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Yao YQ, Cao QY, Li Z. Delaying liver aging: Analysis of structural and functional alterations. World J Gastroenterol 2025; 31:103773. [PMID: 40309235 PMCID: PMC12038549 DOI: 10.3748/wjg.v31.i15.103773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 02/23/2025] [Accepted: 04/07/2025] [Indexed: 04/18/2025] Open
Abstract
This article is based on a recent bibliometric analysis of research progress on liver aging. The liver is notable for its extraordinary ability to rejuvenate, thereby safeguarding and maintaining the organism's integrity. With advancing age, there is a noteworthy reduction in both the liver's size and blood circulation. Furthermore, the wide range of physiological alterations driven on by aging may foster the development of illnesses. Previous studies indicate that liver aging is linked to impaired lipid metabolism and abnormal gene expression associated with chronic inflammation. Factors such as mitochondrial dysfunction and telomere shortening accumulate, which may result in increased hepatic steatosis, which impacts liver regeneration, metabolism, and other functions. Knowing the structural and functional changes could help elderly adults delay liver aging. Increasing public awareness of anti-aging interventions is essential. Besides the use of dietary supplements, alterations in lifestyle, including changes in dietary habits and physical exercise routines, are the most efficacious means to decelerate the aging process of the liver. This article highlights recent advances in the mechanism research of liver aging and summarizes the promising intervention options to delay liver aging for preventing related diseases.
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Affiliation(s)
- Yu-Qin Yao
- College of Health Sciences, School of Life Sciences, Jiangsu Normal University, Xuzhou 221000, Jiangsu Province, China
| | - Qiong-Yue Cao
- College of Health Sciences, School of Life Sciences, Jiangsu Normal University, Xuzhou 221000, Jiangsu Province, China
| | - Zheng Li
- College of Health Sciences, School of Life Sciences, Jiangsu Normal University, Xuzhou 221000, Jiangsu Province, China
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Du Q, Xu J, Zhang M, Yang J. Uncarboxylated osteocalcin induced miR-143-3p targets SP7 and activates PI3K/Akt signaling in TNBC cells to promote invasion and migration. Transl Oncol 2025; 53:102305. [PMID: 39904283 PMCID: PMC11846592 DOI: 10.1016/j.tranon.2025.102305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 01/15/2025] [Accepted: 01/30/2025] [Indexed: 02/06/2025] Open
Abstract
Triple-negative breast cancer (TNBC) is an exceptionally aggressive malignancy with poor prognosis. Patients often have elevated mortality and recurrence rates, along with a pronounced risk of distant metastasis. Our earlier research highlighted the role of uncarboxylated osteocalcin (GluOC) in fueling TNBC cell proliferation and metastasis; however the molecular underpinnings of its impact on cancer invasion and migration remain enigmatic. In this study, we identified miR-143-3p as a significantly downregulated miRNA following GluOC treatment in TNBC cells. Notably, increased miR-143-3p has been linked to more favorable clinical outcomes in patients with TNBC. miR-143-3p expression has been shown to target and repress the expression of SP7. Furthermore, our findings indicate that GluOC modulates the miR-143-3p/PI3K/Akt signaling pathway, which in turn fosters the invasive and migratory capabilities of TNBC cells. In a xenograft animal model, we observed that the administration of GluOC led to a marked enhancement in tumor growth. Conversely, the delivery of miR-143-3p agomir was associated with a notable reduction in tumor growth. Notably, concurrent administration of miR-143-3p agomir and GluOC partially abrogated the tumorigenic effects induced by GluOC alone. Furthermore, GluOC downregulated the expression of miR-143-3p. Our study findings indicate that GluOC plays a role in the invasion and migration of TNBC cells by regulating the miR-143-3p/SP7 and miR-143-3p/PI3K/Akt axes. These insights suggest that GluOC and miR-143-3p are integral to the invasive and migratory processes of TNBC cells and may serve as promising targets for therapeutic interventions in TNBC.
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Affiliation(s)
- Qian Du
- Medical School, University of Chinese Academy of Sciences, Beijing 101400, PR China.
| | - Jiaojiao Xu
- Medical School, University of Chinese Academy of Sciences, Beijing 101400, PR China.
| | - Miao Zhang
- Medical School, University of Chinese Academy of Sciences, Beijing 101400, PR China.
| | - Jianhong Yang
- Medical School, University of Chinese Academy of Sciences, Beijing 101400, PR China.
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Liu M, Wang Y, Wang C, Li P, Qiu J, Yang N, Sun M, Han L. A Microfluidic 3D-Tumor-Spheroid Model for the Evaluation of Targeted Therapies from Angiogenesis-Related Cytokines at the Single Spheroid Level. Adv Healthc Mater 2024; 13:e2402321. [PMID: 39126126 DOI: 10.1002/adhm.202402321] [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: 06/25/2024] [Indexed: 08/12/2024]
Abstract
Angiogenesis is a key player in drug resistance to targeted therapies for breast cancer. The average expression of angiogenesis-related cytokines is widely associated with the treatments of target therapies for a population of cells or spheroids, overlooking the distinct responses for individuals. In this work, a highly integrated microfluidic platform is developed for the generation of monodisperse multicellular tumor spheroids (MTSs), drug treatments, and the measurement of cytokines for individual MTSs in a single chip. The platform allows the correlation evaluation between cytokine secretion and drug treatment at the level of individual spheroids. For validation, quantities of six representative proangiogenic cytokines are tested against treatments with four model drugs at varying times and concentrations. By applying a linear regression model, significant correlations are established between cytokine secretion and the treated drug concentration for individual spheroids. The proposed platform provides a high-throughput method for the investigation of the molecular mechanism of the cytokine response to targeted therapies and paves the way for future drug screening using predictive regression models at the single-spheroid level.
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Affiliation(s)
- Mengqi Liu
- Institute of Marine Science and Technology, Shandong University, Tsingdao, 266237, China
| | - Yihe Wang
- Institute of Marine Science and Technology, Shandong University, Tsingdao, 266237, China
| | - Chao Wang
- Institute of Marine Science and Technology, Shandong University, Tsingdao, 266237, China
| | - Ping Li
- Institute of Marine Science and Technology, Shandong University, Tsingdao, 266237, China
| | - Jiaoyan Qiu
- Institute of Marine Science and Technology, Shandong University, Tsingdao, 266237, China
| | - Ningkai Yang
- Institute of Marine Science and Technology, Shandong University, Tsingdao, 266237, China
| | - Mingyuan Sun
- Institute of Marine Science and Technology, Shandong University, Tsingdao, 266237, China
| | - Lin Han
- Institute of Marine Science and Technology, Shandong University, Tsingdao, 266237, China
- Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, 250100, P. R. China
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Xie J, Yuan C, Yang S, Ma Z, Li W, Mao L, Jiao P, Liu W. The role of reactive oxygen species in severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection-induced cell death. Cell Mol Biol Lett 2024; 29:138. [PMID: 39516736 PMCID: PMC11549821 DOI: 10.1186/s11658-024-00659-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024] Open
Abstract
Coronavirus disease 2019 (COVID-19) represents the novel respiratory infectious disorder caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is characterized by rapid spread throughout the world. Reactive oxygen species (ROS) account for cellular metabolic by-products, and excessive ROS accumulation can induce oxidative stress due to insufficient endogenous antioxidant ability. In the case of oxidative stress, ROS production exceeds the cellular antioxidant capacity, thus leading to cell death. SARS-CoV-2 can activate different cell death pathways in the context of infection in host cells, such as neutrophil extracellular trap (NET)osis, ferroptosis, apoptosis, pyroptosis, necroptosis and autophagy, which are closely related to ROS signalling and control. In this review, we comprehensively elucidated the relationship between ROS generation and the death of host cells after SARS-CoV-2 infection, which leads to the development of COVID-19, aiming to provide a reasonable basis for the existing interventions and further development of novel therapies against SARS-CoV-2.
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Affiliation(s)
- Jiufeng Xie
- College of Life Sciences, Henan Agricultural University, Zhengzhou, 450002, China
| | - Cui Yuan
- College of Life Sciences, Henan Agricultural University, Zhengzhou, 450002, China
| | - Sen Yang
- College of Life Sciences, Henan Agricultural University, Zhengzhou, 450002, China
| | - Zhenling Ma
- College of Life Sciences, Henan Agricultural University, Zhengzhou, 450002, China
| | - Wenqing Li
- College of Life Sciences, Henan Agricultural University, Zhengzhou, 450002, China
| | - Lin Mao
- College of Life Sciences, Henan Agricultural University, Zhengzhou, 450002, China
| | - Pengtao Jiao
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Wei Liu
- College of Life Sciences, Henan Agricultural University, Zhengzhou, 450002, China.
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Zhou X, Zhao J, Yan T, Ye D, Wang Y, Zhou B, Liu D, Wang X, Zheng W, Zheng B, Qian F, Li Y, Li D, Fang L. ANXA9 facilitates S100A4 and promotes breast cancer progression through modulating STAT3 pathway. Cell Death Dis 2024; 15:260. [PMID: 38609357 PMCID: PMC11014919 DOI: 10.1038/s41419-024-06643-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 03/29/2024] [Accepted: 04/03/2024] [Indexed: 04/14/2024]
Abstract
Breast cancer has the highest global incidence and mortality rates among all cancer types. Abnormal expression of the Annexin family has been observed in different malignant tumors, including upregulated ANXA9 in breast cancer. We found highly expressed ANXA9 in metastatic breast cancer tissues, which is correlated with breast cancer progression. In vitro, the functional experiments indicated ANXA9 influenced breast cancer proliferation, motility, invasion, and apoptosis; in vivo, downregulation of ANXA9 suppressed breast cancer xenograft tumor growth and lung metastasis. Mechanically, on one side, we found that ANXA9 could mediate S100A4 and therefore regulate AKT/mTOR/STAT3 pathway to participate p53/Bcl-2 apoptosis; on the other side, we found ANXA9 transferred S100A4 from cells into the tumor microenvironment and mediated the excretion of cytokines IL-6, IL-8, CCL2, and CCL5 to participate angiogenesis via self- phosphorylation at site Ser2 and site Thr69. Our findings demonstrate significant involvement of ANXA9 in promoting breast cancer progression, thereby suggesting that therapeutic intervention via targeting ANXA9 may be effective in treating metastatic breast cancer.
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Affiliation(s)
- Xiqian Zhou
- Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Junyong Zhao
- Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Tao Yan
- Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Danrong Ye
- Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuying Wang
- Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Bai'an Zhou
- Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Diya Liu
- Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xuehui Wang
- Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wenfang Zheng
- Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Bowen Zheng
- Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Fengyuan Qian
- Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yating Li
- Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Dengfeng Li
- Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
- Institute of Breast Disease, School of Medicine, Tongji University, Shanghai, China.
| | - Lin Fang
- Department of Breast and Thyroid Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
- Institute of Breast Disease, School of Medicine, Tongji University, Shanghai, China.
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Du J, Lin Z, Fu XH, Gu XR, Lu G, Hou J. Research progress of the chemokine/chemokine receptor axes in the oncobiology of multiple myeloma (MM). Cell Commun Signal 2024; 22:177. [PMID: 38475811 PMCID: PMC10935833 DOI: 10.1186/s12964-024-01544-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 02/25/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND The incidence of multiple myeloma (MM), a type of blood cancer affecting monoclonal plasma cells, is rising. Although new drugs and therapies have improved patient outcomes, MM remains incurable. Recent studies have highlighted the crucial role of the chemokine network in MM's pathological mechanism. Gaining a better understanding of this network and creating an overview of chemokines in MM could aid in identifying potential biomarkers and developing new therapeutic strategies and targets. PURPOSE To summarize the complicated role of chemokines in MM, discuss their potential as biomarkers, and introduce several treatments based on chemokines. METHODS Pubmed, Web of Science, ICTRP, and Clinical Trials were searched for articles and research related to chemokines. Publications published within the last 5 years are selected. RESULTS Malignant cells can utilize chemokines, including CCL2, CCL3, CCL5, CXCL7, CXCL8, CXCL12, and CXCL13 to evade apoptosis triggered by immune cells or medication, escape from bone marrow and escalate bone lesions. Other chemokines, including CXCL4, CCL19, and CXCL10, may aid in recruiting immune cells, increasing their cytotoxicity against cancer cells, and inducing apoptosis of malignant cells. CONCLUSION Utilizing anti-tumor chemokines or blocking pro-tumor chemokines may provide new therapeutic strategies for managing MM. Inspired by developed CXCR4 antagonists, including plerixafor, ulocuplumab, and motixafortide, more small molecular antagonists or antibodies for pro-tumor chemokine ligands and their receptors can be developed and used in clinical practice. Along with inhibiting pro-tumor chemokines, studies suggest combining chemokines with chimeric antigen receptor (CAR)-T therapy is promising and efficient.
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Affiliation(s)
- Jun Du
- Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Zheng Lin
- Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xue-Hang Fu
- Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Xiao-Ran Gu
- Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Guang Lu
- Department of Hematology, Shengli Oilfield Central Hospital, Dongying, 257099, China.
| | - Jian Hou
- Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
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Zhang Q, Qi S, You J, Wang C. The role of retinal glial cells and related factors in macular edema. Biochem Biophys Res Commun 2024; 695:149415. [PMID: 38159411 DOI: 10.1016/j.bbrc.2023.149415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 12/09/2023] [Accepted: 12/19/2023] [Indexed: 01/03/2024]
Abstract
Macular edema (ME) has emerged as a leading cause of visual impairment, representing a critical clinical manifestation and complication associated with many eye diseases. In the occurrence and development of ME, retinal glial cells like Müller cells and microglial cells play vital roles. Moreover, growth factor and cytokines associated with them, such as vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF), hypoxia-inducible factor-1α (HIF-1α), angiopoietin-like protein 4 (ANGPTL4), interleukin-6(IL-6), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), prostaglandin, etc., also take part in the pathogenesis of ME. Changes in these cytokines can lead to retinal angiogenesis, increased vascular permeability, blood-retinal barrier (BRB) breakdown, and fluid leakage, further causing ME to occur or deteriorate. Research on the role of retinal glial cells and related cytokines in ME will provide new therapeutic directions and effective remedies. This article is a literature review on the role of Müller cells, microglial cells and related factors in ME pathogenesis.
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Affiliation(s)
- Qi Zhang
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, China.
| | - Shounan Qi
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, China.
| | - Jiaxin You
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, China.
| | - Chenguang Wang
- Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, China.
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Li M, Jiang P, Yang Y, Xiong L, Wei S, Wang J, Li C. The role of pyroptosis and gasdermin family in tumor progression and immune microenvironment. Exp Hematol Oncol 2023; 12:103. [PMID: 38066523 PMCID: PMC10704735 DOI: 10.1186/s40164-023-00464-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 11/29/2023] [Indexed: 06/29/2024] Open
Abstract
Pyroptosis, an inflammatory programmed cell death, distinguishes itself from apoptosis and necroptosis and has drawn increasing attention. Recent studies have revealed a correlation between the expression levels of many pyroptosis-related genes and both tumorigenesis and progression. Despite advancements in cancer treatments such as surgery, radiotherapy, chemotherapy, and immunotherapy, the persistent hallmark of cancer enables malignant cells to elude cell death and develop resistance to therapy. Recent findings indicate that pyroptosis can overcome apoptosis resistance amplify treatment-induced tumor cell death. Moreover, pyroptosis triggers antitumor immunity by releasing pro-inflammatory cytokines, augmenting macrophage phagocytosis, and activating cytotoxic T cells and natural killer cells. Additionally, it transforms "cold" tumors into "hot" tumors, thereby enhancing the antitumor effects of various treatments. Consequently, pyroptosis is intricately linked to tumor development and holds promise as an effective strategy for boosting therapeutic efficacy. As the principal executive protein of pyroptosis, the gasdermin family plays a pivotal role in influencing pyroptosis-associated outcomes in tumors and can serve as a regulatory target. This review provides a comprehensive summary of the relationship between pyroptosis and gasdermin family members, discusses their roles in tumor progression and the tumor immune microenvironment, and analyses the underlying therapeutic strategies for tumor treatment based on pyroptotic cell death.
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Affiliation(s)
- Mengyuan Li
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, 100191, China
| | - Ping Jiang
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, 100191, China
| | - Yuhan Yang
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, 100191, China
| | - Liting Xiong
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, 100191, China
| | - Shuhua Wei
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, 100191, China
| | - Junjie Wang
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, 100191, China.
| | - Chunxiao Li
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, 100191, China.
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Shi Z, Yao C, Shui Y, Li S, Yan H. Research progress on the mechanism of angiogenesis in wound repair and regeneration. Front Physiol 2023; 14:1284981. [PMID: 38089479 PMCID: PMC10711283 DOI: 10.3389/fphys.2023.1284981] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 11/13/2023] [Indexed: 12/10/2024] Open
Abstract
Poor wound healing and pathological healing have been pressing issues in recent years, as they impact human quality of life and pose risks of long-term complications. The study of neovascularization has emerged as a prominent research focus to address these problems. During the process of repair and regeneration, the establishment of a new vascular system is an indispensable stage for complete healing. It provides favorable conditions for nutrient delivery, oxygen supply, and creates an inflammatory environment. Moreover, it is a key manifestation of the proliferative phase of wound healing, bridging the inflammatory and remodeling phases. These three stages are closely interconnected and inseparable. This paper comprehensively integrates the regulatory mechanisms of new blood vessel formation in wound healing, focusing on the proliferation and migration of endothelial cells and the release of angiogenesis-related factors under different healing outcomes. Additionally, the hidden link between the inflammatory environment and angiogenesis in wound healing is explored.
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Affiliation(s)
- Zhuojun Shi
- Department of Plastic and Burns Surgery, The Affiliated Hospital of Southwest Medical University, National Key Clinical Construction Specialty, Wound Repair and Regeneration Laboratory, Luzhou, Sichuan, China
| | - Chong Yao
- Department of Plastic and Burns Surgery, The Affiliated Hospital of Southwest Medical University, National Key Clinical Construction Specialty, Wound Repair and Regeneration Laboratory, Luzhou, Sichuan, China
| | - Yujie Shui
- Department of Plastic and Burns Surgery, The Affiliated Hospital of Southwest Medical University, National Key Clinical Construction Specialty, Wound Repair and Regeneration Laboratory, Luzhou, Sichuan, China
| | - Site Li
- Department of Plastic and Burns Surgery, The Affiliated Hospital of Southwest Medical University, National Key Clinical Construction Specialty, Wound Repair and Regeneration Laboratory, Luzhou, Sichuan, China
| | - Hong Yan
- Laboratory of Plastic Surgery, Department of Plastic Surgery and Reconstruction, Second Hospital of West China, Sichuan University, Chengdu, Sichuan, China
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Abdul Kadir FFN, Che Nordin MA, S M N Mydin RB, Choong YS, Che Omar MT. Molecular interaction analysis of anti-IL-8 scFv-10F8-6His against IL-8 monomer through molecular docking and molecular dynamic simulations. J Biomol Struct Dyn 2023; 42:12293-12303. [PMID: 37837430 DOI: 10.1080/07391102.2023.2269254] [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: 09/06/2023] [Accepted: 10/04/2023] [Indexed: 10/16/2023]
Abstract
Elevated interleukin 8 (IL-8) expression has been linked to unfavorable outcomes in a range of inflammatory conditions, such as rheumatoid arthritis, psoriasis, and cancer. The human monoclonal antibody (HuMab) 10F8 and the hybridoma 35B11-B bind to an epitope on human IL-8, respectively. 10F8 inhibited interaction between IL-8 and neutrophils in eczema and pustulosis palmoplantaris patients while 35B11-B decreased size lesion in rat model. The binding interaction of monoclonal antibodies and IL-8, especially how complementarity-determining region (CDR) loops could bind the N-terminal of IL-8, has not been fully deliberated at molecular-level. Here, we used a combination of molecular docking, heated and long coarse-grained molecular dynamics simulations to identify key residues of established interaction. Based on heated MD simulation, docked pose of complexes generated by ClusPro showed good binding stability throughout of 70 ns simulation. Based on long molecular dynamic simulations, key residues for the binding were identified throughout of 1000 ns simulation. TYR-53, ASP-99, and ARG-100 of heavy chain CDR together with TYR-33 of light chain CDR are among the highest contributing energy residues within the binding interaction. Meanwhile, LYS11 and TYR13 of IL-8 are important for the determination of overall binding energy. Furthermore, the result of decomposition residues analysis is in good agreement with the interaction analysis data. Current study provides a list of important interacting residues and further scrutiny on these residues is essential for future development and design of a new and stable recombinant antibody against IL-8.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
| | - Muhamad Alif Che Nordin
- Biological Section, School of Distance Education, Universiti Sains Malaysia, Penang, Malaysia
| | - Rabiatul Basria S M N Mydin
- Biomedical Sciences Department, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Penang, Malaysia
| | - Yee Siew Choong
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Penang, Malaysia
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Chen G. Molecular basis of breast cancer with comorbid depression and the mechanistic insights of Xiaoyaosan in treating breast cancer-associated depression. Medicine (Baltimore) 2023; 102:e35157. [PMID: 37747031 PMCID: PMC10519572 DOI: 10.1097/md.0000000000035157] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/25/2023] [Accepted: 08/18/2023] [Indexed: 09/26/2023] Open
Abstract
Depression and breast cancer (BC) have been found to have a shared genetic basis, multiple loci of effect, and a presumed causal relationship. The treatment of BC combined with depression poses significant challenges. This study aims to use bioinformatics and network pharmacology to explore the molecular basis of BC combined with depression and to elucidate the potential mechanisms of Xiaoyaosan (XYS) in treating this disease. The molecular background of BC complicated with depression was discovered via data mining and bioinformatics. The molecular mechanism of XYS in the treatment of BC with depression was investigated by network pharmacology. The binding affinity between targets and active compounds was evaluated by molecular docking. The impact of XYS on the gene and protein expression of matrix metallopeptidase 9 (MMP9) in microglial cells was assessed using RT-quantitative PCR and western blot analysis, respectively. Differential expression analysis was conducted to identify genes associated with BC, revealing that 2958 genes were involved, with 277 of these genes also being related to depression. XYS was found to contain 173 active compounds and 342 targets, with 44 of these targets being involved in regulating the progression of BC and depression. Enrichment analysis was performed to identify pathways associated with these targets, revealing that they were related to cell proliferation, catalytic activity, cell communication, and interleukin-18 signaling and LXR/RXR activation. Network analysis was conducted to identify key targets of Xiaoyaosan in treating BC combined with depression, with EGF, interleukin 6, epidermal growth factor receptor, and peroxisome proliferator activated receptor gamma being identified as important targets. Molecular docking was also performed to assess the binding affinity between key targets and active compounds, with puerarin showing the strongest affinity for MMP9. In microglial cells, XYS significantly enhances the gene and protein expression of MMP9. This study elucidated the pharmacological mechanism of co-treatment for BC patients complicated with depression and the pharmacological mechanism of XYS against BC plus depression.
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Affiliation(s)
- Gang Chen
- Department of Breast Surgery, Hangzhou Fuyang Women and Children Hospital, Hangzhou, China
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12
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Woxholt S, Ueland T, Aukrust P, Anstensrud AK, Broch K, Tøllefsen IM, Ryan L, Bendz B, Hopp E, Kløw NE, Seljeflot I, Halvorsen B, Dahl TB, Huse C, Andersen GØ, Gullestad L, Wiseth R, Amundsen BH, Damas JK, Kleveland O. Cytokine pattern in patients with ST-elevation myocardial infarction treated with the interleukin-6 receptor antagonist tocilizumab. Open Heart 2023; 10:e002301. [PMID: 37591633 PMCID: PMC10441101 DOI: 10.1136/openhrt-2023-002301] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 07/07/2023] [Accepted: 07/27/2023] [Indexed: 08/19/2023] Open
Abstract
BACKGROUND Tocilizumab improves myocardial salvage index (MSI) in patients with ST-elevation myocardial infarction (STEMI), but its mechanisms of action are unclear. Here, we explored how cytokines were affected by tocilizumab and their correlations with neutrophils, C-reactive protein (CRP), troponin T, MSI and infarct size. METHODS STEMI patients were randomised to receive a single dose of 280 mg tocilizumab (n=101) or placebo (n=98) before percutaneous coronary intervention. Blood samples were collected before infusion of tocilizumab or placebo at baseline, during follow-up at 24-36, 72-168 hours, 3 and 6 months. 27 cytokines were analysed using a multiplex cytokine assay. Cardiac MRI was performed during hospitalisation and 6 months. RESULTS Repeated measures analysis of variance showed significant (p<0.001) between-group difference in changes for IL-6, IL-8 and IL-1ra due to an increase in the tocilizumab group during hospitalisation. IL-6 and IL-8 correlated to neutrophils in the placebo group (r=0.73, 0.68, respectively), which was attenuated in the tocilizumab group (r=0.28, 0.27, respectively). A similar pattern was seen for MSI and IL-6 and IL-8 in the placebo group (r=-0.29, -0.25, respectively) in patients presenting ≤3 hours from symptom onset, which was attenuated in the tocilizumab group (r=-0.09,-0.14, respectively). CONCLUSIONS Tocilizumab increases IL-6, IL-8 and IL-1ra in STEMI. IL-6 and IL-8 show correlations to neutrophils/CRP and markers of cardiac injury in the placebo group that was attenuated in the tocilizumab group. This may suggest a beneficial effect of tocilizumab on the ischaemia-reperfusion injury in STEMI patients. TRIAL REGISTRATION NUMBER NCT03004703.
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Affiliation(s)
- Sindre Woxholt
- Clinic of Cardiology, St Olavs Hospital Trondheim University Hospital, Trondheim, Norway
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
| | - T Ueland
- Research Institute of Internal Medicine, Rikshospitalet University Hospital, Oslo, Norway
- K. G. Jebsen Thrombosis Research and Expertise Center (TREC), UiT The Arctic University of Norway, Tromso, Norway
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Pål Aukrust
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Section of Clinical Immunology and Infectious Disease, Oslo Universitetssykehus, Oslo, Norway
- Research Institute of Internal Medicine, Rikshospitalet Research Institute for Internal Medicine, Oslo, Norway
| | - Anne Kristine Anstensrud
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Cardiology, Oslo University Hospital, Oslo, Norway
| | - Kaspar Broch
- Department of Cardiology, Rikshospitalet University Hospital, Oslo, Norway
- K. G. Jebsen Cardiac Research Centre and Centre for Heart Failure Research, University of Oslo, Oslo, Norway
| | | | - Liv Ryan
- Department of clinical and Molecular medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Bjørn Bendz
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Cardiology, Oslo University Hospital, Oslo, Norway
| | - Einar Hopp
- Department of Radiology and Nuclear Medicine, Rikshospitalet University Hospital, Oslo, Norway
| | - Nils-Einar Kløw
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Radiology, Oslo University Hospital Ullevaal, Oslo, Norway
| | - Ingebjørg Seljeflot
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevaal, Oslo, Norway
| | - Bente Halvorsen
- Research Institute of Internal Medicine, Rikshospitalet University Hospital, Oslo, Norway
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Tuva B Dahl
- Research Institute of Internal Medicine, Rikshospitalet University Hospital, Oslo, Norway
| | - Camilla Huse
- Research Institute of Internal Medicine, Rikshospitalet University Hospital, Oslo, Norway
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Geir Øystein Andersen
- Department of Cardiology, Oslo universitetssykehus Ulleval, Oslo, Norway
- Department of Cardiology, Center for Clinical Heart Research, University of Oslo, Oslo, Norway
| | - Lars Gullestad
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Cardiology, Rikshospitalet University Hospital, Oslo, Norway
- K. G. Jebsen Cardiac Research Centre and Centre for Heart Failure Research, University of Oslo, Oslo, Norway
| | - Rune Wiseth
- Clinic of Cardiology, St Olavs Hospital Trondheim University Hospital, Trondheim, Norway
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
| | - Brage H Amundsen
- Clinic of Cardiology, St Olavs Hospital Trondheim University Hospital, Trondheim, Norway
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
| | - Jan Kristian Damas
- Department of Infectious Diseases, St Olavs Hospital Trondheim University Hospital, Trondheim, Norway
- Department of Clinical and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway
| | - Ola Kleveland
- Clinic of Cardiology, St Olavs Hospital Trondheim University Hospital, Trondheim, Norway
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Bleve A, Motta F, Durante B, Pandolfo C, Selmi C, Sica A. Immunosenescence, Inflammaging, and Frailty: Role of Myeloid Cells in Age-Related Diseases. Clin Rev Allergy Immunol 2023; 64:123-144. [PMID: 35031957 PMCID: PMC8760106 DOI: 10.1007/s12016-021-08909-7] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2021] [Indexed: 12/20/2022]
Abstract
The immune system is the central regulator of tissue homeostasis, ensuring tissue regeneration and protection against both pathogens and the neoformation of cancer cells. Its proper functioning requires homeostatic properties, which are maintained by an adequate balance of myeloid and lymphoid responses. Aging progressively undermines this ability and compromises the correct activation of immune responses, as well as the resolution of the inflammatory response. A subclinical syndrome of "homeostatic frailty" appears as a distinctive trait of the elderly, which predisposes to immune debilitation and chronic low-grade inflammation (inflammaging), causing the uncontrolled development of chronic and degenerative diseases. The innate immune compartment, in particular, undergoes to a sequela of age-dependent functional alterations, encompassing steps of myeloid progenitor differentiation and altered responses to endogenous and exogenous threats. Here, we will review the age-dependent evolution of myeloid populations, as well as their impact on frailty and diseases of the elderly.
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Affiliation(s)
- Augusto Bleve
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Largo Donegani, via Bovio 6, 2 - 28100, Novara, Italy
| | - Francesca Motta
- Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center- IRCCS, via Manzoni 56, Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072, Pieve Emanuele, Milan, Italy
| | - Barbara Durante
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Largo Donegani, via Bovio 6, 2 - 28100, Novara, Italy
| | - Chiara Pandolfo
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Largo Donegani, via Bovio 6, 2 - 28100, Novara, Italy
| | - Carlo Selmi
- Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center- IRCCS, via Manzoni 56, Rozzano, Milan, Italy.
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072, Pieve Emanuele, Milan, Italy.
| | - Antonio Sica
- Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Largo Donegani, via Bovio 6, 2 - 28100, Novara, Italy.
- Humanitas Clinical and Research Center - IRCCS, via Manzoni 56, 20089, Rozzano, Milan, Italy.
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14
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Gremese E, Tolusso B, Bruno D, Perniola S, Ferraccioli G, Alivernini S. The forgotten key players in rheumatoid arthritis: IL-8 and IL-17 - Unmet needs and therapeutic perspectives. Front Med (Lausanne) 2023; 10:956127. [PMID: 37035302 PMCID: PMC10073515 DOI: 10.3389/fmed.2023.956127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 02/21/2023] [Indexed: 04/11/2023] Open
Abstract
Despite the relevant advances in our understanding of the pathogenetic mechanisms regulating inflammation in rheumatoid arthritis (RA) and the development of effective therapeutics, to date, there is still a proportion of patients with RA who do not respond to treatment and end up progressing toward the development of joint damage, extra-articular complications, and disability. This is mainly due to the inter-individual heterogeneity of the molecular and cellular taxonomy of the synovial membrane, which represents the target tissue of RA inflammation. Tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) are crucial key players in RA pathogenesis fueling the inflammatory cascade, as supported by experimental evidence derived from in vivo animal models and the effectiveness of biologic-Disease Modifying Anti-Rheumatic Drugs (b-DMARDs) in patients with RA. However, additional inflammatory soluble mediators such as IL-8 and IL-17 exert their pathogenetic actions promoting the detrimental activation of immune and stromal cells in RA synovial membrane, tendons, and extra-articular sites, as well as blood vessels and lungs, causing extra-articular complications, which might be excluded by the action of anti-TNFα and anti-IL6R targeted therapies. In this narrative review, we will discuss the role of IL-8 and IL-17 in promoting inflammation in multiple biological compartments (i.e., synovial membrane, blood vessels, and lung, respectively) in animal models of arthritis and patients with RA and how their selective targeting could improve the management of treatment resistance in patients.
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Affiliation(s)
- Elisa Gremese
- Division of Clinical Immunology, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy
- Immunology Core Facility, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy
- School of Medicine, Università Cattolica del Sacro Cuore, Rome, Italy
- *Correspondence: Elisa Gremese, Gianfranco Ferraccioli
| | - Barbara Tolusso
- Division of Clinical Immunology, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy
- Immunology Core Facility, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy
| | - Dario Bruno
- Division of Clinical Immunology, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy
- Department of Medicine, University of Verona, Verona, Italy
| | - Simone Perniola
- Division of Clinical Immunology, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy
| | - Gianfranco Ferraccioli
- School of Medicine, Università Cattolica del Sacro Cuore, Rome, Italy
- *Correspondence: Elisa Gremese, Gianfranco Ferraccioli
| | - Stefano Alivernini
- Immunology Core Facility, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy
- School of Medicine, Università Cattolica del Sacro Cuore, Rome, Italy
- Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy
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15
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Ghasemi K, Ghasemi K. Evaluation of the Tocilizumab therapy in human cancers: Latest evidence and clinical potential. J Clin Pharm Ther 2022; 47:2360-2368. [PMID: 36271617 DOI: 10.1111/jcpt.13781] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 08/20/2022] [Accepted: 09/04/2022] [Indexed: 12/24/2022]
Abstract
Tocilizumab (Actemra®), as the first human interleukin-6 receptor (IL-6R) antagonist, has been used in treating moderate to severe active rheumatoid arthritis (RA) patients who were undertreatment with one or more disease-modifying anti-rheumatic drugs (DMARDs) and did not improve significantly. Tocilizumab also has been administrated and confirmed in several inflammatory-based diseases. Recently, tocilizumab has been prescribed to treat patients with advanced coronavirus disease (COVID-19) and is used as one of the effective drugs in reducing the increased inflammation in these patients. On the other hand, cancer treatment has been considered by researchers one of the most important challenges to human health. Regarding inflammatory-associated malignancies, it has been shown that inflammatory mediators such as interleukin-1 beta (IL-1β), IL-6, and tumour necrosis factor-alpha (TNF-α) may play a role in tumorigenesis, thus targeting these cytokines as evidence suggested can be useful in the treatment of these types of cancers. This review summarized the role of the IL-6/IL-6R axis in inflammation-based cancers and discussed the effectiveness and challenges of treating cancer with tocilizumab.
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Affiliation(s)
- Kimia Ghasemi
- Department of Pharmacology and Toxicology, School of Pharmacy; Fertility and Infertility Research Center, Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Kosar Ghasemi
- Department of Pharmacology and Toxicology, School of Pharmacy; Cellular and Molecular Research Center, Jundishapur University of Medical Sciences, Ahvaz, Iran
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16
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Lv Y, Bai Z, Wang X, Liu J, Li Y, Zhang X, Shan Y. Comprehensive evaluation of breast cancer immunotherapy and tumor microenvironment characterization based on interleukin genes-related risk model. Sci Rep 2022; 12:20524. [PMID: 36443508 PMCID: PMC9705306 DOI: 10.1038/s41598-022-25059-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022] Open
Abstract
Breast cancer (BRCA) is the most prevalent malignancy and the leading cause of death in women. Interleukin (IL) genes are critical in tumor initiation and control. Nevertheless, the prognosis value of the IL in BRCA remains unclear. We collected data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), and 94 IL genes were identified from GeneCard. Based on the random forest (RF), least absolute shrinkage and selection operator (LASSO) analysis, and multivariate Cox regression analysis, we constructed an IL signature. GSE22219, GSE25065, and GSE21653 were derived as validation sets. The expression differences in the tumor microenvironment (TME), immunotherapy, and chemosensitivity of BRCA between the high- and low-risk groups were evaluated. Overall, 21 IL genes were selected to construct an IL risk model, of which IL18BP, IL17D, and IL23A were the first time identified as prognostic genes in BRCA. IL score could distinguish BRCA patients with inferior outcomes, and AUC of it was 0.70, 0.76, and 0.72 for 1-,3- and 5- years, respectively, which was also verified in GSE22219, GSE25065, and GSE21653 cohorts. Meanwhile, compared to luminal A and luminal B, HER2-positive and TNBC had significantly higher IL score. Besides, the high-risk group had a significantly higher prevalence of TP53 and TTN but a lower prevalence of PIK3CA, as well as higher tumor mutation burden (TMB) and neoantigen level. High- and low-risk groups exhibited notable differences in immunomodulators and tumor infiltrates immune cells (TIICs), and the high-risk group had significantly lower Tumor Immune Dysfunction and Exclusion (TIDE) score. Additionally, the high-risk group has more responders to immune or anti-HER2 combination therapy, whereas the low-risk group has higher sensitivity to docetaxel and paclitaxel. Consequently, we constructed a reliable risk model based on the IL genes, which can provide more information on both the risk stratification and personalizing management strategies for BRCA.
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Affiliation(s)
- Yalei Lv
- Department of Medical Oncology, Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, 050011, China
| | - Zihe Bai
- Department of Medical Oncology, Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, 050011, China
| | - Xiaoyan Wang
- The Fifth Ward of Medical Oncology, Shijiazhuang People's Hospital, Shijiazhuang, China
| | - Jiayin Liu
- Department of Medical Oncology, Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, 050011, China
| | - Yuntao Li
- Breast Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiaolin Zhang
- Department of Epidemiology and Statistics, Hebei Medical University, Shijiazhuang, China
| | - Yujie Shan
- Department of Medical Oncology, Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, 050011, China.
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17
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Fang Y, Chen M, Li G, Yang Y, He P, Chen J, Cheng L, Wu H. Cancer-associated fibroblast-like fibroblasts in vocal fold leukoplakia suppress CD8 +T cell functions by inducing IL-6 autocrine loop and interacting with Th17 cells. Cancer Lett 2022; 546:215839. [PMID: 35961512 DOI: 10.1016/j.canlet.2022.215839] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/14/2022] [Accepted: 07/25/2022] [Indexed: 11/19/2022]
Abstract
The characteristics of fibroblast cells in head and neck precancerous lesion and its ability to secrete inflammatory cytokines and affect CD8+T cell functions remain unclear. Herein, we reported the existence of fibroblasts in human-derived vocal fold leukoplakia (VFL) with positive staining of fibroblast activation protein (FAP) and α-smooth muscle actin (α-SMA). The fibroblasts from VFL and cancer-associated fibroblasts (CAFs) from head and neck squamous cell carcinoma (HNSCC) displayed similar cellular functions and robust inflammatory cytokine secretions. The effects of fibroblasts from VFL in inducing the apoptosis, depletion of CD8+ T cells and recruitment of regulatory T cells (Treg cells) were observed. We further assessed the autocrine loop within VFL fibroblasts to self-stimulate by secreting IL-6, TGF-β through the IL-6/JAK2/STAT3 pathway. The synergistic stimulation of IL-6 and TGF-β promoted Th17 cell differentiation and IL-17A secretion, which could result in fibroblast activation in another positive loop. Tocilizumab (TOC), a monoclonal antibody targeting IL-6R, managed to suppress the overexpression of both IL-6 and TGF-β in VFL fibroblasts, and thus blocking IL-6 autocrine loop and CAF-Th17 loop in vitro. In a murine model of oral leukoplakia (OL), local injection of TOC inhibited the outgrowth of lesions and showed notable effect in control of OL progression in vivo. Our findings establish a novel rationale for blocking the IL-6/JAK2/STAT3 pathway to inhibit vocal fold (oral) leukoplakia progression and postpone HNSCC tumorigenesis.
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Affiliation(s)
- Yi Fang
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China; Shanghai Key Clinical Disciplines of Otorhinolaryngology, Shanghai, 200031, China
| | - Min Chen
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China; Shanghai Key Clinical Disciplines of Otorhinolaryngology, Shanghai, 200031, China
| | - Guangfei Li
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China; Shanghai Key Clinical Disciplines of Otorhinolaryngology, Shanghai, 200031, China
| | - Yue Yang
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China; Shanghai Key Clinical Disciplines of Otorhinolaryngology, Shanghai, 200031, China
| | - Peijie He
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China; Shanghai Key Clinical Disciplines of Otorhinolaryngology, Shanghai, 200031, China
| | - Jian Chen
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China; Shanghai Key Clinical Disciplines of Otorhinolaryngology, Shanghai, 200031, China.
| | - Lei Cheng
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China; Shanghai Key Clinical Disciplines of Otorhinolaryngology, Shanghai, 200031, China.
| | - Haitao Wu
- ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China; Shanghai Key Clinical Disciplines of Otorhinolaryngology, Shanghai, 200031, China.
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18
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Managing Cancer Drug Resistance from the Perspective of Inflammation. JOURNAL OF ONCOLOGY 2022; 2022:3426407. [PMID: 36245983 PMCID: PMC9553519 DOI: 10.1155/2022/3426407] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 08/17/2022] [Indexed: 11/17/2022]
Abstract
The development of multidrug resistance in cancer chemotherapy is a major obstacle to the effective treatment of human malignant tumors. Several epidemiological studies have demonstrated that inflammation is closely related to cancer and plays a key role in the development of both solid and liquid tumors. Therefore, targeting inflammation and the molecules involved in the inflammatory process may be a good strategy for treating drug-resistant tumors. In this review, we discuss the molecular mechanisms underlying inflammation in regulating anticancer drug resistance by modulating drug action and drug-mediated cell death pathways. Inflammation alters the effectiveness of drugs through modulation of the expression of multidrug efflux transporters (e.g., ABCG2, ABCB1, and ABCC1) and drug-metabolizing enzymes (e.g., CYP1A2 and CYP3A4). In addition, inflammation can protect cancer cells from drug-mediated cell death by regulating DNA damage repair, downstream adaptive response (e.g., apoptosis, autophagy, and oncogenic bypass signaling), and tumor microenvironment. Intriguingly, manipulating inflammation may affect drug resistance through various molecular mechanisms validated by in vitro/in vivo models. In this review, we aim to summarize the underlying molecular mechanisms that inflammation participates in cancer drug resistance and discuss the potential clinical strategies targeting inflammation to overcome drug resistance.
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19
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Zhang J, Yan H, Li J, Li B. Aqueous Humor Factors' Predictive Effects in Treating Refractor Macular Edema: An Overview. J Interferon Cytokine Res 2022; 42:515-524. [PMID: 36036998 DOI: 10.1089/jir.2022.0082] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The refractory macular edema (RME) seriously affects the patient's vision due to its repetition and ineffective drug response. RME is mainly related to the inflammatory pathway and angiogenesis pathway. At present, microglia activation and angiogenesis have also been widely focused on. With the promotion of the concept of precision diagnosis and treatment, intraocular fluid is becoming a popular evidence-based method. The detection and evaluation of aqueous humor factors can provide more accurate evidences and guidance for the treatment of RME. The purpose of this article is to review the treatment prediction and assessment progress of aqueous humor cytokines for the RME, giving evidence to provide a basis for expanding the diagnosis and treatment ideas of RME and guiding the development of personalized medical treatment.
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Affiliation(s)
- Jie Zhang
- Department of Ophthalmology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Hui Yan
- Department of Ophthalmology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jing Li
- Department of Ophthalmology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Bing Li
- Department of Ophthalmology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
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20
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Aliyu M, Zohora FT, Anka AU, Ali K, Maleknia S, Saffarioun M, Azizi G. Interleukin-6 cytokine: An overview of the immune regulation, immune dysregulation, and therapeutic approach. Int Immunopharmacol 2022; 111:109130. [PMID: 35969896 DOI: 10.1016/j.intimp.2022.109130] [Citation(s) in RCA: 134] [Impact Index Per Article: 44.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/26/2022] [Accepted: 08/03/2022] [Indexed: 12/19/2022]
Abstract
Several studies have shown that interleukin 6 (IL-6) is a multifunctional cytokine with both pro-inflammatory and anti-inflammatory activity, depending on the immune response context. Macrophages are among several cells that secrete IL-6, which they express upon activation by antigens, subsequently inducing fever and production of acute-phase proteins from the liver. Moreover, IL-6 induces the final maturation of B cells into memory B cells and plasma cells as well as an adaptive role for short-term energy allocation. Activation of IL-6 receptors results in the intracellular activation of the JAK/STAT pathway with resultant production of inflammatory cytokines. Several mechanisms-controlled IL-6 expression, but aberrant production was shown to be crucial in the pathogenesis of many diseases, which include autoimmune and chronic inflammatory diseases. IL-6 in combination with transforming growth factor β (TGF-β) induced differentiation of naïve T cells to Th17 cells, which is the cornerstone in autoimmune diseases. Recently, IL-6 secretion was shown to form the backbone of hypercytokinemia seen in the Coronavirus disease 2019 (COVID-19)-associated hyperinflammation and multiorgan failure. There are two classes of approved IL-6 inhibitors: anti-IL-6 receptor monoclonal antibodies (e.g., tocilizumab) and anti-IL-6 monoclonal antibodies (i.e., siltuximab). These drugs have been evaluated in patients with rheumatoid arthritis, juvenile idiopathic arthritis, cytokine release syndrome, and COVID-19 who have systemic inflammation. JAK/STAT pathway blockers were also successfully used in dampening IL-6 signal transduction. A better understanding of different mechanisms that modulate IL-6 expression will provide the much-needed solution with excellent safety and efficacy profiles for the treatment of autoimmune and inflammatory diseases in which IL-6 derives their pathogenesis.
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Affiliation(s)
- Mansur Aliyu
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, International Campus, TUMS-IC, Tehran, Iran; Department of Medical Microbiology, Faculty of Clinical Science, College of Health Sciences, Bayero University, Kano, Nigeria
| | - Fatema Tuz Zohora
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Malaysia
| | - Abubakar Umar Anka
- Department of Medical Laboratory Science, College of Medical Sciences, Ahmadu Bello University, Zaria, Nigeria
| | - Kashif Ali
- Department of Pharmacy Abdul Wali, Khan University Mardan, Pakistan
| | - Shayan Maleknia
- Biopharmaceutical Research Center, AryoGen Pharmed Inc., Alborz University of Medical Sciences, Karaj, Iran
| | - Mohammad Saffarioun
- Biopharmaceutical Research Center, AryoGen Pharmed Inc., Alborz University of Medical Sciences, Karaj, Iran
| | - Gholamreza Azizi
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.
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21
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Méndez-Clemente A, Bravo-Cuellar A, González-Ochoa S, Santiago-Mercado M, Palafox-Mariscal L, Jave-Suárez L, Solorzano-Ibarra F, Villaseñor-García M, Ortiz-Lazareno P, Hernández-Flores G. Dual STAT‑3 and IL‑6R inhibition with stattic and tocilizumab decreases migration, invasion and proliferation of prostate cancer cells by targeting the IL‑6/IL‑6R/STAT‑3 axis. Oncol Rep 2022; 48:138. [PMID: 35703345 PMCID: PMC9245073 DOI: 10.3892/or.2022.8349] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 04/26/2022] [Indexed: 11/05/2022] Open
Abstract
Prostate cancer (PCa) is a key public health problem worldwide; at diagnosis, a high percentage of patients exhibit tumor cell invasion of adjacent tissue. STAT‑3, IL‑6 receptor (R) and IL‑6 serum levels are associated with enhanced PCa migratory, invasive, clonogenic and metastatic ability. Inhibiting the STAT‑3 pathway at different levels (cytokines, receptors, and kinases) exhibits relative success in cancer. The present study investigated the effect of Stattic (Stt) + Tocilizumab (Tcz) on proliferative, clonogenic, migratory and invasive ability of human metastatic PCa (assessed by colony formation, wound healing and migration assay). RWPE‑1 (epithelial prostate immortalized cells), 22Rv1 (Tumor cells), LNCaP (Metastatic cells) and DU‑145 (metastatic, castration‑resistant prostate cells) cells were used in vitro to evaluate levels of cytokines, chemokines, growth factors (Cytometric Bead Array), STAT‑3, phosphorylated STAT‑3 (In‑Cell Western), IL‑6R, vimentin and epithelial (E‑) cadherin (Western Blot). The effect of inhibition of STAT‑3 (expressed constitutively in DU‑145 cells) with Stt and/or Tcz on expression levels of vimentin, VEGF, and E‑cadherin, as well as proliferative, clonogenic, migratory and invasive capacity of metastatic PCa cells was assessed. The expression levels of IL‑6, C‑X‑C chemokine ligand 8, VEGF and vimentin, as well as proliferation and migration, were increased in metastatic PCa cells. Treatment with Stt or Tcz decreased vimentin and VEGF and increased E‑cadherin expression levels and inhibited proliferative, clonogenic, migratory and invasive capacity of DU‑145 cells; addition of IL‑6 decreased this inhibitory effect. However, Stt + Tcz maintained inhibition even in the present of high concentrations of IL‑6. Stt + Tcz decreased expression of vimentin and VEGF and inhibited the proliferative, clonogenic, migratory and invasive capacity of metastatic PCa cells. To the best of our knowledge, the present study is the first to combine Stt, a STAT‑3 inhibitor, with Tcz, an antibody against IL‑6R, to target tumor cells.
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Affiliation(s)
- Anibal Méndez-Clemente
- Doctoral Program in Biomedical Sciences Orientation Immunology, University Center for Health Sciences (CUCS), University of Guadalajara (UdeG), Guadalajara, Jalisco 44340, México
| | - Alejandro Bravo-Cuellar
- Immunology Division, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, México
| | - Salvador González-Ochoa
- Doctoral Program in Biomedical Sciences Orientation Immunology, University Center for Health Sciences (CUCS), University of Guadalajara (UdeG), Guadalajara, Jalisco 44340, México
| | - Maria Santiago-Mercado
- Immunology Division, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, México
| | - Luis Palafox-Mariscal
- Doctoral Program in Biomedical Sciences Orientation Immunology, University Center for Health Sciences (CUCS), University of Guadalajara (UdeG), Guadalajara, Jalisco 44340, México
| | - Luis Jave-Suárez
- Doctoral Program in Biomedical Sciences Orientation Immunology, University Center for Health Sciences (CUCS), University of Guadalajara (UdeG), Guadalajara, Jalisco 44340, México
| | - Fabiola Solorzano-Ibarra
- Chronic Degenerative Diseases Research Institute Postdoctoral Stays Program for Mexico 2021, Department of Molecular and Genomic Biology, University of Guadalajara (UdeG), University Center for Health Sciences (CUCS), Guadalajara, Jalisco 44340, México
| | - Maria Villaseñor-García
- Immunology Division, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, México
| | - Pablo Ortiz-Lazareno
- Immunology Division, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, México
| | - Georgina Hernández-Flores
- Immunology Division, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, México
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Fibronectin Functions as a Selective Agonist for Distinct Toll-like Receptors in Triple-Negative Breast Cancer. Cells 2022; 11:cells11132074. [PMID: 35805158 PMCID: PMC9265717 DOI: 10.3390/cells11132074] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/17/2022] [Accepted: 06/25/2022] [Indexed: 02/04/2023] Open
Abstract
The microenvironment of tumors is characterized by structural changes in the fibronectin matrix, which include increased deposition of the EDA isoform of fibronectin and the unfolding of the fibronectin Type III domains. The impact of these structural changes on tumor progression is not well understood. The fibronectin EDA (FnEDA) domain and the partially unfolded first Type III domain of fibronectin (FnIII-1c) have been identified as endogenous damage-associated molecular pattern molecules (DAMPs), which induce innate immune responses by serving as agonists for Toll-Like Receptors (TLRs). Using two triple-negative breast cancer (TNBC) cell lines MDA-MB-468 and MDA-MB-231, we show that FnEDA and FnIII-1c induce the pro-tumorigenic cytokine, IL-8, by serving as agonists for TLR5 and TLR2, the canonical receptors for bacterial flagellin and lipoprotein, respectively. We also find that FnIII-1c is not recognized by MDA-MB-468 cells but is recognized by MDA-MB-231 cells, suggesting a cell type rather than ligand specific utilization of TLRs. As IL-8 plays a major role in the progression of TNBC, these studies suggest that tumor-induced structural changes in the fibronectin matrix promote an inflammatory microenvironment conducive to metastatic progression.
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Ning WJ, Liu X, Zeng HY, An ZQ, Luo WX, Xia NS. Recent progress in antibody-based therapeutics for triple-negative breast cancer. Expert Opin Drug Deliv 2022; 19:815-832. [PMID: 35738312 DOI: 10.1080/17425247.2022.2093853] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Triple-negative breast cancer (TNBC) is a subtype of severely aggressive breast cancer that lacks the expression of oestrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 (HER2) and is highly metastatic and related to a poor prognosis. Current standard treatments are still limited to systemic chemotherapy, radiotherapy, and surgical resection. More effective treatments are urgently needed. AREAS COVERED The immunogenicity of TNBC has provided opportunities for the development of targeted immunotherapy. In this review, we focus on the recent development in antibody-based drug modalities, including angiogenesis inhibitors, immune checkpoint inhibitors, antibody-drug conjugates, immunoconjugates, T cell-redirecting bispecific antibodies and CAR-T cells, and their mechanisms of action in TNBC. EXPERT OPINION At present, the treatment of TNBC is still a major challenge that needs to be addressed. Novel immunotherapies are promising opportunities for improving the management of this aggressive disease.
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Affiliation(s)
- Wen-Jing Ning
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - Xue Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - Hong-Ye Zeng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - Zhi-Qiang An
- Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Wen-Xin Luo
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - Ning-Shao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
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Interleukin-6 Signaling in Triple Negative Breast Cancer Cells Elicits the Annexin A1/Formyl Peptide Receptor 1 Axis and Affects the Tumor Microenvironment. Cells 2022; 11:cells11101705. [PMID: 35626741 PMCID: PMC9139391 DOI: 10.3390/cells11101705] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 05/06/2022] [Accepted: 05/16/2022] [Indexed: 11/17/2022] Open
Abstract
Annexin A1 (AnxA1) is a pleiotropic protein that exerts essential roles in breast cancer (BC) growth and aggressiveness. In our previous work, we described the autocrine signaling of AnxA1 through formyl peptide receptor 1 (FPR1) in the triple-negative (TN) BC cell line, MDA-MB-231. Here, we aimed to describe the interaction between the AnxA1/FPR1 and the Interleukin-6 (IL-6) signaling pathways and their role in the tumor microenvironment (TME). First, we demonstrated that AnxA1 and IL-6 expression levels are correlated in BC tissue samples. In three TNBC cell lines, overexpression of both AnxA1 and IL-6 was also identified. Next, we inhibited FPR1, the IL-6 receptor and STAT3 in both MDA-MB-231 and MDA-MB-157 cells. The FPR1 inhibition led to increased levels of IL-6 and secreted AnxA1 in both cell lines. On the other side, inhibition of the IL-6 receptor or STAT3 led to the impairment of AnxA1 secretion, suggesting the essential role of the IL-6 signaling cascade in the activation of the AnxA1/FPR1 autocrine axis. Finally, we described the interaction between IL-6 and the AnxA1/FPR1 pathways and their role on the TME by analyzing the effect of supernatants derived from MDA-MB-231 and MDA-MB-157 cells under the inhibition of FPR1 or IL-6 signaling on fibroblast cell motility.
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Combination Blockade of the IL6R/STAT-3 Axis with TIGIT and Its Impact on the Functional Activity of NK Cells against Prostate Cancer Cells. J Immunol Res 2022; 2022:1810804. [PMID: 35465350 PMCID: PMC9020142 DOI: 10.1155/2022/1810804] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 03/15/2022] [Indexed: 02/07/2023] Open
Abstract
Background/Aims. Prostate cancer (PCa) is one of the neoplasms with the highest incidence and mortality rate in men worldwide. Advanced stages of the disease are usually very aggressive, and most are treated with chemotherapeutic drugs that generally cause side effects in these patients. However, additional therapeutic targets such as the IL6R/STAT-3 axis and TIGIT have been proposed, mainly due to their relevance in the development of PCa and regulation of NK cell-mediated cytotoxicity. Here, we evaluate the effect of inhibitors directed against these therapeutic targets primarily via an analysis of NK cell function versus prostate cancer cells. Methods. We analyzed the secretion of cytokines, chemokines, and growth factors in 22Rv1, LNCaP, and DU145 cells. In these cells, we also evaluated the expression of NK ligands, IL6R, STAT-3, and phosporylated STAT-3. In NK-92 cells, we evaluated the effects of Stattic (Stt) and tocilizumab (Tcz) on NK receptors. In addition, we assessed if the disruption of the IL6R/STAT-3 pathway and blockade of TIGIT potentiated the cytotoxicity of NK-92 cells versus DU145 cells. Results. DU145 abundantly secretes M-CSF, VEGF, IL-6, CXCL8, and TGF-β. Furthermore, the expression of CD155 was found to increase in accordance with aggressiveness and metastatic status in the prostate cancer cells. Stt and Tcz induce a decrease in STAT-3 phosphorylation in the DU145 cells and, in turn, induce an increase of NKp46 and a decrease of TIGIT expression in NK-92 cells. Finally, the disruption of the IL6R/STAT-3 axis in prostate cancer cells and the blocking of TIGIT on NK-92 were observed to increase the cytotoxicity of NK-92 cells against DU145 cells through an increase in sFasL, granzyme A, granzyme B, and granulysin. Conclusions. Our results reveal that the combined use of inhibitors directed against the IL6R/STAT-3 axis and TIGIT enhances the functional activity of NK cells against castration-resistant prostate cancer cells.
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STAT3 Signaling in Breast Cancer: Multicellular Actions and Therapeutic Potential. Cancers (Basel) 2022; 14:cancers14020429. [PMID: 35053592 PMCID: PMC8773745 DOI: 10.3390/cancers14020429] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/10/2022] [Accepted: 01/12/2022] [Indexed: 02/05/2023] Open
Abstract
Simple Summary Many signaling pathways are overactive in breast cancer, and among them is the STAT3 signaling pathway. STAT3 is activated by secreted factors within the breast tumor, many of which are elevated and correlate to advanced disease and poor survival outcomes. This review examines how STAT3 signaling is activated in breast cancer by the proinflammatory, gp130 cytokines, interleukins 6 and 11. We evaluate how this signaling cascade functions in the various cells of the tumor microenvironment to drive disease progression and metastasis. We discuss how our understanding of these processes may lead to the development of novel therapeutics to tackle advanced disease. Abstract Interleukin (IL)-6 family cytokines, such as IL-6 and IL-11, are defined by the shared use of the gp130 receptor for the downstream activation of STAT3 signaling and the activation of genes which contribute to the “hallmarks of cancer”, including proliferation, survival, invasion and metastasis. Increased expression of these cytokines, or the ligand-specific receptors IL-6R and IL-11RA, in breast tumors positively correlate to disease progression and poorer patient outcome. In this review, we examine evidence from pre-clinical studies that correlate enhanced IL-6 and IL-11 mediated gp130/STAT3 signaling to the progression of breast cancer. Key processes by which the IL-6 family cytokines contribute to the heterogeneous nature of breast cancer, immune evasion and metastatic potential, are discussed. We examine the latest research into the therapeutic targeting of IL-6 family cytokines that inhibit STAT3 transcriptional activity as a potential breast cancer treatment, including current clinical trials. The importance of the IL-6 family of cytokines in cellular processes that promote the development and progression of breast cancer warrants further understanding of the molecular basis for its actions to help guide the development of future therapeutic targets.
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Chamardani TM, Amiritavassoli S. Inhibition of NETosis for treatment purposes: friend or foe? Mol Cell Biochem 2022; 477:673-688. [PMID: 34993747 PMCID: PMC8736330 DOI: 10.1007/s11010-021-04315-x] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 11/25/2021] [Indexed: 12/29/2022]
Abstract
Active neutrophils participate in innate and adaptive immune responses through various mechanisms, one of the most important of which is the formation and release of neutrophil extracellular traps (NETs). The NETs are composed of network-like structures made of histone proteins, DNA and other released antibacterial proteins by activated neutrophils, and evidence suggests that in addition to the innate defense against infections, NETosis plays an important role in the pathogenesis of several other non-infectious pathological states, such as autoimmune diseases and even cancer. Therefore, targeting NET has become one of the important therapeutic approaches and has been considered by researchers. NET inhibitors or other molecules involved in the NET formation, such as the protein arginine deiminase 4 (PAD4) enzyme, an arginine-to-citrulline converter, participate in chromatin condensation and NET formation, is the basis of this therapeutic approach. The important point is whether complete inhibition of NETosis can be helpful because by inhibiting this mechanism, the activity of neutrophils is suppressed. In this review, the biology of NETosis and its role in the pathogenesis of some important diseases have been summarized, and the consequences of treatment based on inhibition of NET formation have been discussed.
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28
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Huang Y, Yang X, Meng Y, Shao C, Liao J, Li F, Li R, Jing Y, Huang A. The hepatic senescence-associated secretory phenotype promotes hepatocarcinogenesis through Bcl3-dependent activation of macrophages. Cell Biosci 2021; 11:173. [PMID: 34530917 PMCID: PMC8447591 DOI: 10.1186/s13578-021-00683-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 08/23/2021] [Indexed: 12/27/2022] Open
Abstract
Background Liver cancer is one of the most common malignancies in the world with a poor prognosis. Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, accounting for 80–90% of cases. The initiation and progression of HCC are closely associated with chronic liver inflammation. In addition, HCC is often accompanied by cell senescence. Senescent hepatocytes can secrete various inflammatory factors, collectively called the senescence-associated secretory phenotype (SASP). The SASP has been confirmed to promote the occurrence of liver cancer by affecting the inflammatory microenvironment. However, its role and the underlying mechanism of hepatic SASP in hepatocarcinogenesis are not clearly understood. Therefore, a better understanding of the pathogenic mechanisms of the effect of the hepatic SASP on the occurrence of HCC is still needed. Methods The study aims to explore the role of SASP factors and the underlying mechanism in tumorigenesis and the progression of HCC in vivo. We used diethylnitrosamine (DEN) combined with carbon tetrachloride (CCl4) (DEN-CCl4) to establish liver cancer model in wild-type (WT) mice and Bcl3 knockout (Bcl3−/−) mice. β-galactosidase (β-gal) staining was performed to evaluate the degree of cellular senescence. Immunohistochemistry (IHC) were used to detect the degree of cellular senescence and the activation of macrophage. PCR chip and clinical tissue chip assays were used to estimate the RNA levels of SASP factors and NF-κB related genes, and their protein levels were examined by Western blot assays. Results DEN-CCl4 induced cellular senescence in mouse hepatocytes. In addition, senescent hepatocytes might release a variety of inflammatory factors that further activate macrophages, thereby changing the microenvironmental state and promoting the occurrence of HCC. Mechanistically, the NF-κB pathway is important because it regulates the SASP. Therefore, we used a PCR chip to detect the expression of NF-κB-related genes in senescent liver tissue. Our results showed that the expression of Bcl3 was increased in senescent hepatocytes, and knocking out Bcl3 significantly inhibited the secretion of hepatocyte SASP factors and the activation of macrophages, thereby inhibiting hepatocarcinogenesis. Finally, in clinical tissues adjacent to HCC tissues in patients, the expression of Bcl3 and IL-8 correlated with poor prognosis in HCC patients. Conclusion The hepatic SASP can further induce the activation of macrophages during hepatocarcinogenesis, thereby promoting the occurrence of HCC, and that this process is closely related to the expression of Bcl3 in hepatocytes. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-021-00683-5.
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Affiliation(s)
- Yihua Huang
- Department of Pathology, School of Basic Medical Sciences, Fujian Medical University, 88 Jiaotong Road, Fuzhou, Fujian, 350004, People's Republic of China
| | - Xue Yang
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Yan Meng
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Changchun Shao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Jianping Liao
- Department of Pathology, School of Basic Medical Sciences, Fujian Medical University, 88 Jiaotong Road, Fuzhou, Fujian, 350004, People's Republic of China
| | - Fengwei Li
- Department of Hepatic Surgery IV, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, 200438, China
| | - Rong Li
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, 200438, China
| | - Yingying Jing
- Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China.
| | - Aimin Huang
- Department of Pathology, School of Basic Medical Sciences, Fujian Medical University, 88 Jiaotong Road, Fuzhou, Fujian, 350004, People's Republic of China.
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Liu S, Zhang C, Wang B, Zhang H, Qin G, Li C, Cao L, Gao Q, Ping Y, Zhang K, Lian J, Zhao Q, Wang D, Zhang Z, Zhao X, Yang L, Huang L, Yang B, Zhang Y. Regulatory T cells promote glioma cell stemness through TGF-β-NF-κB-IL6-STAT3 signaling. Cancer Immunol Immunother 2021; 70:2601-2616. [PMID: 33576874 PMCID: PMC8360896 DOI: 10.1007/s00262-021-02872-0] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 01/20/2021] [Indexed: 12/14/2022]
Abstract
Glioma stem cells (GSCs) contribute to the malignant growth of glioma, but little is known about the interaction between GSCs and tumor microenvironment. Here, we found that intense infiltration of regulatory T cells (Tregs) facilitated the qualities of GSCs through TGF-β secretion that helped coordinately tumor growth. Mechanistic investigations indicated that TGF-β acted on cancer cells to induce the core cancer stem cell-related genes CD133, SOX2, NESTIN, MUSASHI1 and ALDH1A expression and spheres formation via NF-κB-IL6-STAT3 signaling pathway, resulting in the increased cancer stemness and tumorigenic potential. Furthermore, Tregs promoted glioma tumor growth, and this effect could be abrogated with blockade of IL6 receptor by tocilizumab which also demonstrated certain level of therapeutic efficacy in xenograft model. Additionally, expression levels of CD133, IL6 and TGF-β were found to serve as prognosis markers of glioma patients. Collectively, our findings reveal a new immune-associated mechanism underlying Tregs-induced GSCs. Moreover, efforts to target this network may be an effective strategy for treating glioma.
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Affiliation(s)
- Shasha Liu
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Chaoqi Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
- Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Boqiao Wang
- Henan University of Chinese Medicine, Zhengzhou, 450052, Henan, China
| | - Huanyu Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Guohui Qin
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Congcong Li
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Ling Cao
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Qun Gao
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yu Ping
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Kai Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Jingyao Lian
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Qitai Zhao
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Dan Wang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Zhen Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Xuan Zhao
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Li Yang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Lan Huang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Bo Yang
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yi Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, 450052, Henan, China.
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
- Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, 450052, Henan, China.
- School of Life Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China.
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Liu XL, Liu WJ, Chen Q, Liu J, Yang CQ, Zhang G, Zhang SL, Guo WH, Li JB, Zhao G, Yin DC, Zhang CY. miR-506-loaded gelatin nanospheres target PENK and inactivate the ERK/Fos signaling pathway to suppress triple-negative breast cancer aggressiveness. Mol Carcinog 2021; 60:538-555. [PMID: 34062009 DOI: 10.1002/mc.23310] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/07/2021] [Accepted: 05/09/2021] [Indexed: 12/13/2022]
Abstract
Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. Some microRNAs (miRNAs) were abnormally expressed in TNBC, and they are closely related to the occurrence and progression of TNBC. Here, we found that miR-506 was significantly downregulated in TNBC and relatively lower miR-506 expression predicted a poorer prognosis. Moreover, we found that miR-506 could inhibit MDA-MB-231 cell viability, colony formation, migration, and invasion, and suppress the ERK/Fos oncogenic signaling pathway through upregulating its direct target protein proenkephalin (PENK). Therefore, miR-506 was proposed as a nucleic acid drug for TNBC therapy. However, miRNA is unstable in vivo, which limiting its application as a therapeutic drug via conventional oral or injected therapies. Here, a gelatin nanosphere (GN) delivery system was applied for the first time to load exogenous miRNA. Exogenous miR-506 mimic was loaded on GNs and injected into the in situ TNBC animal model, and the miR-506 could achieve sustained and controlled release. The results confirmed that overexpression of miR-506 and PENK in vivo through loading on GNs inhibited in situ triple-negative breast tumor growth and metastasis significantly in the xenograft model. Moreover, we indicated that the ERK/Fos signaling pathway was intensively inactivated after overexpression of miR-506 and PENK both in vitro and in vivo, which was further validated by the ERK1/2-specific inhibitor SCH772984. In conclusion, this study demonstrates that miR-506-loaded GNs have great potential in anti-TNBC aggressiveness therapy.
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Affiliation(s)
- Xin-Li Liu
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Wen-Jing Liu
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Qiang Chen
- State Key Laboratory of Solidification Processing, Northwestern Polytechnical University, Xi'an, China
| | - Jie Liu
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Chang-Qing Yang
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Ge Zhang
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Shi-Long Zhang
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Wei-Hong Guo
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Jing-Bao Li
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Gang Zhao
- Breast Surgery, The First Hospital of Jilin University, Changchun, China
| | - Da-Chuan Yin
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Chen-Yan Zhang
- Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
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