol 2021; 19:135. [PMID: 33926457 PMCID: PMC8086290 DOI: 10.1186/s12957-021-02244-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Background The prognosis of colon cancer (CC) is challenging to predict due to its highly heterogeneous nature. Ferroptosis, an iron-dependent form of cell death, has roles in various cancers; however, the correlation between ferroptosis-related genes (FRGs) and prognosis in CC remains unclear. Methods The expression profiles of FRGs and relevant clinical information were retrieved from the Cancer Genome Atlas (TCGA) database. Cox regression analysis and the least absolute shrinkage and selection operator (LASSO) regression model were performed to build a prognostic model in TCGA cohort. Results Ten FRGs, five of which had mutation rates ≥ 3%, were found to be related to the overall survival (OS) of patients with CC. Patients were divided into high- and low-risk groups based on the results of Cox regression and LASSO analysis. Patients in the low-risk group had a significantly longer survival time than patients in the high-risk group (P < 0.001). Enrichment analyses in different risk groups showed that the altered genes were associated with the extracellular matrix, fatty acid metabolism, and peroxisome. Age, risk score, T stage, N stage, and M stage were independent predictors of patient OS based on the results of Cox analysis. Finally, a nomogram was constructed to predict 1-, 3-, and 5-year OS of patients with CC based on the above five independent factors. Conclusion A novel FRG model can be used for prognostic prediction in CC and may be helpful for individualized treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s12957-021-02244-z.
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Affiliation(s)
- Ye Wang
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, People's Republic of China
| | - Heng-Bo Xia
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, People's Republic of China
| | - Zhang-Ming Chen
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, People's Republic of China
| | - Lei Meng
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, People's Republic of China
| | - A-Man Xu
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui Province, People's Republic of China.
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Lu D, Xia Q, Yang Z, Gao S, Sun S, Luo X, Li Z, Zhang X, Han S, Li X, Cao M. ENO3 promoted the progression of NASH by negatively regulating ferroptosis via elevation of GPX4 expression and lipid accumulation. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:661. [PMID: 33987359 PMCID: PMC8106050 DOI: 10.21037/atm-21-471] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background ENO3 expression is upregulated in Non-alcoholic fatty liver disease (NAFLD) patient tissues, demonstrated that ENO3 might play crucial roles in NAFLD. However, the mechanism of ENO3 in NAFLD remains unclear. Therefore, this study aimed to investigate the regulatory mechanism of ENO3 in the progression of non-alcoholic steatohepatitis (NASH) in vivo and vitro NASH model. Methods In vivo and vitro NASH model were established by methionine-choline deficient (MCD)-diet feeding and high free fatty acid (HFFA) induction in L02 cells. Loss and gain function of ENO3 and GPX4 was performed to study the mechanism in NASH. Western blot was used to detect the expression of ENO3 and GPX4. Hematoxylin and eosin (H&E), picrosirius Red and Oil Red O staining was used to evaluate histopathology of liver in NASH model. Ferroptosis indicators were measured by assay kits according to the manufacturer's instructions. Results NASH mouse model was successfully established induced by MCD diet with steatosis, inflammatory infiltration, ballooning and fibrosis observed in the liver tissue. The expression of ENO3 and GPX4 was significantly elevated while ferroptosis was inhibited in NASH mice and cell model. Upregulation of both ENO3 and GPX4 could promote the lipid accumulation in L02 cells. In addition, overexpressed ENO3 attenuated the status of ferroptosis. Conclusions In the present study, we demonstrate that ENO3 promoted the progression of NASH by negatively regulating ferroptosis via elevating GPX4 expression and lipid accumulation. These findings provided solid foundation for the mechanism of ferroptosis on the progression of NASH regulated by ENO3, suggesting that ENO3 may be a potential therapeutic target for NASH.
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Affiliation(s)
- Di Lu
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
| | - Qiaoyun Xia
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
| | - Zhiyu Yang
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
| | - Shanjun Gao
- Microbiome Laboratory, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Suofeng Sun
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
| | - Xiaoying Luo
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
| | - Zhen Li
- Microbiome Laboratory, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiulei Zhang
- Microbiome Laboratory, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuangyin Han
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
| | - Xiuling Li
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
| | - Mingbo Cao
- Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, China
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The emerging role of ferroptosis in intestinal disease. Cell Death Dis 2021; 12:289. [PMID: 33731703 PMCID: PMC7969743 DOI: 10.1038/s41419-021-03559-1] [Citation(s) in RCA: 139] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 02/23/2021] [Accepted: 02/24/2021] [Indexed: 02/06/2023]
Abstract
Ferroptosis is a newly recognised type of regulated cell death (RCD) characterised by iron-dependent accumulation of lipid peroxidation. It is significantly distinct from other RCDs at the morphological, biochemical, and genetic levels. Recent reports have implicated ferroptosis in multiple diseases, including neurological disorders, kidney injury, liver diseases, and cancer. Ferroptotic cell death has also been associated with dysfunction of the intestinal epithelium, which contributes to several intestinal diseases. Research on ferroptosis may provide a new understanding of intestinal disease pathogenesis that benefits clinical treatment. In this review, we provide an overview of ferroptosis and its underlying mechanisms, then describe its emerging role in intestinal diseases, including intestinal ischaemia/reperfusion (I/R) injury, inflammatory bowel disease (IBD), and colorectal cancer (CRC).
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Wang H, Peng S, Cai J, Bao S. Silencing of PTPN18 Induced Ferroptosis in Endometrial Cancer Cells Through p-P38-Mediated GPX4/xCT Down-Regulation. Cancer Manag Res 2021; 13:1757-1765. [PMID: 33642877 PMCID: PMC7903946 DOI: 10.2147/cmar.s278728] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 01/05/2021] [Indexed: 12/22/2022] Open
Abstract
Background Endometrial cancer (EC) is the fourth most common neoplasm and the eighth leading cause of cancer death in females worldwide. PTPN18 is a member of the protein tyrosine phosphatases (PTP) family, which is associated with the occurrence and progression of various human cancers. PTPN18 was up-regulated in endometrial cancer tissues and high level of PTPN18 promoted proliferation and metastasis of EC cells. Methods The expression of PTPN18, GPX4 and xCT in endometrial cancer tissues and KLE cells was detected by immunohistochemistry and Western blot, respectively. Lentiviral transfection were used to silence PTPN18 level in KLE cells. The Ros level in KLE cells was examined by ELISA assay. Results In the present study, we found that silencing of PTPN18 induced ferroptosis in KLE endometrial cancer cells. PTPN18 knockdown increased intracellular ROS level and down-regulated GPX4 and xCT expression. Besides, silencing of PTPN18 also induced the expression of p-p38. Conclusion We concluded that silencing of PTPN18 might induce ferroptosis by targeting the p-p38/GPX4/xCT axis. The results provide critical insight into the application of PTPN18 knockdown in EC intervention.
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Affiliation(s)
- Haibo Wang
- Department of Gynaecology and Obstetrics, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, 570311, People's Republic of China
| | - Siyuan Peng
- Department of Gynaecology and Obstetrics, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, 570311, People's Republic of China
| | - Junhong Cai
- Key Laboratory of Cell and Molecular Genetic Translational Medicine in Hainan Province, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, 570311, People's Republic of China
| | - Shan Bao
- Department of Gynaecology and Obstetrics, Hainan General Hospital/Hainan Affiliated Hospital of Hainan Medical University, Haikou, 570311, People's Republic of China
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