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Wu Y, Zhao J, Lu X. Profiling the Ocular Landscape of sEVs miRNAs: Mechanisms and Applications. Exp Eye Res 2025; 256:110396. [PMID: 40280535 DOI: 10.1016/j.exer.2025.110396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/23/2025] [Accepted: 04/21/2025] [Indexed: 04/29/2025]
Abstract
In this review, we comprehensively discuss the application of sEVs miRNAs in ophthalmic diseases by examining their basic characteristics and clinical application potential. Initially, we provide an overview of sEVs, including their definition, source, and functions, while particularly highlighting the importance of miRNAs contained in sEVs and its prospects in the treatment of ocular diseases. Subsequently, the structure and composition of sEVs as well as the biological functions of their encapsulated miRNAs, which expands the current knowledge about their roles in ophthalmic physiology and pathology. In addition, the functions of sEVs miRNAs in the growth of ocular tissues, ocular tissue homeostasis, and common eye diseases such as glaucoma, age-related macular degeneration, and diabetic retinopathy, are discussed. The application potential of sEVs miRNAs as diagnostic biomarkers and drug delivery systems for ophthalmic conditions and therapeutic value in diverse eye diseases are explored. Finally, the current challenges affecting research in this field are outlined to provide a basis that guide future utilization of sEVs miRNAs in ophthalmic disease research and clinical management of diverse ophthalmological conditions.
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Affiliation(s)
- Yifei Wu
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, 253 Gongye Middle Avenue, Guangzhou, 510280, GuangDong, China
| | - Jiaqi Zhao
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, 253 Gongye Middle Avenue, Guangzhou, 510280, GuangDong, China
| | - Xiaohe Lu
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, 253 Gongye Middle Avenue, Guangzhou, 510280, GuangDong, China.
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2
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Zhang Z, Mao C, Wu Y, Wang Y, Cong H. Application of non‑coding RNAs in tumors (Review). Mol Med Rep 2025; 31:164. [PMID: 40211701 PMCID: PMC12015154 DOI: 10.3892/mmr.2025.13529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Accepted: 01/31/2025] [Indexed: 04/25/2025] Open
Abstract
Tumors are associated with the highest mortality rates worldwide. For more than a decade, research has focused on the genetic involvement of proteins in cancer; however, a complete class of molecular non‑coding (nc)RNAs have been discovered in recent years, and these are considered to be associated with cancer. Notably, ncRNAs are highly conserved and multifunctional. These interact with multiple signaling pathways, influencing cell cycle progression and various physiological processes. Therefore, the present review aimed to investigate ncRNA, microRNA, transfer RNA‑derived small RNA, PIWI‑interacting RNA and long non‑coding RNA to further understand the associated generation processes, functional mechanisms and therapeutic roles in tumors. The present review demonstrated the critical role of ncRNAs in tumors, and may provide a novel theoretical basis for the role of ncRNAs as biomarkers or therapeutic tools in the treatment of cancer.
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Affiliation(s)
- Zhihan Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
- Department of Clinical Medicine, Medical School of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Chunyan Mao
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
- Department of Clinical Medicine, Medical School of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Yi Wu
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
- Department of Clinical Medicine, Medical School of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Yin Wang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
- Department of Clinical Medicine, Medical School of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Hui Cong
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
- Department of Blood Transfusion, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
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3
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Ye Y, Liu T, Xu F, Shen J, Xu S. Integrated analyses reveal CXCL11 as an inhibitor in ovarian cancer and its facilitation of an M1 macrophage switch via the JAK2/STAT1 pathway. Int Immunopharmacol 2025; 159:114900. [PMID: 40409100 DOI: 10.1016/j.intimp.2025.114900] [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: 11/22/2024] [Revised: 04/28/2025] [Accepted: 05/14/2025] [Indexed: 05/25/2025]
Abstract
M1-like tumor-associated macrophages (TAMs) have been put forth as a critical component in the advancement of cancer biology, including oncogenesis, development, invasion, metastasis, and the formation of tumor microenvironment (TME). Nevertheless, there has been a paucity of research examining the functions and associated molecular mechanisms of the M1-like TAMs in ovarian cancer (OC). The objective of this study is twofold: first, to gain a deeper understanding of the positive role of M1-like TAMs in OC; and second, to identify reliable biomarkers to stratify the risk of disease progression in OC patients via integrated analyses. Leveraging combined single-cell RNA sequencing (scRNA-seq) and bulk transcriptomic data, we systematically identified M1 macrophage-associated molecules and established their prognostic significance in OC. CXCL11 was pinpointed as the central biomarker, with its protective role further validated through bioinformatics analyses and in vitro functional assays. Collectively, our findings advance the understanding of M1 macrophage-related molecular networks in OC and reveal CXCL11 as a dual-functional entity: a favorable prognostic biomarker and a positive regulatory molecule of M1 polarization via the JAK2-STAT1 pathway. These insights position CXCL11 as a promising therapeutic target and prognostic indicator for OC, offering a new perspective for the immunotherapy of OC.
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Affiliation(s)
- Yingjun Ye
- Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Tingwei Liu
- Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Fangfang Xu
- Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jiacheng Shen
- Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shaohua Xu
- Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.
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4
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Jin X, Zhang N, Yan T, Wei J, Hao L, Sun C, Zhao H, Jiang S. Lactate-mediated metabolic reprogramming of tumor-associated macrophages: implications for tumor progression and therapeutic potential. Front Immunol 2025; 16:1573039. [PMID: 40433363 PMCID: PMC12106438 DOI: 10.3389/fimmu.2025.1573039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Accepted: 04/21/2025] [Indexed: 05/29/2025] Open
Abstract
The tumor microenvironment (TME) is characterized by distinct metabolic adaptations that not only drive tumor progression but also profoundly influence immune responses. Among these adaptations, lactate, a key metabolic byproduct of aerobic glycolysis, accumulates in the TME and plays a pivotal role in regulating cellular metabolism and immune cell function. Tumor-associated macrophages (TAMs), known for their remarkable functional plasticity, serve as critical regulators of the immune microenvironment and tumor progression. Lactate modulates TAM polarization by influencing the M1/M2 phenotypic balance through diverse signaling pathways, while simultaneously driving metabolic reprogramming. Furthermore, lactate-mediated histone and protein lactylation reshapes TAM gene expression, reinforcing their immunosuppressive properties. From a therapeutic perspective, targeting lactate metabolism has shown promise in reprogramming TAMs and enhancing anti-tumor immunity. Combining these metabolic interventions with immunotherapies may further augment treatment efficacy. This review underscores the crucial role of lactate in TAM regulation and tumor progression, highlighting its potential as a promising therapeutic target in cancer treatment.
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Affiliation(s)
- Xiaohan Jin
- Center for Post-Doctoral Studies, Shandong University of Traditional Chinese Medicine, Jinan, China
- Clinical Medical Laboratory Center, Jining No.1 People’s Hospital, Jining, China
- Jining No.1 People’s Hospital, Shandong First Medical University, Jining, China
| | - Ni Zhang
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tinghao Yan
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jingyang Wei
- Second College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lingli Hao
- Jining No.1 People’s Hospital, Shandong First Medical University, Jining, China
| | - Changgang Sun
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Haibo Zhao
- Jining No.1 People’s Hospital, Shandong First Medical University, Jining, China
| | - Shulong Jiang
- Clinical Medical Laboratory Center, Jining No.1 People’s Hospital, Jining, China
- Jining No.1 People’s Hospital, Shandong First Medical University, Jining, China
- Second College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
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5
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Bai X, Guo YR, Zhao ZM, Li XY, Dai DQ, Zhang JK, Li YS, Zhang CD. Macrophage polarization in cancer and beyond: from inflammatory signaling pathways to potential therapeutic strategies. Cancer Lett 2025; 625:217772. [PMID: 40324582 DOI: 10.1016/j.canlet.2025.217772] [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: 02/26/2025] [Revised: 04/30/2025] [Accepted: 05/02/2025] [Indexed: 05/07/2025]
Abstract
Macrophages are innate immune cells distributed throughout the body that play vital roles in organ development, tissue homeostasis, and immune surveillance. Macrophages acquire a binary M1/M2 polarized phenotype through signaling cascades upon sensing different signaling molecules in the environment, thereby playing a core role in a series of immune tasks, rendering precise regulation essential. M1/M2 macrophage phenotypes regulate inflammatory responses, while controlled activation of inflammatory signaling pathways is involved in regulating macrophage polarization. Among the relevant signaling pathways, we focus on the six well-characterized NF-κB, MAPK, JAK-STAT, PI3K/AKT, inflammasome, and cGAS-STING inflammatory pathways, and elucidate their roles and crosstalk in macrophage polarization. Furthermore, the effects of many environmental signals that influence macrophage polarization are investigated by modulating these pathways in vivo and in vitro. We thus detail the physiological and pathophysiological status of these six inflammatory signaling pathways and involvement in regulating macrophage polarization in cancer and beyond, as well as describe potential therapeutic approaches targeting these signaling pathways. In this review, the latest research advances in inflammatory signaling pathways regulating macrophage polarization are reviewed, as targeting these inflammatory signaling pathways provides suitable strategies to intervene in macrophage polarization and various tumor and non-tumor diseases.
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Affiliation(s)
- Xiao Bai
- Department of Surgical Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Yun-Ran Guo
- Health Sciences Institute of China Medical University, Shenyang 110122, China
| | - Zhe-Ming Zhao
- Department of Surgical Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Xin-Yun Li
- Clinical Medicine, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China
| | - Dong-Qiu Dai
- Department of Surgical Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China; Cancer Center, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Jia-Kui Zhang
- Department of Surgical Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Yong-Shuang Li
- Department of Surgical Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
| | - Chun-Dong Zhang
- Department of Surgical Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China; Central Laboratory, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
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6
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Gu S, Xu L, Huang B, Xiong K, Yang X, Ye J. Decoding Macrophage Dynamics: A Pathway to Understanding and Treating Inflammatory Skin Diseases. Int J Mol Sci 2025; 26:4287. [PMID: 40362523 PMCID: PMC12071885 DOI: 10.3390/ijms26094287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2025] [Revised: 04/27/2025] [Accepted: 04/29/2025] [Indexed: 05/15/2025] Open
Abstract
Psoriasis and atopic dermatitis (AD) are both chronic inflammatory skin diseases. Their pathogenesis remains incompletely understood. The polarization states of macrophages, as a crucial part of the innate immune system, are influenced by various factors such as cytokines, inflammatory mediators, and epigenetics. Research has demonstrated that macrophages play a "double-edged sword" role in the pathological process of inflammatory skin diseases: they both drive inflammation progression and participate in tissue repair. This article summarizes the roles of macrophages in the inflammatory development and tissue homeostasis of psoriasis and atopic dermatitis. It explores the impact of different factors on macrophages and inflammatory skin diseases. In conclusion, understanding the classification and plasticity of macrophages is crucial for a deeper understanding of the pathogenesis of psoriasis and AD and the development of personalized treatments.
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Affiliation(s)
- Shengliang Gu
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China; (S.G.); (L.X.); (B.H.)
- Yunnan Provincial Clinical Medical Centre for Traditional Chinese Medicine Project (Dermatology), Kunming 650500, China
| | - Lei Xu
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China; (S.G.); (L.X.); (B.H.)
| | - Bin Huang
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China; (S.G.); (L.X.); (B.H.)
| | - Kai Xiong
- The First School of Clinical Medicine, Guizhou University of Chinese Medicine, Guiyang 550025, China;
| | - Xuesong Yang
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China; (S.G.); (L.X.); (B.H.)
- Yunnan Provincial Clinical Medical Centre for Traditional Chinese Medicine Project (Dermatology), Kunming 650500, China
| | - Jianzhou Ye
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming 650500, China; (S.G.); (L.X.); (B.H.)
- Yunnan Provincial Clinical Medical Centre for Traditional Chinese Medicine Project (Dermatology), Kunming 650500, China
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7
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Azar BKY, Vakhshiteh F. The Pre-metastatic Niche: How Cancer Stem Cell-Derived Exosomal MicroRNA Fit into the Puzzle. Stem Cell Rev Rep 2025; 21:1062-1074. [PMID: 40095238 DOI: 10.1007/s12015-025-10866-z] [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] [Accepted: 03/12/2025] [Indexed: 03/19/2025]
Abstract
Cancer metastasis is a complicated biological process that critically affects cancer progression, patient outcomes, and treatment plans. A significant step in metastasis is the formation of a pre-metastatic niche (PMN). A small subset of cells within tumors, known as cancer stem cells (CSCs), possess unique characteristics including, differentiation into different cell types within the tumor, self-renewal, and resistance to conventional therapies, that enable them to initiate tumors and drive metastasis. PMN plays an important role in preparing secondary organs for the arrival and proliferation of CSCs, thereby facilitating metastasis. CSC-derived exosomes are crucial components in the complex interplay between CSCs and the tumor microenvironment. These exosomes function as transporters of various substances that can promote cancer progression, metastasis, and modulation of pre-metastatic environments by delivering microRNA (miRNA, miR) cargo. This review aims to illustrate how exosomal miRNAs (exo-miRs) secreted by CSCs can predispose PMN and promote angiogenesis and metastasis.
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Affiliation(s)
- Behjat Kheiri Yeghaneh Azar
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Faezeh Vakhshiteh
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran.
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Yuan S, Liu BH, Cheng WW, Meng H, Hou XT, Xue JC, Zhang HM, Zhang QG. Polyphyllin Ⅵ modulates macrophage polarization through autophagy-NLRP3 inflammasome to alleviate inflammatory bowel disease. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 143:156640. [PMID: 40339551 DOI: 10.1016/j.phymed.2025.156640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 02/18/2025] [Accepted: 03/11/2025] [Indexed: 05/10/2025]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract with a rising global prevalence. If left untreated, it can result in severe complications, including colon cancer. Key factors in IBD pathogenesis include macrophages, NOD-like receptor thermal protein domain associated protein 3 (NLRP3), and autophagy. Polyphyllin Ⅵ (PPⅥ), a metanoidal saponin derived from the traditional Chinese herb Chonglou, exhibits significant anti-inflammatory and anti-cancer properties, making it a compound of considerable therapeutic interest. PURPOSE The present study investigated the relevant mechanism of PPⅥ on protecting IBD from the perspective of NLRP3 as well as macrophage immunomodulation and laid a theoretical foundation for the development of novel IBD therapeutic drugs. METHODS The IBD mice were prepared by dextran sodium sulfate, and RAW 264.7 inflammatory cells were established through LPS and ATP stimulation. The indicators of macrophage polarization, NLRP3, and autophagy were detected using Western Blot, RT-qPCR, H&E staining, immunofluorescence, and flow cytometry. RESULTS PPⅥ can enhance the inflammatory state of LPS-induced RAW264.7 macrophages, which can reduce weight loss, decrease DAI score, increase colon length, reduce oxidative stress, and decrease intestinal epithelial barrier damage, and thus diminish inflammatory injury in DSS-induced IBD mice. PPⅥ can modify intestinal inflammation and injury by modulating macrophage function. The administration of PPⅥ can maintain the balance between M1-type macrophages and M2-type macrophages while regulating the intestinal macrophage polarization via the NLRP3 inflammasome and autophagy through wildtype mice, cells, and Nlrp3-/- mice. CONCLUSION PPⅥ can regulate macrophage polarization through autophagic modulation of NLRP3 inflammasome to promote the repair of intestinal epithelial damage and maintain the integrity of the mucosal barrier, which contributes to the attenuation of inflammatory injury in DSS-induced IBD mice and provides a database for the development of novel clinical drugs. INNOVATIONS 1. This subject discovered the protective effect of PPⅥ on IBD mice. 2. This subject proved that macrophages have an important role in the intestinal protection of PPⅥ in IBD mice, and PPⅥ can inhibit the polarization of M1-type macrophages and promote the polarization of M2-type macrophages. 3. This subject demonstrated that PPⅥ could regulate macrophage polarization through NLRP3 inflammasome and ameliorate intestinal inflammation in vitro, in vivo, and in Nlrp3-/- mice. 4. This subject confirmed that PPⅥ could regulate macrophage polarization to alleviate inflammatory injury by inhibiting NLRP3 inflammasome through modulating autophagy in vitro, in vivo, and the application of inhibitors. 5. This study explored the developmental value of PPⅥ and laid the theoretical foundation for the development of novel therapeutic drugs as well as therapeutic strategies for IBD.
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Affiliation(s)
- Shuo Yuan
- Chronic Diseases Research Center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China.
| | - Bao-Hong Liu
- Chronic Diseases Research Center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China.
| | - Wen-Wen Cheng
- Chronic Diseases Research Center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China.
| | - Huan Meng
- Chronic Diseases Research Center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China.
| | - Xiao-Ting Hou
- Chronic Diseases Research Center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China.
| | - Jia-Chen Xue
- Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, 116001, China.
| | - Hua-Min Zhang
- Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, 116001, China.
| | - Qing-Gao Zhang
- Chronic Diseases Research Center, Dalian University College of Medicine, Dalian, Liaoning, 116622, China.
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Wang L, Liu H, Chen G, Wu Q, Xu S, Zhou Q, Zhao Y, Wang Q, Yan T, Cheng X. TOM1L1 mediated the sort of tumor suppressive miR-378a-3p into exosomes and the excretion out of cells to promote ESCC progression. Cancer Gene Ther 2025; 32:507-520. [PMID: 40123000 DOI: 10.1038/s41417-025-00889-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 02/20/2025] [Accepted: 03/06/2025] [Indexed: 03/25/2025]
Abstract
Exosomes mediate cell-to-cell communication by releasing miRNAs, mRNA, etc. However, there is little research about the effects on the donor cells after miRNAs are excreted out of cells through exosomes. Here, we found that miR-378a-3p was specifically enriched in exosomes and inhibited cell proliferation, migration, invasion, and colony formation in ESCC. In addition, miR-378a-3p was sorted into exosomes through TOM1L1 and extracted mainly out of ESCC cells. Overexpression of TOM1L1 led to tumor suppressor miR-378a-3p accumulation in exosomes rather than in donor cells, promoting ESCC progression. Moreover, miR-378a-3p targets DYRK1A that directly binds to NPM1 and the phosphorylation state of NPM1 at Ser125 to suppress tumor growth. Taken together, our findings demonstrate that TOM1L1-mediated the tumor suppressor miR-378a-3p into exosomes and excreted out of cells to promote tumor progression.
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Affiliation(s)
- Lu Wang
- Key Laboratory of Cellular Physiology of the Ministry of Education & Department of Pathology, Shanxi Medical University, Taiyuan, People's Republic of China
| | - Huijuan Liu
- Key Laboratory of Cellular Physiology of the Ministry of Education & Department of Pathology, Shanxi Medical University, Taiyuan, People's Republic of China
| | - Guohui Chen
- Key Laboratory of Cellular Physiology of the Ministry of Education & Department of Pathology, Shanxi Medical University, Taiyuan, People's Republic of China
| | - Qinglu Wu
- Key Laboratory of Cellular Physiology of the Ministry of Education & Department of Pathology, Shanxi Medical University, Taiyuan, People's Republic of China
| | - Songrui Xu
- Key Laboratory of Cellular Physiology of the Ministry of Education & Department of Pathology, Shanxi Medical University, Taiyuan, People's Republic of China
| | - Qichao Zhou
- Key Laboratory of Cellular Physiology of the Ministry of Education & Department of Pathology, Shanxi Medical University, Taiyuan, People's Republic of China
| | - Yadong Zhao
- Key Laboratory of Cellular Physiology of the Ministry of Education & Department of Pathology, Shanxi Medical University, Taiyuan, People's Republic of China
| | - Qiaorong Wang
- Key Laboratory of Cellular Physiology of the Ministry of Education & Department of Pathology, Shanxi Medical University, Taiyuan, People's Republic of China
| | - Ting Yan
- Key Laboratory of Cellular Physiology of the Ministry of Education & Department of Pathology, Shanxi Medical University, Taiyuan, People's Republic of China.
| | - Xiaolong Cheng
- Key Laboratory of Cellular Physiology of the Ministry of Education & Department of Pathology, Shanxi Medical University, Taiyuan, People's Republic of China.
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10
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Ji CF, Ji JF, Yu XB, Wang ZX. N‑methyladenosine reader YTHDF2‑mediated AC026691.1 degradation promotes gastric cancer cell proliferation, migration and M2 macrophage polarization. Mol Med Rep 2025; 31:120. [PMID: 40052573 PMCID: PMC11914866 DOI: 10.3892/mmr.2025.13485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Accepted: 01/03/2025] [Indexed: 03/20/2025] Open
Abstract
The present study aimed to explore the effects of key N6‑methyladenosine (m6A)‑related long non‑coding RNAs (lncRNAs) on the malignant behavior and macrophage polarization of gastric cancer cells, and their preliminary mechanisms. Gastric cancer‑related lncRNA datasets were downloaded from The Cancer Genome Atlas database, and m6A‑related differentially expressed lncRNAs (DElncRNAs) were analyzed. Subsequently, Cox regression and lasso regression analyses were used to screen the m6A‑related DElncRNAs associated with the prognosis of patients with gastric cancer. Additionally, reverse transcription‑quantitative polymerase chain reaction (qPCR) was employed to detect the expression levels of m6A‑related lncRNAs in normal gastric epithelial cells (GES‑1) and human gastric cancer cells (AGS and MKN‑45). In addition, the methylation levels of lncRNAs were measured using a methylated RNA immunoprecipitation qPCR assay kit, and the interaction between m6A‑related lncRNAs and m6A‑related proteins was observed by RNA pull‑down assay. Subsequently, m6A‑related lncRNAs and proteins were knocked down separately or simultaneously in gastric cancer cell lines. Bioinformatics analysis revealed that m6A‑related AC026691.1 was significantly associated with the prognosis of patients with gastric cancer and had a potential binding site for YT521‑B homology domain family member 2 (YTHDF2). The RNA pull‑down assay indicated that YTHDF2 not only had binding sites with AC026691.1 but could also markedly promote the degradation of m6A‑related AC026691.1. Furthermore, AC026691.1 was lowly expressed in gastric cancer cells, whereas YTHDF2 was highly expressed. Knockdown of YTHDF2 inhibited the proliferation, migration and epithelial‑mesenchymal transition of gastric cancer cells, and reduced M2 macrophage polarization. By contrast, knocking down AC026691.1 showed the opposite trend. Knockdown of YTHDF2 and AC026691.1 further confirmed the stable impact of YTHDF2 on AC026691.1. In conclusion, the degradation of AC026691.1 modified by YTHDF2‑mediated m6A may promote gastric cancer cell proliferation, migration, epithelial‑mesenchymal transition and M2 macrophage polarization.
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Affiliation(s)
- Cong-Fei Ji
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
- Department of Oncology, Affiliated Tumor Hospital of Nantong University, Nantong, Jiangsu 226006, P.R. China
| | - Jin-Feng Ji
- Department of Integrative Chinese and Western Medicine, Affiliated Tumor Hospital of Nantong University, Nantong, Jiangsu 226006, P.R. China
| | - Xiao-Bing Yu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Zhen-Xin Wang
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
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Yang C, Gao Z, Tang R, Zhou L, Zhou P, Shi W, Ren D, Chen H, Zhang Z, Xie X, Lin J, Ye Y, Feng Z, Feng X, He Y, Zhi Y, Liu D, Zhang X, Jiang L. POU6F2 promotes liver metastasis of gastric adenocarcinoma by dual mechanism of transcriptional upregulation of SNAI1 and IGF2/PI3K/AKT signaling-induced conversion of hepatic stellate cells into cancer-associated fibroblasts. Br J Cancer 2025:10.1038/s41416-025-03017-1. [PMID: 40301686 DOI: 10.1038/s41416-025-03017-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 03/10/2025] [Accepted: 04/02/2025] [Indexed: 05/01/2025] Open
Abstract
BACKGROUND Activation of cancer-associated fibroblasts (CAFs) plays an important role in tumor metastasis. The purpose of this study is to investigate the role of POU6F2 in conversion of hepatic stellate cells (HSCs) into CAFs in liver metastasis of gastric adenocarcinoma (GAC). METHODS POU6F2 expression was examined by real-time PCR, Western blot and immunohistochemical staining. The functional roles of POU6F2 in GAC liver metastasis were investigated both cellular experiments in vitro and in vivo using a mouse model of subcutaneous splenic injection. ChIP and ELISA assays were used to explore the underlying molecular mechanism of POU6F2 in liver metastasis of GAC. RESULTS Here we reported that POU6F2 was upregulated in GAC tissue with liver metastasis, which predicted poor early liver metastasis. Upregulating POU6F2 promoted EMT, invasion and migration of GAC cells in vitro, and the liver metastasis of GAC cells in vivo. Mechanic investigation further revealed that upregulating POU6F2 promoted the invasion and metastasis of GAC by transcriptional upregulation of EMT-inducer SNAI1, and promoting the conversion of HSCs into CAFs dependent on transcriptional upregulation of IGF2-induced activation of PI3K/AKT signaling. CONCLUSION Our findings uncover a novel dual mechanism by which POU6F2 promotes liver metastasis of GAC.
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Affiliation(s)
- Chunxiao Yang
- The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, Guangzhou Medical University, Guangzhou, China
| | - Zhiqing Gao
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, Guangzhou Medical University, Guangzhou, China
- Department of Molecular Medicine, School of Basic Medicine, Southern Medical University, Guangzhou, China
| | - Ruiming Tang
- The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China
| | - Lihuan Zhou
- The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China
| | - Ping Zhou
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, Guangzhou Medical University, Guangzhou, China
| | - Wangpan Shi
- Department of Pathology, University of California San Diego Health System, San Diego, CA, USA
| | - Dong Ren
- Departments of Pathology, University of California Irvine Medical Center, Orange, CA, USA
| | - Han Chen
- The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, Guangzhou Medical University, Guangzhou, China
| | - Zhuojun Zhang
- The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, Guangzhou Medical University, Guangzhou, China
| | - Xiaoyi Xie
- The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, Guangzhou Medical University, Guangzhou, China
| | - Jiaqian Lin
- The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, Guangzhou Medical University, Guangzhou, China
| | - Yingming Ye
- Department of Pathogen Biology and Immunology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, China
| | - Zhengfu Feng
- The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China
| | - Xiaoli Feng
- The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China
| | - Yaoming He
- Department of Gastrointestinal Surgery, Jiangmen Central Hospital, Jiangmen, China
| | - Yaofeng Zhi
- Clinical Experimental Center, Jiangmen Key Laboratory of Precision and Clinical Translation Medicine, Jiangmen Clinical Medical College of Guangdong Medical University, Jiangmen Central Hospital, Jiangmen, China
| | - Dongmei Liu
- Clinical Experimental Center, Jiangmen Key Laboratory of Precision and Clinical Translation Medicine, Jiangmen Clinical Medical College of Guangdong Medical University, Jiangmen Central Hospital, Jiangmen, China
| | - Xin Zhang
- Clinical Experimental Center, Jiangmen Key Laboratory of Precision and Clinical Translation Medicine, Jiangmen Clinical Medical College of Guangdong Medical University, Jiangmen Central Hospital, Jiangmen, China.
| | - Lili Jiang
- The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China.
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, Guangzhou Medical University, Guangzhou, China.
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Pawluczyk IZA, Bhachu JS, Brown JR, Lacey M, Mbadugha C, Straatman K, Wimbury D, Selvaskandan H, Barratt J. B cell-derived exosomal miR-483-5p and its potential role in promoting kidney function loss in IgA nephropathy. Kidney Int 2025:S0085-2538(25)00324-2. [PMID: 40268167 DOI: 10.1016/j.kint.2025.03.019] [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: 07/27/2023] [Revised: 02/24/2025] [Accepted: 03/18/2025] [Indexed: 04/25/2025]
Abstract
INTRODUCTION While mesangial IgA deposition is the pathognomonic feature of IgA nephropathy (IgAN), the extent of mesangial IgA accumulation does not correlate with the future risk of kidney failure. This has led to the search for other serum factors that may influence clinical outcome. The emergence of microRNAs (miRs) as negative regulators of gene expression and the increasingly recognized role of extracellular miRs in intercellular communication has prompted study of the influence of miRs on inflammatory and scarring pathways in the kidneys. METHODS Here, next generation sequencing and subsequent qPCR validation identified a significant increase in the serum levels of miR-483-5p, largely packaged within exosomes. RESULTS Levels of miR-483-5p in serum exosomes were greatest in those IgAN patients with higher levels of proteinuria who subsequently developed kidney failure. Exosomal miR-483-5p content significantly correlated with numerous soluble isoforms of the tumor necrosis factor (TNF) receptor super family suggesting lymphocytes as a source of the miR-enriched exosomes. In PBMC miR-483-5p expression was almost exclusively seen in CD19+ lymphocytes. Activation of a human IgA secreting B-cell line with soluble TNFR1 induced miR-483-5p synthesis and enrichment within exosomes. Exposure to miR-483-5p-enriched B cell exosomes resulted in a proinflammatory phenotypic change in cultured human collecting duct epithelial cells, likely mediated through suppression of the transcription factor SOCS3. miR-483-5p-enriched exosomes were also present in the urine of patients with IgAN. CONCLUSIONS Interaction of B lymphocyte-derived miR-enriched exosomes with tubular epithelial cells may provide an explanation for the progressive tubulointerstitial scarring and loss of kidney function seen in IgAN.
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Affiliation(s)
- Izabella Z A Pawluczyk
- Mayer IgA Nephropathy Laboratories, Department Cardiovascular Sciences, University of Leicester, Leicester, UK.
| | - Jasraj S Bhachu
- Mayer IgA Nephropathy Laboratories, Department Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - Jeremy R Brown
- Mayer IgA Nephropathy Laboratories, Department Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - Michael Lacey
- Mayer IgA Nephropathy Laboratories, Department Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - Chidimma Mbadugha
- Mayer IgA Nephropathy Laboratories, Department Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - Kees Straatman
- Advanced Imaging Facility, Core Biotechnology Services, University of Leicester, Leicester, UK
| | - David Wimbury
- Mayer IgA Nephropathy Laboratories, Department Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - Haresh Selvaskandan
- Mayer IgA Nephropathy Laboratories, Department Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - Jonathan Barratt
- Mayer IgA Nephropathy Laboratories, Department Cardiovascular Sciences, University of Leicester, Leicester, UK
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QUAN JINGDAN, WAN ZIXIN, WU WEI, CAO XINYUAN, QIU JIAYUAN, LIU XIAOYE, ZHANG ZHIWEI. Classical biomarkers and non-coding RNAs associated with diagnosis and treatment in gastric cancer. Oncol Res 2025; 33:1069-1089. [PMID: 40296904 PMCID: PMC12034007 DOI: 10.32604/or.2025.063005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Accepted: 03/17/2025] [Indexed: 04/30/2025] Open
Abstract
One of the most prevalent malignant tumors worldwide, stomach cancer still has a high incidence and fatality rate in China, and the number of young people developing early-onset gastric cancer is steadily increasing. The 5-year survival rate of stomach cancer is typically 30%-35%, the prognosis is bad, the patients' quality of life is low, and the progression of advanced gastric cancer cannot be effectively managed despite the use of surgical surgery, chemotherapy, and other medicines. We urgently need molecular biomarkers with high specificity and sensitivity to increase the early gastric cancer detection rate, extend patient survival, and improve patient quality of life. The initial diagnosis of gastric cancer primarily depends on gastroscopy and biopsy, and invasive procedures cause significant discomfort to patients. Similar to this, treating advanced and metastatic stomach cancer is a pressing issue that requires attention. More and more immune checkpoint molecules have been discovered, and corresponding inhibitors are gradually being applied to clinical diagnosis and treatment. Recently, some non-coding RNAs have begun to be used as new targets for the treatment of gastric cancer. Some non-coding RNAs are highly present in the serum or urine of gastric cancer patients and can be used as diagnostic markers or prognostic indicators. Many clinical trials targeting non-coding RNAs have also shown good therapeutic effects. In general, targeting non-coding RNAs has shown good therapeutic effects. The biomarkers for gastric cancer detection and treatment are reviewed in this article, focusing on the new non-coding RNAs used in diagnosis, prognosis, and treatment. Patients with stomach cancer should have access to more precise and efficient diagnosis and treatment choices as a result of ongoing technological advancements and thorough research.
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Affiliation(s)
- JINGDAN QUAN
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Hengyang Medical College, University of South China, Hengyang, 421001, China
| | - ZIXIN WAN
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Hengyang Medical College, University of South China, Hengyang, 421001, China
| | - WEI WU
- Hengyang Medical College, University of South China, Hengyang, 421001, China
| | - XINYUAN CAO
- Hengyang Medical College, University of South China, Hengyang, 421001, China
| | - JIAYUAN QIU
- Hengyang Medical College, University of South China, Hengyang, 421001, China
| | - XIAOYE LIU
- Hengyang Medical College, University of South China, Hengyang, 421001, China
| | - ZHIWEI ZHANG
- Key Laboratory of Cancer Cellular and Molecular Pathology in Hunan Province, Cancer Research Institute of Hengyang Medical College, University of South China, Hengyang, 421001, China
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14
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Li X, Lu X, Liu M, Chen J, Lu X. Extracellular vesicles: messengers of cross-talk between gastric cancer cells and the tumor microenvironment. Front Cell Dev Biol 2025; 13:1561856. [PMID: 40309240 PMCID: PMC12040901 DOI: 10.3389/fcell.2025.1561856] [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: 01/16/2025] [Accepted: 03/31/2025] [Indexed: 05/02/2025] Open
Abstract
Gastric cancer is a common malignancy characterized by an insidious onset and high mortality rate. Exosomes, a special type of extracellular vesicle, contain various bioactive molecules and have been found to play crucial roles in maintaining normal physiological functions and homeostasis in the body. Recent research has shown that the contents of exosome play a significant role in the progression and metastasis of gastric cancer through communication and regulatory functions. These mechanisms involve promoting gastric cancer cell proliferation and drug resistance. Additionally, other cells in the gastric cancer microenvironment can regulate the progression of gastric cancer through exosomes. These include exosomes derived from fibroblasts and immune cells, which modulate gastric cancer cells. Therefore, in this review, we provide a brief overview of recent advances in the contents and occurrence mechanisms of exosome. This review specifically focused on the regulatory mechanisms of exosomes derived from gastric cancer and other cellular subtypes in the tumor microenvironment. Subsequently, we summarize the latest research progress on the use of exosomes in liquid biopsy, discussing the potential of gastric cancer exosomes in clinical applications.
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Affiliation(s)
- Xiwen Li
- Kunshan Hospital of Chinese Medicine, Affiliated Hospital of Yangzhou University, Kunshan, China
| | - Xian Lu
- Kunshan Hospital of Chinese Medicine, Affiliated Hospital of Yangzhou University, Kunshan, China
| | - Mi Liu
- Kunshan Hospital of Chinese Medicine, Affiliated Hospital of Yangzhou University, Kunshan, China
- College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
- Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Soochow University, Suzhou, China
| | - Junjie Chen
- Department of Clinical Medical Research Center, Affiliated Hospital of Nantong University, Nantong, China
| | - Xirong Lu
- Kunshan Hospital of Chinese Medicine, Affiliated Hospital of Yangzhou University, Kunshan, China
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15
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Xu Y, Xu L, Chen Q, Zou C, Huang J, Zhang L. Crosstalk between exosomes and tumor-associated macrophages in hepatocellular carcinoma: implication for cancer progression and therapy. Front Immunol 2025; 16:1512480. [PMID: 40264760 PMCID: PMC12011854 DOI: 10.3389/fimmu.2025.1512480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 02/26/2025] [Indexed: 04/24/2025] Open
Abstract
Hepatocellular carcinoma (HCC), the most prevalent type of primary liver cancer, represents a significant cause of cancer-related mortality. While our understanding of its pathogenesis is comparatively comprehensive, the influence of the tumor microenvironment (TME) on its progression warrants additional investigation. Tumor-associated macrophages (TAMs) have significant impacts on cancer cell proliferation, migration, invasion, and immune response, facilitating a complex interaction within the TME. Exosomes, which measure between 30 and 150 nanometers in size, are categorized into small extracellular vesicles, secreted by a wide range of eukaryotic cells. They can transfer biological molecules including proteins, non-coding RNAs, and lipids, which mediates the intercellular communication within the TME. Emerging evidence has revealed that exosomes regulate macrophage polarization, thus impacting cancer progression and immune responses within the TME of HCC. Moreover, TAM-derived exosomes also play crucial roles in malignant transformation, which hold immense potential for cancer therapy. In this review, we elaborate on the crosstalk between exosomes and TAMs within TME during HCC development. Moreover, we delve into the feasible treatment approaches for exosomes in cancer therapy and emphasize the limitations and challenges for the translation of exosomes derived from TAMs into clinical courses for cancer therapy, which may provide new perspectives on further ameliorations of therapeutic regimes based on exosomes to advance their clinical applications.
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Affiliation(s)
- Ying Xu
- Department of Anesthesiology Operating Room, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Linyue Xu
- School of Sports Medicine and Health, Chengdu Sport University, Chengdu, China
| | - Qiuyan Chen
- School of Sports Medicine and Health, Chengdu Sport University, Chengdu, China
| | - Can Zou
- School of Sports Medicine and Health, Chengdu Sport University, Chengdu, China
| | - Ju Huang
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Limei Zhang
- Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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16
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Chu C, Liu B, Zhang Y, Xu Z, Wang B, Chin KL. MicroRNA-668-3p Mediates Macrophage M2 Polarization by Targeting NFKBIA to Affect Gastric Cancer Cell Proliferation and Migration. TOHOKU J EXP MED 2025; 265:173-182. [PMID: 39505541 DOI: 10.1620/tjem.2024.j115] [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] [Indexed: 11/08/2024]
Abstract
Macrophage polarization is implicated in the pathological mechanism of gastric cancer (GC). This study investigated how the miR-668-3p/ Nuclear factor kappa B inhibitor alpha (NFKBIA) axis drives macrophage polarization to contribute to GC progression. Inhibitors or shRNA were used to interfere with the expression of miR-668-3p or NFKBIA in the GC cell line. Subsequently, CCK-8, EdU, wound healing, and transwell assays were used to assess the biological behavior of the GC cells. Bioinformatics analysis predicted the target connection between miR-668-3p and NFKBIA, and a dual luciferase reporter gene experiment confirmed this relationship. After THP-1 macrophages were co-cultured with the supernatant of transfected GC cells, the M1 and M2 macrophage phenotypes were determined. Subsequently, these THP-1 macrophages were co-cultured with GC cells using the Transwell, and the biological behaviors of the GC cells were determiend. miR-668-3p inhibitor suppressed proliferation, invasion and migration of GC cells. The phenotype of M1 macrophage (IL-1β, TNF-α and IL-6) was boosted yet the phenotype of M2 macrophage (CD206, Fizz1 and IL-10) was declined by miR-668-3p inhibitor. NFKBIA was the target gene of miR-668-3p and it reversed the effects of miR-668-3p inhibitor on macrophage polarization and biological behaviors of the GC cells.miR-668-3p suppressed NFKBIA in GC cells to mediate M2 polarization of macrophages, thereby facilitating the tumorigenesis of GC.
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Affiliation(s)
- Chenghao Chu
- Department of General Surgery, Anqing First People's Hospital
- Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah
| | - Bin Liu
- Department of General Surgery, Anqing First People's Hospital
- Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah
| | - Yongwei Zhang
- Department of General Surgery, Anqing First People's Hospital
- Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah
| | - Zhangxuan Xu
- Department of General Surgery, Anqing First People's Hospital
| | - Bin Wang
- Department of General Surgery, Anqing First People's Hospital
| | - Kai Ling Chin
- Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah
- Borneo Medical and Health Research Centre, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah
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Li T, Li T, Liang Y, Yuan Y, Liu Y, Yao Y, Lei X. Colorectal cancer cells-derived exosomal miR-188-3p promotes liver metastasis by creating a pre-metastatic niche via activation of hepatic stellate cells. J Transl Med 2025; 23:369. [PMID: 40134019 PMCID: PMC11938777 DOI: 10.1186/s12967-025-06334-4] [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: 12/18/2024] [Accepted: 03/01/2025] [Indexed: 03/27/2025] Open
Abstract
BACKGROUND/AIM Metastasis is the leading cause of mortality for colorectal cancer (CRC). Cancer-derived exosomes are widely recognized as the primary catalysts behind the development of pre-metastasis niche (PMN) in distal sites. However, the exact mechanism behind this process in CRC remains elusive. This study aimed to investigate the function and mechanisms underlying the role of exosomal miR-188-3p in activating hepatic stellate cells (HSCs) to develop the PMN and promote liver metastasis. METHODS We extracted exosomes from CRC cells using ultracentrifugation. Exosomes were identified using transmission electron microscopy, nanoparticle tracking analysis, and Western blot. Exosome uptake was assessed using fluorescence tracing, exosome PKH67 staining, and real-time quantitative PCR. The effects of CRC cell-derived exosomes on HSCs migration were evaluated using Transwell migration and wound healing assays. Key differentially expressed miRNAs were screened from the GEO database, and bioinformatics prediction along with dual-luciferase reporter assays were used to identify downstream target genes of miR-188-3p. Downstream related proteins of the target genes were detected by Western blot. In vivo, the distribution of exosomes and activation of HSCs in the liver were explored by tail vein injection of exosomes into nude mice. Further, the impact of exosomal miR-188-3p on liver metastasis was investigated using a spleen injection liver metastasis model. Finally, the expression levels of miR-188-3p in exosomes from CRC patient plasma were determined by real-time quantitative PCR, and the relationship between the expression of miR-188-3p in plasma exosomes and CRC prognosis was analyzed. RESULTS The expression level of miR-188-3p within plasma exosomes demonstrated a statistically significant increase in CRC with liver metastasis compared to those without liver metastases. We also demonstrated the transferability of miR-188-3p from CRC cells to HSCs cells via the exosomes. Exosomal miR-188-3p plays a pivotal role in orchestrating the establishment of PMN through targeting PHLPP2 to activate HSCs before tumor metastasis. Exosomal miR-188-3p was found to actively foster in vivo metastasis of CRC. Additionally, plasma exosomal miR-188-3p potentially serves as a viable blood-based biomarker for CRLM. CONCLUSION Exosomal miR-188-3p derived from CRC cells can promote liver metastasis by activating HSCs to form a PMN through targeting PHLPP2 to activate the AKT/mTOR pathway. These results offer a new perspective on the mechanisms driving CRLM.
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Affiliation(s)
- Tao Li
- Department of General surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
- Gastrointestinal Surgical Institute, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Taiyuan Li
- Department of General surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
- Gastrointestinal Surgical Institute, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Yahang Liang
- Department of General surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
- Gastrointestinal Surgical Institute, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Yuli Yuan
- Department of General surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
- Gastrointestinal Surgical Institute, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Yang Liu
- Department of General surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
- Gastrointestinal Surgical Institute, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Yao Yao
- Department of General surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
- Gastrointestinal Surgical Institute, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Xiong Lei
- Department of General surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China.
- Gastrointestinal Surgical Institute, Nanchang University, Nanchang, 330006, Jiangxi, China.
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18
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Li P, Fan Z, Huang Y, Luo L, Wu X. Mitochondrial dynamics at the intersection of macrophage polarization and metabolism. Front Immunol 2025; 16:1520814. [PMID: 40196123 PMCID: PMC11973336 DOI: 10.3389/fimmu.2025.1520814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 03/04/2025] [Indexed: 04/09/2025] Open
Abstract
Macrophages are vital sentinels in innate immunity, and their functions cannot be performed without internal metabolic reprogramming. Mitochondrial dynamics, especially mitochondrial fusion and fission, contributes to the maintenance of mitochondrial homeostasis. The link between mitochondrial dynamics and macrophages in the past has focused on the immune function of macrophages. We innovatively summarize and propose a link between mitochondrial dynamics and macrophage metabolism. Among them, fusion-related FAM73b, MTCH2, SLP-2 (Stomatin-like protein 2), and mtSIRT, and fission-related Fis1 and MTP18 may be the link between mitochondrial dynamics and macrophage metabolism association. Furthermore, post-translational modifications (PTMs) of mtSIRT play prominent roles in mitochondrial dynamics-macrophage metabolism connection, such as deacetylates and hypersuccinylation. MicroRNAs such as miR-150, miR-15b, and miR-125b are also possible entry points. The metabolic reprogramming of macrophages through the regulation of mitochondrial dynamics helps improve their adaptability and resistance to adverse environments and provides therapeutic possibilities for various diseases.
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Affiliation(s)
- Pan Li
- Department of Environment and Safety Engineering, Taiyuan Institute of Technology, Taiyuan, China
| | - Zhengbo Fan
- People’s Government of Huangshui Town, Shizhu Tujia Autonomous County, Chongqing, China
| | - Yanlan Huang
- College of Veterinary Medicine, Southwest University, Chongqing, China
| | - Liang Luo
- College of Veterinary Medicine, Southwest University, Chongqing, China
| | - Xiaoyan Wu
- National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China
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Wang F, Li L, Sun X, Cai X, Wang J, Luo H, Wang Y, Ni D, Wang D. The feedback loop between miR-222-3p and ZEB1 harnesses metastasis in renal cell carcinoma. Cell Death Discov 2025; 11:97. [PMID: 40074730 PMCID: PMC11903659 DOI: 10.1038/s41420-025-02385-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 02/12/2025] [Accepted: 03/03/2025] [Indexed: 03/14/2025] Open
Abstract
Renal cell carcinoma (RCC) is an aggressive malignancy originating from the renal parenchyma, often leading to high mortality due to local invasion and distant metastasis. MicroRNAs (miRNAs) play essential roles in RCC progression. Through miRNA sequencing, we identified significant upregulation of miR-222-3p in metastatic RCC tissues. Exosomes from highly metastatic RCC cells were found to transfer miR-222-3p to low-metastatic cells, enhancing their migration and invasion. Mechanistically, miR-222-3p directly targets the 3' untranslated region (3'UTR) of the tumor-suppressor TRPS1, reducing its expression. TRPS1 downregulation releases its inhibitory effect on ZEB1, a key regulator of epithelial-mesenchymal transition (EMT), thereby promoting EMT and metastatic traits. ZEB1 further transactivates miR-222-3p, establishing a positive feedback loop. Additionally, miR-222-3p promotes a pre-metastatic niche by inducing M2 macrophage polarization, facilitating distant metastasis. These findings highlight miR-222-3p as a critical driver of RCC metastasis and suggest its potential as a diagnostic marker and therapeutic target for RCC.
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Affiliation(s)
- Fan Wang
- Department of Thyroid and Breast Surgery, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, China
| | - Liao Li
- Department of Child Healthcare, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, China
| | - Xiangfu Sun
- Department of Cardiothoracic Surgery, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, China
| | - Xianfu Cai
- Department of Renal Transplantation, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Jianjun Wang
- Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Huiwen Luo
- NHC Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Yaodong Wang
- Department of Urology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Dong Ni
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Decai Wang
- Department of Urology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China.
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Li K, Gu X, Zhu Y, Guan N, Wang J, Wang L. Human Umbilical Cord Mesenchymal Stem Cells-Derived Exosomes Attenuates Experimental Periodontitis in Mice Partly by Delivering miRNAs. Int J Nanomedicine 2025; 20:2879-2899. [PMID: 40078652 PMCID: PMC11900796 DOI: 10.2147/ijn.s502192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 02/20/2025] [Indexed: 03/14/2025] Open
Abstract
Introduction Periodontitis is the most common non-communicable disease in humans. The main challenge in the treatment of periodontitis is to effectively control periodontal inflammation and promote tissue repair. Human umbilical cord mesenchymal stem cells-derived exosomes (hucMSCs-exo) have been reported to modulate inflammatory responses and promote tissue repairment mainly through miRNAs in several diseases. However, the effect of hucMSCs-exo on periodontitis remains unknown. In this study, we hypothesized that hucMSCs-exo could inhibit bone destruction in periodontitis mice. Methods In this study, we constructed and characterized the exo@H drug delivery platform. Lipopolysaccharide was used to construct an inflammatory microenvironment in vitro to detect MC3T3-E1 cells proliferation and bone regeneration capacity. Ligation induced to construct an experimental periodontitis mouse model. The distance of the cement-enamel junction (CEJ) to the alveolar bone crest (ABC) was measured for bone resorption evaluation. Hematoxylin-eosin (H&E) staining and Tartrate resistant acid phosphatase (TRAP) staining were used to observe periodontal tissue changes. MicroRNA (miRNA) sequencing was used to detect differential genes and for bioinformatics analysis. Real-time quantitative polymerase chain reaction (qRT-PCR). WB assay and dual luciferase assay were used to further validate the screened differentially expressed miRNAs and the targeted binding relationship with the corresponding target genes. Results We found that lyophilized hucMSCs-exo promoted the proliferation and osteogenic differentiation of MC3T3-E1 cells, and showed more significant proliferative and osteogenic differentiation abilities in combination with the hydrogel (P < 0.05). Using periodontitis mice, bone resorption evaluation revealed a significant reduction in alveolar bone resorption in the exo@H group compared to the hydrogel group (P < 0.01), and exo@H was able to reduce the inflammatory response of periodontal tissues and the number of osteoclasts on the surface of the alveolar bone compared to the hydrogel group. Moreover, 59 miRNAs were upregulated, such as let-7f-5p and miR-203-3p, which positively targeted IL-13 and Nit2, respectively. Discussion These results suggest that exo@H provides protection against periodontitis partly by delivering miRNAs to periodontal tissue. Our results confirm the feasibility of the exo@H delivery platform we constructed and the effectiveness of its use for periodontitis treatment, and this study provides a promising approach for the treatment of periodontitis via miRNA.
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Affiliation(s)
- Ke Li
- Department of Periodontics and Mucosa, The second Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 121000, People’s Republic of China
| | - Xiaoli Gu
- Department of Periodontics and Mucosa, The second Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 121000, People’s Republic of China
| | - Yanan Zhu
- Department of Periodontics and Mucosa, The second Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 121000, People’s Republic of China
| | - Ning Guan
- Key Laboratory of Brain and Spinal Cord Injury Research, First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 121000, People’s Republic of China
| | - Jinlei Wang
- School of Pharmacy, Jinzhou Medical University, Jinzhou, Liaoning, 121000, People’s Republic of China
| | - Linyuan Wang
- Department of Periodontics and Mucosa, The second Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, 121000, People’s Republic of China
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21
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Ma S, Wang Y, Fan S, Jiang W, Sun M, Jing M, Bi W, Zhou M, Wu D. TSH-stimulated hepatocyte exosomes modulate liver-adipose triglyceride accumulation via the TGF-β1/ATGL axis in mice. Lipids Health Dis 2025; 24:81. [PMID: 40050912 PMCID: PMC11884018 DOI: 10.1186/s12944-025-02509-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 02/28/2025] [Indexed: 03/10/2025] Open
Abstract
Subclinical hypothyroidism (SCH) contributes to obesity, with the liver acting as a crucial metabolic regulator. Thyroid-stimulating hormone (TSH) affects systemic lipid balance, potentially linking SCH to obesity. While the direct impact of TSH on hepatic lipid metabolism has been extensively documented, its role in modulating lipid dynamics in peripheral organs through liver-mediated pathways remains insufficiently understood. This study identifies TSH-stimulated hepatocyte-derived exosomes (exosomesTSH) as key mediators in liver-adipose communication, promoting triglyceride accumulation in adipocytes via the transforming growth factor-beta 1 (TGF-β1)/adipose triglyceride lipase (ATGL) axis. ExosomesTSH enhance lipid storage in adipocytes, significantly increasing triglyceride content and lipid droplet formation while reducing lipolysis, effects that are dependent on TSH receptor (TSHR) activation in hepatocytes. In vivo, exosomesTSH induce weight gain and adipose tissue expansion, impairing glucose metabolism in both chow- and high-fat diet-fed mice. Mechanistically, exosomesTSH upregulate TGF-β1 and downregulate ATGL in adipocytes, establishing the TGF-β1/ATGL pathway as essential for exosome-mediated lipid accumulation. Further, miR-139-5p is identified as a modulator of TGF-β1 expression within this pathway, with overexpression of miR-139-5p alleviating exosomesTSH-induced lipid accumulation in adipocytes. This study elucidates a novel miR-139-5p-dependent mechanism through which TSH modulates lipid metabolism via liver-derived exosomes, highlighting the pivotal role of miR-139-5p in linking SCH to adipose lipid accumulation through the TGF-β1/ATGL signaling axis.
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Affiliation(s)
- Shizhan Ma
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Yayun Wang
- Department of Neurology, Qingdao Traditional Chinese Medicine Hospital Affiliated of Qingdao University, Qingdao, Shandong, 266033, China
| | - Shuteng Fan
- Department of Nursing, Taishan Vocational College of Nursing, Taian, Shandong, 271000, China
| | - Wanli Jiang
- First School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
| | - Mingliang Sun
- Department of Endocrinology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250014, China
| | - Mengzhe Jing
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Wenkai Bi
- Department of Nuclear Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
| | - Meng Zhou
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
| | - Dongming Wu
- Department of Geriatric Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250014, China.
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22
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Zhang Y, Wang B, Chen J, Li T. Role of exosomal miRNAs and macrophage polarization in gastric cancer: A novel therapeutic strategy. Eur J Pharmacol 2025; 990:177268. [PMID: 39805486 DOI: 10.1016/j.ejphar.2025.177268] [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: 10/04/2024] [Revised: 01/09/2025] [Accepted: 01/09/2025] [Indexed: 01/16/2025]
Abstract
Gastric cancer (GC) is one of the most common gastrointestinal cancers worldwide, with consistently high morbidity and mortality rates and poor prognosis. Most patients are diagnosed at an advanced stage due to the lack of specific presentation in the early stages. Exosomes are a class of extracellular vesicles (EVs) widely found in body fluids and can release genetic material or multiple proteins to facilitate intercellular communication. In recent years, exosomal miRNAs have gained attention for their role in various cancers. These exosomal miRNAs can impact GC development and progression by targeting specific genes or influencing signaling pathways and cytokines involved in Angiogenesis, epithelial-mesenchymal transition (EMT), drug resistance, and immune regulation. They show great potential in terms of diagnosis, prognosis, and treatment of GC. Notably, the gastrointestinal tract has the largest number of macrophages, which play a significant role in GC progression. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) and can influence macrophage programming through various mediators, including macrophage polarization. Macrophage polarization is involved in inflammatory responses and significantly impacts the GC process.
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Affiliation(s)
- Yun Zhang
- School of Clinical Medicine, Ningxia Medical University, Ningxia, China; General Hospital of Ningxia Medical University, Ningxia, China
| | - Baozhen Wang
- School of Clinical Medicine, Ningxia Medical University, Ningxia, China; General Hospital of Ningxia Medical University, Ningxia, China
| | - Jing Chen
- School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
| | - Tao Li
- Department of Surgical Oncology, Tumor Hospital, The General Hospital of Ningxia Medical University, Ningxia, China.
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23
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Jiang T, Zhang J, Zhao S, Zhang M, Wei Y, Liu X, Zhang S, Fan W, Liu Y, Lv Y, Zhang G. MCT4: a key player influencing gastric cancer metastasis and participating in the regulation of the metastatic immune microenvironment. J Transl Med 2025; 23:276. [PMID: 40045374 PMCID: PMC11884109 DOI: 10.1186/s12967-025-06279-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 02/20/2025] [Indexed: 03/09/2025] Open
Abstract
BACKGROUND MCT4 is a lactate transporter associated with glycolysis, which has been found to be associated with various tumorigenesis and development processes. Gastric cancer is a malignant disease with high incidence and mortality. The role of MCT4 in the occurrence and development of gastric cancer has not been clarified. METHODS In this study, we comprehensively utilized single-cell sequencing and external transcriptome sequencing databases to deeply analyze the mechanism of the impact of MCT4 on gastric cancer and its microenvironment. We verified the function of MCT4 in gastric cancer through in vitro cell line experiments and in vivo experiments using gastric cancer liver metastasis and subcutaneous tumor models. Meanwhile, we collected tumor and normal tissue samples from clinical gastric cancer patients and employed immunohistochemistry and multiplex immunofluorescence techniques to detect the expression and localization of relevant indicators, thereby validating the results of computer simulation analysis and providing a basis for revealing the internal relationship between MCT4 and gastric cancer. RESULTS The expression of MCT4 is upregulated in gastric cancer patients, and the upregulation is more significant than that in patients with gastric cancer metastasis. MCT4 can mediate the proliferation and migration of gastric cancer cells in vitro. MCT4 can mediate the metastasis of gastric cancer cells in vivo. Multi-omics analysis showed that the expression of MCT4 was related to the composition of the immune microenvironment, and it could mediate the emergence of the inhibitory immune microenvironment. The results of immunofluorescence and immunohistochemistry proved the robustness of the multi-omics analysis. CONCLUSION Our study found that MCT4 plays an important role in the occurrence and development of gastric cancer, which may mediate the occurrence of gastric cancer metastasis and shape the immunosuppressive tumor microenvironment.
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Affiliation(s)
- Tao Jiang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Blood-Stasis-Toxin Syndrome of Zhejiang Province, Hangzhou, China
| | - Jingcheng Zhang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Blood-Stasis-Toxin Syndrome of Zhejiang Province, Hangzhou, China
| | - Sicheng Zhao
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Blood-Stasis-Toxin Syndrome of Zhejiang Province, Hangzhou, China
| | - Mingsi Zhang
- School of Sport, Loughborough University, Loughborough, LE, UK
| | - Yunhai Wei
- Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, No.1558, Sanhuan North Road, Wuxing District, Huzhou, 313000, Zhejiang Province, China
| | - Xiaojuan Liu
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Blood-Stasis-Toxin Syndrome of Zhejiang Province, Hangzhou, China
| | - Shuo Zhang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Blood-Stasis-Toxin Syndrome of Zhejiang Province, Hangzhou, China
| | - Wei Fan
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Blood-Stasis-Toxin Syndrome of Zhejiang Province, Hangzhou, China
| | - Yueying Liu
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Blood-Stasis-Toxin Syndrome of Zhejiang Province, Hangzhou, China
| | - Yuanlin Lv
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
| | - Guangji Zhang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
- Key Laboratory of Blood-Stasis-Toxin Syndrome of Zhejiang Province, Hangzhou, China.
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24
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Liu C, Li Z, Cheng F, Li W, Li T. Research progress on molecular mechanism of liver metastasis of gastric cancer and treatment with traditional Chinese medicine. J Cancer 2025; 16:1944-1957. [PMID: 40092702 PMCID: PMC11905405 DOI: 10.7150/jca.105223] [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: 10/15/2024] [Accepted: 12/17/2024] [Indexed: 03/19/2025] Open
Abstract
Gastric cancer liver metastasis (GCLM) refers to the process of cancer cells from the stomach spreading to the liver, which is an important sign of the deterioration of gastric cancer (GC) and has a profound influence on the treatment and prognosis of patients. Once GC has liver metastasis, the treatment becomes more complex and challenging, which seriously affects the survival rate of patients with GC. Therefore, studying the mechanism and treatment of GCLM is extremely necessary. At present, the continuous research on GCLM has revealed that the mechanism of its occurrence and development involves the comprehensive effect of multiple targets and links. Traditional Chinese medicine (TCM) has the advantages of wide sources, excellent efficacy, and small toxicity and side effects, which have become the focus of current antitumor research. TCM, Chinese medicine monomers, or TCM compounds can inhibit the growth and metastasis of GC. In recent years, Chinese medicine has made substantial achievements in experimental research on the intervention of GCLM. This article reviews the progress of its intervention mechanism.
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Affiliation(s)
- Caiyue Liu
- Ningxia Medical University School of Traditional Chinese Medicine, Yinchuan, P. R. China
| | - Zheng Li
- Ningxia Medical University School of Traditional Chinese Medicine, Yinchuan, P. R. China
| | - Fane Cheng
- The First Clinical Medical College of Beijing University of Traditional Chinese Medicine, Beijing, P. R. China
| | - Weiqiang Li
- Ningxia Medical University School of Traditional Chinese Medicine, Yinchuan, P. R. China
- Key Laboratory of Ningxia Minority Medicine Modernization, Ministry of Education (Ningxia Medical University), Yinchuan, P. R. China
- Ningxia medical university affiliated traditional Chinese medicine hospital, Yinchuan, P. R. China
| | - Tingting Li
- Ningxia Medical University School of Traditional Chinese Medicine, Yinchuan, P. R. China
- Key Laboratory of Ningxia Minority Medicine Modernization, Ministry of Education (Ningxia Medical University), Yinchuan, P. R. China
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25
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Xu W, Xu J, Liu J, Wang N, Zhou L, Guo J. Liver Metastasis in Cancer: Molecular Mechanisms and Management. MedComm (Beijing) 2025; 6:e70119. [PMID: 40027151 PMCID: PMC11868442 DOI: 10.1002/mco2.70119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 01/15/2025] [Accepted: 01/20/2025] [Indexed: 03/05/2025] Open
Abstract
Liver metastasis is a leading cause of mortality from malignant tumors and significantly impairs the efficacy of therapeutic interventions. In recent years, both preclinical and clinical research have made significant progress in understanding the molecular mechanisms and therapeutic strategies of liver metastasis. Metastatic tumor cells from different primary sites undergo highly similar biological processes, ultimately achieving ectopic colonization and growth in the liver. In this review, we begin by introducing the inherent metastatic-friendly features of the liver. We then explore the panorama of liver metastasis and conclude the three continuous, yet distinct phases based on the liver's response to metastasis. This includes metastatic sensing stage, metastatic stress stage, and metastasis support stage. We discuss the intricate interactions between metastatic tumor cells and various resident and recruited cells. In addition, we emphasize the critical role of spatial remodeling of immune cells in liver metastasis. Finally, we review the recent advancements and the challenges faced in the clinical management of liver metastasis. Future precise antimetastatic treatments should fully consider individual heterogeneity and implement different targeted interventions based on stages of liver metastasis.
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Affiliation(s)
- Wenchao Xu
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Key Laboratory of Research in Pancreatic TumorChinese Academy of Medical SciencesBeijingChina
- National Infrastructures for Translational MedicinePeking Union Medical College HospitalBeijingChina
- State Key Laboratory of ComplexSevere, and Rare DiseasesPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Jia Xu
- State Key Laboratory of Fine ChemicalsDepartment of Pharmaceutical SciencesSchool of Chemical EngineeringDalian University of TechnologyDalianChina
| | - Jianzhou Liu
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Key Laboratory of Research in Pancreatic TumorChinese Academy of Medical SciencesBeijingChina
- National Infrastructures for Translational MedicinePeking Union Medical College HospitalBeijingChina
- State Key Laboratory of ComplexSevere, and Rare DiseasesPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Nanzhou Wang
- Department of Colorectal SurgeryState Key Laboratory of Oncology in South ChinaSun Yat‐sen University Cancer CenterGuangdong Provincial Clinical Research Center for CancerGuangzhouChina
| | - Li Zhou
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Key Laboratory of Research in Pancreatic TumorChinese Academy of Medical SciencesBeijingChina
- National Infrastructures for Translational MedicinePeking Union Medical College HospitalBeijingChina
- State Key Laboratory of ComplexSevere, and Rare DiseasesPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Junchao Guo
- Department of General SurgeryPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Key Laboratory of Research in Pancreatic TumorChinese Academy of Medical SciencesBeijingChina
- National Infrastructures for Translational MedicinePeking Union Medical College HospitalBeijingChina
- State Key Laboratory of ComplexSevere, and Rare DiseasesPeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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26
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Zheng Z, Zhai Y, Yan X, Wang Z, Zhang H, Xu R, Liu X, Cai J, Zhang Z, Shang Y, Zhang J, Yin J. Functions and Clinical Applications of Exosomes in Gastric Cancer. Int J Biol Sci 2025; 21:2330-2345. [PMID: 40083701 PMCID: PMC11900809 DOI: 10.7150/ijbs.98087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 02/04/2025] [Indexed: 03/16/2025] Open
Abstract
Gastric cancer is a common and highly invasive type of malignant tumor, the pathogenesis of which remains unclarified. However, exosomes are now known to play important roles in gastric cancer development and treatment. Cells use exosomes for the packaging and transportation of a variety of bioactive molecules, such as proteins, double-stranded DNA, and micro-ribonucleic acids, to other sites. Exosome-specific membrane structures and exosomal contents are widely involved in processes that facilitate material exchange and intercellular communication between gastric cancer cells. They help in forming a pre-metastatic microenvironment, promoting the proliferation and apoptosis of gastric cancer cells, and driving invasion, metastasis, and resistance to anti-tumor drugs. In this review, we aimed to summarize the findings of research articles indexed in the PubMed, Web of Science, and Embase databases and published up to May 31, 2024, on the role of exosomes in the pathogenesis of gastric cancer and their potential clinical applications in its treatment. Thus, research on exosomes may lead to breakthroughs in the early diagnosis of gastric cancer and identification of novel treatments.
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Affiliation(s)
- Zhi Zheng
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Institute of Clinical Medicine, Beijing, China
| | - Yuhao Zhai
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Institute of Clinical Medicine, Beijing, China
| | - Xiaosheng Yan
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Institute of Clinical Medicine, Beijing, China
| | - Zimeng Wang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Institute of Clinical Medicine, Beijing, China
| | - Haiqiao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Institute of Clinical Medicine, Beijing, China
| | - Rui Xu
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiaoye Liu
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Institute of Clinical Medicine, Beijing, China
| | - Jun Cai
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Institute of Clinical Medicine, Beijing, China
| | - Zhongtao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Institute of Clinical Medicine, Beijing, China
| | - Yuxi Shang
- Department of Hematology, Fuxing Hospital, Eighth Clinical Medical College, Capital Medical University, Beijing, China
| | - Jun Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Institute of Clinical Medicine, Beijing, China
| | - Jie Yin
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China
- National Clinical Research Center for Digestive Diseases, Beijing, China
- Beijing Institute of Clinical Medicine, Beijing, China
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Liu X, Liu J, Wang X, Zou Y, Tao X, Li J, Ye M, Xu W, Deng Y, Liu L, Sun J, Zhang Q. Cancer-secreted exosomal miR-1246 promotes colorectal cancer liver metastasis by activating hepatic stellate cells. Mol Med 2025; 31:68. [PMID: 39979806 PMCID: PMC11841005 DOI: 10.1186/s10020-025-01112-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 01/31/2025] [Indexed: 02/22/2025] Open
Abstract
Colorectal cancer liver metastases (CRLM) are the primary cause of mortality in colorectal cancer (CRC) patients, highlighting the importance of understanding the underlying mechanisms. The tumor microenvironment (TME) and its interaction with tumor cells play a crucial role in CRLM progression. Notably, the stability and peak levels of tumor-derived exosomal miRNAs facilitate intercellular communication in the TME. Hepatic stellate cells (HSCs), key liver mesenchymal cells, constitute about 33% of the liver's nonsolid cell population and exhibit plasticity. However, the specific role of tumor-derived exosomal miRNAs in the crosstalk between HSCs and tumor cells during the CRLM process remains unclear. We studied CRC-secreted exosomal miR-1246 and its impact on HSCs, as well as its effects on CRC cell proliferation and metastasis. Our findings demonstrate that CRC-secreted exosomal miR-1246 can be internalized by HSCs, leading to their activation and facilitating the metastatic potential of CRC cells. Mechanistically, exosomal miR-1246 targets INSIG1, resulting in SREBP2 nucleation and cholesterol metabolism alterations. This accumulation of free cholesterol (FC) regulates the TLR4/NF-κB/TGF-β pathway, promoting HSC activation. Activated HSCs, in turn, enhance liver metastasis of CRC cells through the TNFSF13/TNFRSF13B axis. Our study reveals the role of CRC-secreted exosomal miR-1246 in triggering HSC activation and reprogramming the TME, ultimately facilitating liver metastasis in CRC patients. Exosomal miR-1246 could serve as a potential non-invasive biomarker for predicting colorectal cancer liver metastasis, enhancing our understanding of CRC-associated liver metastases.
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Affiliation(s)
- Xiaolong Liu
- Department of General Surgery, The Third Affiliated Hospital of Southern Medical University, 183 West Zhongshan Avenue, Guangzhou, Guangdong, 510630, People's Republic of China
| | - Jialong Liu
- Department of General Surgery, The Third Affiliated Hospital of Southern Medical University, 183 West Zhongshan Avenue, Guangzhou, Guangdong, 510630, People's Republic of China
| | - Xuanyin Wang
- Department of General Surgery, The Third Affiliated Hospital of Southern Medical University, 183 West Zhongshan Avenue, Guangzhou, Guangdong, 510630, People's Republic of China
| | - Yang Zou
- Department of General Surgery, The Third Affiliated Hospital of Southern Medical University, 183 West Zhongshan Avenue, Guangzhou, Guangdong, 510630, People's Republic of China
| | - Xinyi Tao
- Department of General Surgery, The Third Affiliated Hospital of Southern Medical University, 183 West Zhongshan Avenue, Guangzhou, Guangdong, 510630, People's Republic of China
| | - Jingyu Li
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No.106, Zhongshan 2 Road, Guangzhou, Guangdong, 510080, People's Republic of China
| | - Mengnan Ye
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No.106, Zhongshan 2 Road, Guangzhou, Guangdong, 510080, People's Republic of China
| | - Wanbei Xu
- Department of General Surgery, The Third Affiliated Hospital of Southern Medical University, 183 West Zhongshan Avenue, Guangzhou, Guangdong, 510630, People's Republic of China
| | - Yunyao Deng
- Department of General Surgery, The Third Affiliated Hospital of Southern Medical University, 183 West Zhongshan Avenue, Guangzhou, Guangdong, 510630, People's Republic of China
| | - Lixin Liu
- Department of General Surgery, The Third Affiliated Hospital of Southern Medical University, 183 West Zhongshan Avenue, Guangzhou, Guangdong, 510630, People's Republic of China.
| | - Jingbo Sun
- Department of General Surgery, The Third Affiliated Hospital of Southern Medical University, 183 West Zhongshan Avenue, Guangzhou, Guangdong, 510630, People's Republic of China.
| | - Qingling Zhang
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, No.106, Zhongshan 2 Road, Guangzhou, Guangdong, 510080, People's Republic of China.
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28
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Yuan Q, Jia L, Yang J, Li W. The role of macrophages in liver metastasis: mechanisms and therapeutic prospects. Front Immunol 2025; 16:1542197. [PMID: 40034694 PMCID: PMC11872939 DOI: 10.3389/fimmu.2025.1542197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 01/21/2025] [Indexed: 03/05/2025] Open
Abstract
Metastasis is a hallmark of advanced cancer, and the liver is a common site for secondary metastasis of many tumor cells, including colorectal, pancreatic, gastric, and prostate cancers. Macrophages in the tumor microenvironment (TME) promote tumor cell metastasis through various mechanisms, including angiogenesis and immunosuppression, and play a unique role in the development of liver metastasis. Macrophages are affected by a variety of factors. Under conditions of hypoxia and increased acidity in the TME, more factors are now found to promote the polarization of macrophages to the M2 type, including exosomes and amino acids. M2-type macrophages promote tumor cell angiogenesis through a variety of mechanisms, including the secretion of factors such as VEGF, IL-1β, and TGF-β1. M2-type macrophages are subjected to multiple regulatory mechanisms. They also interact with various cells within the tumor microenvironment to co-regulate certain conditions, including the creation of an immunosuppressive microenvironment. This interaction promotes tumor cell metastasis, drug resistance, and immune escape. Based on the advent of single-cell sequencing technology, further insights into macrophage subpopulations in the tumor microenvironment may help in exploring new therapeutic targets in the future. In this paper, we will focus on how macrophages affect the TME, how tumor cells and macrophages as well as other immune cells interact with each other, and further investigate the mechanisms involved in liver metastasis of tumor cells and their potential as therapeutic targets.
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Affiliation(s)
| | | | | | - Wei Li
- *Correspondence: Jiahua Yang, ; Wei Li,
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Tang L, Zhang W, Qi T, Jiang Z, Tang D. Exosomes play a crucial role in remodeling the tumor microenvironment and in the treatment of gastric cancer. Cell Commun Signal 2025; 23:82. [PMID: 39948541 PMCID: PMC11827163 DOI: 10.1186/s12964-024-02009-7] [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: 09/03/2024] [Accepted: 12/21/2024] [Indexed: 02/16/2025] Open
Abstract
Gastric cancer (GC) is a common and frequent malignant cancer of the digestive system with a poor prognosis. In addition to common therapies such as surgical resection and chemotherapy, novel biological interventions are quite valuable for research. Exosomes are extracellular vesicles (EVs) that originate from various cell types and contain proteins, RNA, DNA, and other components that transmit biological signals and mediate intercellular communication. Numerous studies have shown that exosomes shape the tumor microenvironment (TME) by affecting hypoxia, inflammation, immunity, metabolism, and interstitial changes in the tumor, playing a crucial role in the development and metastasis of GC. This article reviews the important role of exosomes in the TME of GC and explores their potential clinical applications in GC treatment.
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Affiliation(s)
- Lingyun Tang
- Clinical Medical College, Yangzhou University, Yangzhou, 225000, China
| | - Wenjie Zhang
- School of Medicine, Chongqing University, Chongqing, 400030, China
| | - Teng Qi
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou, 225000, China
| | - Zhengting Jiang
- Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Northern Jiangsu People's Hospital, Yangzhou, 225000, China.
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Northern Jiangsu People's Hospital; The Yangzhou Clinical Medical College of Xuzhou Medical University; The Yangzhou School of Clinical Medicine of Dalian Medical University; The Yangzhou School of Clinical Medicine of Nanjing Medical University; Northern Jiangsu People's Hospital, Clinical Teaching Hospital of Medical School, Nanjing University, Yangzhou, 225000, China.
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Pote MS, Gacche RN. Exosomal signaling in cancer metastasis: Molecular insights and therapeutic opportunities. Arch Biochem Biophys 2025; 764:110277. [PMID: 39709108 DOI: 10.1016/j.abb.2024.110277] [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: 05/02/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 12/23/2024]
Abstract
Exosomes are membrane-bound extracellular vesicles that play a role in exchanging biological products across membranes and serve as intermediaries in intercellular communication to maintain normal homeostasis. Numerous molecules, including lipids, proteins, and nucleic acids are enclosed in exosomes. Exosomes are constantly released into the extracellular environment and exhibit distinct characteristics based on the secreted cells that produce them. Exosome-mediated cell-to-cell communication has reportedly been shown to affect multiple cancer hallmarks, such as immune response modulation, pre-metastatic niche formation, angiogenesis, stromal cell reprogramming, extracellular matrix architecture remodeling, or even drug resistance, and eventually the development and metastasis of cancer cells. Exosomes can be used as therapeutic targets and possible diagnostic biomarkers by selectively loading oncogenic molecules into them. We highlight the important roles that exosomes play in cancer development in this review, which may lead to the development of fresh approaches for future clinical uses.
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Affiliation(s)
- Manasi S Pote
- Tumor Biology Laboratory, Department of Biotechnology, Savitribai Phule Pune University, Pune, 411 007, (MS), India
| | - Rajesh N Gacche
- Tumor Biology Laboratory, Department of Biotechnology, Savitribai Phule Pune University, Pune, 411 007, (MS), India.
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Shi J, Zhu X, Yang JB. Advances and challenges in molecular understanding, early detection, and targeted treatment of liver cancer. World J Hepatol 2025; 17:102273. [PMID: 39871899 PMCID: PMC11736488 DOI: 10.4254/wjh.v17.i1.102273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/12/2024] [Accepted: 11/27/2024] [Indexed: 01/06/2025] Open
Abstract
In this review, we explore the application of next-generation sequencing in liver cancer research, highlighting its potential in modern oncology. Liver cancer, particularly hepatocellular carcinoma, is driven by a complex interplay of genetic, epigenetic, and environmental factors. Key genetic alterations, such as mutations in TERT, TP53, and CTNNB1, alongside epigenetic modifications such as DNA methylation and histone remodeling, disrupt regulatory pathways and promote tumorigenesis. Environmental factors, including viral infections, alcohol consumption, and metabolic disorders such as nonalcoholic fatty liver disease, enhance hepatocarcinogenesis. The tumor microenvironment plays a pivotal role in liver cancer progression and therapy resistance, with immune cell infiltration, fibrosis, and angiogenesis supporting cancer cell survival. Advances in immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies have shown potential, but the unique immunosuppressive milieu in liver cancer presents challenges. Dysregulation in pathways such as Wnt/β-catenin underscores the need for targeted therapeutic strategies. Next-generation sequencing is accelerating the identification of genetic and epigenetic alterations, enabling more precise diagnosis and personalized treatment plans. A deeper understanding of these molecular mechanisms is essential for advancing early detection and developing effective therapies against liver cancer.
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Affiliation(s)
- Ji Shi
- Department of Research and Development, Ruibiotech Company Limited, Beijing 100101, China
| | - Xu Zhu
- Department of Research and Development, Ruibiotech Company Limited, Beijing 100101, China
| | - Jun-Bo Yang
- Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518000, Guangdong Province, China.
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Cui Y, Chang Y, Ma X, Sun M, Huang Y, Yang F, Li S, Zhuo W, Liu W, Yang B, Lin A, Ou G, Yang Y, Xie S, Zhou T. Ephrin A1 Stimulates CCL2 Secretion to Facilitate Premetastatic Niche Formation and Promote Gastric Cancer Liver Metastasis. Cancer Res 2025; 85:263-276. [PMID: 39412948 DOI: 10.1158/0008-5472.can-24-1254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 09/04/2024] [Accepted: 10/10/2024] [Indexed: 10/18/2024]
Abstract
The liver is a primary target for distal metastasis of gastric cancer. The hepatic premetastatic niche (PMN) facilitates crucial communications between primary tumor and liver, thereby playing an essential role in hepatic metastasis. Identification of the molecular mechanisms driving PMN formation in gastric cancer could facilitate development of strategies to prevent and treat liver metastasis. Here, we uncovered a role for ephrin A1 (EFNA1) signaling in development of the PMN. EFNA1 overexpression in gastric cancer cells significantly increased C-C motif chemokine ligand 2 (CCL2) secretion through the Hippo-YAP pathway. Secreted CCL2 activated hepatic stellate cells (HStC) within the hepatic PMN via the WNT/β-catenin pathway. Inhibition of CCL2 significantly suppressed HStC activation and reduced liver metastasis triggered by EFNA1 signaling in gastric cancer cells. Moreover, high CCL2 expression correlated with poor survival in patients with cancer. Overall, these findings reveal that EFNA1 signaling in gastric cancer cells upregulates CCL2, which activates HStCs to engender establishment of a hepatic PMN that supports liver metastasis. Significance: Cross-talk between gastric cancer cells and hepatic stellate cells mediated by the EFNA1/CCL2 axis induces premetastatic niche development to facilitate metastatic spread, nominating CCL2 as a therapeutic target to suppress liver metastasis.
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Affiliation(s)
- Yun Cui
- Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Yongxia Chang
- Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Xixi Ma
- Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Meng Sun
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China
- Binjiang Institute of Zhejiang University, Hangzhou, China
| | - Yuliang Huang
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China
| | - Feng Yang
- Binjiang Institute of Zhejiang University, Hangzhou, China
| | - Shuang Li
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Zhuo
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Liu
- Metabolic Medicine Center, International Institutes of Medicine and the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China
| | - Bo Yang
- Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
- School of Medicine, Hangzhou City University, Hangzhou, China
| | - Aifu Lin
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, China
| | - Guangshuo Ou
- School of Life Sciences, Tsinghua University, Beijing, China
| | - Yuehong Yang
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China
| | - Shanshan Xie
- Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Tianhua Zhou
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
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Karere GM, Hsu FC, Hepple RT, Coen PM, Cummings S, Newman A, Glynn NW, Sparks L, Lane NE, Xu J, Wagner N, Li G, Chan J, Cox LA, Kritchevsky S. MicroRNA signatures of VO 2 peak in older adult participants of the Study of Muscle, Mobility and Aging. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.08.631999. [PMID: 39829832 PMCID: PMC11741432 DOI: 10.1101/2025.01.08.631999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Background Peak oxygen consumption during exercise (VO 2 peak), is a direct measure of cardiorespiratory fitness (CF), a key indicator of physical function and overall health. However, the molecular changes that underpin VO 2 peak variation are not clear. Our objective is to understand the miRNA signatures that relate to VO 2 peak variation, which could provide insights to novel mechanisms that contribute to low VO 2 peak. Methods We used small RNA sequencing to analyze serum samples from 72 participants (70-79 yrs old, 53% female) of the Study of Muscle, Mobility and Aging (SOMMA). We analyzed samples from individuals with low or high VO 2 peak (N=18/group) as well as samples from 36 randomly selected participants spanning the entire spectrum of VO 2 peak. We used LIMMA analysis package for regression analysis and to identify differentially expressed miRNAs. We used receiver operating characteristic curve analysis to evaluate the Area Under the Curve (AUC) and sensitivity and specificity rates. Results We identified 1,055 miRNAs expressed in all serum samples. Expression of 65 miRNAs differed between participants with low and high VO 2 peak (p < 0.05). After p-value adjustment, expression of 5 miRNAs (miR-1301-3p, -431-5p, -501-5p, -519a-3p, and -18a-3p) remained significantly different (FDR = 0.05). The five miRNAs had AUC ranging from 0.77 to 0.84. The optimal sensitivity and specificity ranged from 70 to 80% and 80 to 90%, respectively. After adjustment for age and sex covariates, 46 miRNAs significantly correlated with VO 2 peak (p < 0.05) and miR-519a-3p remained significant based on adjusted of p-values. Conclusions We identified a miRNA signature of VO 2 peak in older individuals that might provide insights to novel mechanisms that drive low VO 2 peak. Future studies will validate the findings in a larger, longitudinal study cohort.
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Sun X, Zhang J, Dong B, Xiong Q, Wang X, Gu Y, Wang Z, Liu H, Zhang J, He X, Liu H, Zhong Y, Yi C, Chi X, Liu Z, Pang X, Cui Y. Targeting SLITRK4 Restrains Proliferation and Liver Metastasis in Colorectal Cancer via Regulating PI3K/AKT/NFκB Pathway and Tumor-Associated Macrophage. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2400367. [PMID: 39499724 PMCID: PMC11714161 DOI: 10.1002/advs.202400367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 10/28/2024] [Indexed: 11/07/2024]
Abstract
Liver metastasis is the major cause of death in colorectal cancer (CRC) due to the lack of effective treatment. To explore novel drivers of CRC liver metastasis, the transcriptomes of primary paracancerous, colorectal tumors and metastases from human patients are profiled. It is found that SLIT- and NTRK-like family member 4 (SLITRK4) is the top upregulated gene in liver metastases and is associated with worse overall survival of CRC patients. Multiple in vitro and in vivo models suggested SLITRK4 promoted CRC tumorigenesis, invasion, migration, and angiogenesis, and inhibition of it restrained CRC tumor growth and liver metastasis with a more profound effect on the tumor microenvironment (TME). Mechanistically, SLITRK4 overexpression significantly activated the PI3K/AKT/NFκB pathway, regulated extracellular matrix organization, and multiple cytokines expression. Furthermore, the results from coculture models and single-cell RNA sequencing analyses suggested SLITRK4 promoted tumor-associated macrophages (TAMs) infiltration and polarization. In addition, macrophage depletion significantly inhibited SLITRK4-induced liver metastasis in CRC. Finally, pharmacological inhibition of SLITRK4 by using lipid-polymer hybrid nanoparticles (NPs) for systemic siRNA delivery can effectively inhibit CRC liver metastasis. Taken together, these results pinpoint that SLITRK4 regulates CRC tumorigenesis and liver metastasis, and siRNA delivering NPs agents validate the therapeutic potential of targeting SLITRK4 in CRC.
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Affiliation(s)
- Xiaojiao Sun
- State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing100191China
| | - Junling Zhang
- Department of General SurgeryPeking University First HospitalXishiku Street, BeijingXicheng100034China
| | - Bingqi Dong
- Department of General SurgeryPeking University First HospitalXishiku Street, BeijingXicheng100034China
| | - Qingqing Xiong
- Department of Hepatobiliary CancerLiver Cancer CenterTianjin Medical University Cancer InstituteTianjin300060China
| | - Xin Wang
- Department of General SurgeryPeking University First HospitalXishiku Street, BeijingXicheng100034China
| | - Yanlun Gu
- State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing100191China
- Department of PharmacyPeking University First HospitalXishiku Street, BeijingXicheng100034China
- Institute of Clinical PharmacologyPeking UniversityXueyuan Road 38, BeijingHaidian100191China
| | - Zhiqi Wang
- State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing100191China
| | - Huiyu Liu
- State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing100191China
| | - Jixin Zhang
- Department of PathologyPeking University First HospitalXishiku Street, BeijingXicheng100034China
| | - Xu He
- Department of PharmacyPeking University First HospitalXishiku Street, BeijingXicheng100034China
- Institute of Clinical PharmacologyPeking UniversityXueyuan Road 38, BeijingHaidian100191China
| | - Hongjin Liu
- Department of General SurgeryPeking University First HospitalXishiku Street, BeijingXicheng100034China
| | - Yi Zhong
- State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing100191China
| | - Chuxiao Yi
- State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing100191China
| | - Xiaowei Chi
- State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing100191China
| | - Zhenming Liu
- State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing100191China
| | - Xiaocong Pang
- State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing100191China
- Department of PharmacyPeking University First HospitalXishiku Street, BeijingXicheng100034China
- Institute of Clinical PharmacologyPeking UniversityXueyuan Road 38, BeijingHaidian100191China
| | - Yimin Cui
- State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing100191China
- Department of PharmacyPeking University First HospitalXishiku Street, BeijingXicheng100034China
- Institute of Clinical PharmacologyPeking UniversityXueyuan Road 38, BeijingHaidian100191China
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Duan X, Yu X, Gan J. Extracellular vesicle-packaged miR-4253 secreted by cancer-associated fibroblasts facilitates cell proliferation in gastric cancer by inducing macrophage M2 polarization. Cancer Biol Ther 2024; 25:2424490. [PMID: 39505708 PMCID: PMC11542604 DOI: 10.1080/15384047.2024.2424490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 10/28/2024] [Accepted: 10/29/2024] [Indexed: 11/08/2024] Open
Abstract
Cancer-associated fibroblasts (CAFs) can interact with macrophages in the tumor microenvironment by secreting extracellular vesicles (EVs), thereby affecting tumor progression. However, the mechanisms of CAF-secreted EVs in gastric cancer (GC) remain not well understood. Here, we investigated the effect of CAF-EVs on macrophage polarization in GC and the underlying mechanisms. Macrophage polarization was evaluated using flow cytometry and quantitative real-time polymerase chain reaction. GC cell proliferation was determined using cell counting kit-8, EdU, and colony formation assays. The molecular mechanism was explored using microarray analysis, dual-luciferase reporter assay, and RNA pull-down analysis. The results showed that CAFs secreted EVs that inhibit macrophage M1 polarization and promote M2 polarization. Moreover, miR-4253 expression was increased in CAF-EVs, and inhibition of miR-4253 reversed the macrophage polarization induced by EVs. IL6R was identified as the target of miR-4253. Additionally, macrophages treated with EVs that encapsulated miR-4253 promote GC cell proliferation. In conclusion, CAF-secreted EVs packaging miR-4253 facilitate macrophage polarization from M1 to M2 phenotype by targeting IL6R, thereby accelerating GC cell proliferation. The findings suggest that EV-encapsulated miR-4253 may be a promising therapeutic target of GC.
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Affiliation(s)
- Xinxing Duan
- General Surgery Center, Jiujiang City Key Laboratory of Cell Therapy, Jiujiang, China
| | - Xiong Yu
- General Surgery Center, Jiujiang City Key Laboratory of Cell Therapy, Jiujiang, China
| | - Jin Gan
- General Surgery Center, Jiujiang City Key Laboratory of Cell Therapy, Jiujiang, China
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Liu Z, Du D, Zhang S. Tumor-derived exosomal miR-1247-3p promotes angiogenesis in bladder cancer by targeting FOXO1. Cancer Biol Ther 2024; 25:2290033. [PMID: 38073044 PMCID: PMC10761019 DOI: 10.1080/15384047.2023.2290033] [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: 09/01/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
Tumor-derived exosomes are highly correlated with tumor progression and angiogenesis. This study was designed to probe the role of tumor-derived exosomal miR-1247-3p in mediating the angiogenesis in bladder cancer. Exosomes isolation from the culture medium of normal or bladder cancer cell lines was performed using a differential centrifugation method. miR-1247-3p expression in exosomes and cells was detected by quantitative real-time PCR (qRT-PCR). The effect of exosomes on the angiogenesis of human umbilical vein endothelial cells (HUVECs) was assessed using cell counting kit-8 (CCK-8), transwell and tube formation assays. The interaction between miR-1247-3p and forkhead box protein O1 (FOXO1) was studied using luciferase reporter and RNA pull down assays. Exosomes were successfully isolated from T24, UM-UC-3, and SV-HUC-1 cells, as confirmed by corresponding identifications. Functional experiments revealed that exosomes derived from T24 and UM-UC-3 cells significantly enhanced the abilities of proliferation, migration, angiogenesis, and vascular endothelial-derived growth factor (VEGF) secretion in HUVECs. miR-1247-3p was highly expressed in exosomes derived from T24 and UM-UC-3 cells, and exosomes derived from miR-1247-3p inhibitor-transfected cells reduced HUVEC viability, migration, tube formation, and VEGF level. FOXO1 was confirmed as a direct target of miR-1247-3p. Rescue assays suggested that the effect of miR-1247-3p inhibition on the viability, migration, and angiogenesis of HUVECs was partly abrogated by the knockdown of FOXO1. Our data suggest that miR-1247-3p is up-regulated in tumor-derived exosomes, thereby inhibiting FOXO1 expression and facilitating angiogenesis in bladder cancer.
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Affiliation(s)
- Zonglai Liu
- Medical College, China Three Gorges University, Yichang, Hubei, China
- Department of Urology, The Second People’s Hospital of China Three Gorges University, Yichang, Hubei, China
| | - Dan Du
- Medical College, China Three Gorges University, Yichang, Hubei, China
- Department of Urology, The Second People’s Hospital of China Three Gorges University, Yichang, Hubei, China
| | - Shizhong Zhang
- Medical College, China Three Gorges University, Yichang, Hubei, China
- Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University, Yichang, Hubei, China
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Tian H, Tian Y, Li D, Zhao M, Luo Q, Kong L, Qin T. Artificial intelligence model predicts M2 macrophage levels and HCC prognosis with only globally labeled pathological images. Front Oncol 2024; 14:1474155. [PMID: 39759153 PMCID: PMC11695232 DOI: 10.3389/fonc.2024.1474155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 12/09/2024] [Indexed: 01/07/2025] Open
Abstract
Background and aims The levels of M2 macrophages are significantly associated with the prognosis of hepatocellular carcinoma (HCC), however, current detection methods in clinical settings remain challenging. Our study aims to develop a weakly supervised artificial intelligence model using globally labeled histological images, to predict M2 macrophage levels and forecast the prognosis of HCC patients by integrating clinical features. Methods CIBERSORTx was used to calculate M2 macrophage abundance. We developed a slide-level, weakly-supervised clustering method for Whole Slide Images (WSIs) by integrating Masked Autoencoders (MAE) with ResNet-32t to predict M2 macrophage abundance. Results We developed an MAE-ResNet model to predict M2 macrophage levels using WSIs. In the testing dataset, the area under the curve (AUC) (95% CI) was 0.73 (0.59-0.87). We constructed a Cox regression model showing that the predicted probabilities of M2 macrophage abundance were negatively associated with the prognosis of HCC (HR=1.89, p=0.031). Furthermore, we incorporated clinical data, screened variables using Lasso regression, and built the comprehensive prediction model that better predicted prognosis. (HR=2.359, p=0.001). Conclusion Our models effectively predicted M2 macrophage levels and HCC prognosis. The findings suggest that our models offer a novel method for determining biomarker levels and forecasting prognosis, eliminating additional clinical tests, thereby delivering substantial clinical benefits.
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Affiliation(s)
- Huiyuan Tian
- Department of Scientific Research and Foreign Affairs, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, Henan, China
| | - Yongshao Tian
- School of Computer Science and Technology, University of Science and Technology of China, Hefei, Anhui, China
| | - Dujuan Li
- Department of Pathology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, Henan, China
| | - Minfan Zhao
- School of Computer Science and Technology, University of Science and Technology of China, Hefei, Anhui, China
| | - Qiankun Luo
- Department of Hepatobiliary and Pancreatic Surgery, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, Henan, China
| | - Lingfei Kong
- Department of Pathology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, Henan, China
| | - Tao Qin
- Department of Hepatobiliary and Pancreatic Surgery, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, Henan, China
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Wu Y, Zhang J, Li G, Wang L, Zhao Y, Zheng B, Lin F, Xie L. Exosomal miR-320d promotes angiogenesis and colorectal cancer metastasis via targeting GNAI1 to affect the JAK2/STAT3 signaling pathway. Cell Death Dis 2024; 15:913. [PMID: 39695099 DOI: 10.1038/s41419-024-07297-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 12/01/2024] [Accepted: 12/06/2024] [Indexed: 12/20/2024]
Abstract
Colorectal cancer is a common malignant tumor, whose growth and metastasis are influenced by numerous factors. MicroRNAs have garnered increasing attention in recent years due to their involvement in tumor development. Exosomes are involved in intercellular signaling and influence tumor development by promoting tumor cell proliferation and metastasis through activation of angiogenesis and other mechanisms. This study aimed to investigate how the exosomes containing miR-320d from colorectal cancer (CRC) cells promote colorectal cancer metastasis by regulating angiogenesis. CRC-derived exosomes containing miR-320d can be transferred to vascular endothelial cells, facilitating their proliferation, invasion, migration, and angiogenesis. By targeting GNAI1, miR-320d in these exosomes reduces GNAI1 levels in endothelial cells, causing more JAK2/STAT3 activation and VEGFA production. This ultimately enhances the migration and angiogenic capacity of vascular endothelial cells. Moreover, CRC patients with high levels of miR-320d in their blood respond better to treatment with bevacizumab. In vivo experiments further proved the role of miR-320d from CRC exosomes in increasing tumor size, blood vessel formation, and the spread of cancer to the liver. In this study, we have demonstrated that exosomal miR-320d promotes cancer cell metastasis and enhances angiogenesis by downregulating GNAI1 expression and enhancing JAK2/STAT3.
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Affiliation(s)
- Yawen Wu
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- Clinical Laboratory, Children's Hospital Affiliated to Shandong University, Jinan, Shandong Province, China
| | - Jie Zhang
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Guanghao Li
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Li Wang
- Department of Clinical Laboratory, Hangzhou Fuyang District First People's Hospital, Hangzhou, Zhejiang, China
| | - Yajing Zhao
- Department of Clinical Laboratory, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, PR China
| | - Baibing Zheng
- Department of Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin, China
| | - Fanfeng Lin
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Li Xie
- Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
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Sun Y, He X, Han J, Yin W, Wang H, Li J, Liu W, Kuai X, Lv J, Ji J. Activated hepatic stellate cell-derived small extracellular vesicles facilitate M2 macrophage polarization and hepatoma progression via miR-27a-3p. Front Immunol 2024; 15:1489679. [PMID: 39742261 PMCID: PMC11685157 DOI: 10.3389/fimmu.2024.1489679] [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: 09/01/2024] [Accepted: 12/03/2024] [Indexed: 01/03/2025] Open
Abstract
The progression of hepatoma is heavily influenced by the microenvironment. Tumor-associated macrophages (TAMs) are considered to play a critical role in the tumor microenvironment (TME) and increase the aggressiveness of hepatoma. The activation of hepatic stellate cells (HSCs) is involved in hepatoma progression, and accumulating evidence demonstrates a change in microRNA (miRNA) expression during HSC activation. Therefore, the potential roles of HSCs-related miRNAs in macrophage differentiation and hepatoma progression deserve to be explored. The present study aimed to investigate the effects of miRNAs carried by small extracellular vesicles (sEVs) released by activated HSCs on hepatoma progression. The results indicated that miR-27a-3p was significantly upregulated in cells and corresponding sEVs during the activation of primary rat HSCs and human HSC line-LX2 cells. Furthermore, miR-27a-3p contributed to the proliferation and migration of hepatoma cells and promoted M2 polarization of macrophage. HSC-sEVs overexpressing miR-27a-3p can directly facilitate tumor progression and modulate macrophage polarization, indirectly contributing to hepatoma progression. Finally, Sprouty2 (SPRY2) was verified to be the target gene of miR-27a-3p. In conclusion, activated HSC-derived sEVs with high levels of miR-27a-3p might induce M2 macrophage polarization and promote hepatoma progression, providing new insights into the mechanism of hepatoma progression.
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Affiliation(s)
- Yufeng Sun
- Department of Pathology, Medical School of Nantong University, Nantong, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Nantong, China
| | - Xiaoqian He
- Department of Pathology, Medical School of Nantong University, Nantong, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Nantong, China
| | - Jiayi Han
- Department of Pathology, Medical School of Nantong University, Nantong, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Nantong, China
| | - Wenxuan Yin
- Department of Pathology, Medical School of Nantong University, Nantong, China
| | - Haichen Wang
- Department of Pathology, Medical School of Nantong University, Nantong, China
| | - Jing Li
- Department of Pathology, Medical School of Nantong University, Nantong, China
| | - Weiqi Liu
- Department of Pathology, Medical School of Nantong University, Nantong, China
| | - Xingwang Kuai
- Department of Pathology, Medical School of Nantong University, Nantong, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Nantong, China
| | - Jiaying Lv
- Department of Pathology, Medical School of Nantong University, Nantong, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Nantong, China
| | - Juling Ji
- Department of Pathology, Medical School of Nantong University, Nantong, China
- Key Laboratory of Microenvironment and Translational Cancer Research, Nantong, China
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Liu C, Guo H, Jin F. Research trends and hotspots in gastric carcinoma associated exosome: a bibliometric analysis. Front Oncol 2024; 14:1457346. [PMID: 39703839 PMCID: PMC11655325 DOI: 10.3389/fonc.2024.1457346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 11/08/2024] [Indexed: 12/21/2024] Open
Abstract
Background Stomach cancer is considered the fifth most common cancer worldwide. This study utilized bibliometric analysis to construct a visualization map of the relationship between stomach cancer and exosomes, aiming to reveal research trends and emerging themes, and provide direction for future research. Method Retrieve relevant literature on gastric cancer exosomes in the Web of Science Core Collection (WoSCC) over the past 25 years according to search criteria, and conduct bibliometric and visualization analysis using bibliometric software VOSviewer and CiteSpace. Results This study included a total of 727 articles, with an overall increasing trend in annual publication output. There were 68 countries involved, with China having the largest number of publications followed by the United States. A total of 957 research institutions were involved, with most of the top 10 institutions in terms of publication output being universities in China. The top 5 journals are Molecular Cancer, Cell death & disease, Cancers, International journal of molecular sciences, and Frontiers in oncology. A total of 4529 authors were involved, with 5 authors having a publication output of no less than 13 articles. A total of 35516 references were cited, with a total number of citations. The top publication is "Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells". Conclusion Over the past 25 years, researchers have been dedicated to studying the field of exosomes related to gastric cancer, and research in this area is currently progressing steadily. Based on previous studies, exosomes in gastric adenocarcinoma serve as biomarkers, potential therapeutic targets, and post-resistance treatment, which represents current hotspots and emerging frontiers in research.
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Affiliation(s)
- Chunqiu Liu
- Integrated Traditional Chinese and Western Medicine Oncology Department, Tangshan People’s Hospital, Tangshan, Hebei, China
| | - Honglei Guo
- Department of Chinese Medicine, Tianjin Medical University General Hospital, Tianjin, China
| | - Fangzhou Jin
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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Zhang J, Qu M, Mo Z, Sui H, Liu L, Fu D. Ionizable cationic lipid nanoparticles loaded with miRNA‐125b/BLZ945 for pancreatic cancer treatment. Biotechnol Appl Biochem 2024. [DOI: 10.1002/bab.2701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Accepted: 11/12/2024] [Indexed: 04/29/2025]
Abstract
AbstractIn prior research, both miRNA‐125b and BLZ945 have shown potential in effectively inhibiting M2 macrophage polarization and producing antitumor effects. Nevertheless, their physicochemical characteristics present significant challenges for efficient in vivo delivery. Ionizable cationic lipid nanoparticles (LNPs), recognized for their superior biocompatibility and drug‐loading capacity, serve as a novel carrier for nucleic acid‐based therapeutics. In our study, we successfully encapsulated both agents within LNPs and conducted a thorough characterization. Subsequently, we investigated their potential to repolarize M2 macrophages in vitro and evaluated their in vivo distribution, biosafety, and antitumor efficacy. The findings revealed that the LNPs maintained excellent drug‐loading efficiency, consistent particle size, and stable zeta potential. All formulations effectively inhibited M2 macrophage polarization in vitro. Upon administration in vivo, the LNPs not only demonstrated favorable biosafety profiles but also accumulated efficiently in tumor tissues, substantially reducing tumor burden, particularly notable in co‐loaded LNPs. Our results affirm that LNPs are an effective carrier for miRNA‐125b and BLZ945, highlighting this encapsulation approach as promising for the treatment of solid tumors and meriting further investigation. Practitioner points: (i) Ionizable cationic nanoparticles provide high and stable encapsulation rates to efficiently load nucleic acid polymers into the LNP, avoiding the rapid accumulation of circulating macrophages, which can lead to reduced penetration of the LNP into target tissues. Therefore, it can be used as a novel drug delivery method to benefit clinical patients. (ii) miRNA‐125b LNP/BLZ945 LNP attenuated the depleting effect of BLZ945 on macrophages and significantly inhibited macrophage M2 polarization. It could be effectively distributed in tumors and showed good biosafety while exerting antitumor effects, bringing hope to clinical pancreatic tumor patients.
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Affiliation(s)
- Jiajie Zhang
- Department of Pancreatic Surgery, Huashan Hospital Fudan University Shanghai China
- Department of Radiation Oncology UNC School of Medicine Chapel Hill North Carolina USA
| | - Ming Qu
- Department of Radiology China‐Japan Union Hospital of Jilin University Changchun China
- Jilin Institute of Radiology Intervention Changchun China
| | - Zhanhao Mo
- Department of Radiology China‐Japan Union Hospital of Jilin University Changchun China
- Jilin Institute of Radiology Intervention Changchun China
| | - He Sui
- Department of Radiology China‐Japan Union Hospital of Jilin University Changchun China
- Jilin Institute of Radiology Intervention Changchun China
| | - Lin Liu
- Department of Radiology China‐Japan Union Hospital of Jilin University Changchun China
- Jilin Institute of Radiology Intervention Changchun China
| | - Deliang Fu
- Department of Pancreatic Surgery, Huashan Hospital Fudan University Shanghai China
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Rabas N, Ferreira RMM, Di Blasio S, Malanchi I. Cancer-induced systemic pre-conditioning of distant organs: building a niche for metastatic cells. Nat Rev Cancer 2024; 24:829-849. [PMID: 39390247 DOI: 10.1038/s41568-024-00752-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/28/2024] [Indexed: 10/12/2024]
Abstract
From their early genesis, tumour cells integrate with the surrounding normal cells to form an abnormal structure that is tightly integrated with the host organism via blood and lymphatic vessels and even neural associations. Using these connections, emerging cancers send a plethora of mediators that efficiently perturb the entire organism and induce changes in distant tissues. These perturbations serendipitously favour early metastatic establishment by promoting a more favourable tissue environment (niche) that supports the persistence of disseminated tumour cells within a foreign tissue. Because the establishment of early metastatic niches represents a key limiting step for metastasis, the creation of a more suitable pre-conditioned tissue strongly enhances metastatic success. In this Review, we provide an updated view of the mechanisms and mediators of primary tumours described so far that induce a pro-metastatic conditioning of distant organs, which favours early metastatic niche formation. We reflect on the nature of cancer-induced systemic conditioning, considering that non-cancer-dependent perturbations of tissue homeostasis are also able to trigger pro-metastatic conditioning. We argue that a more holistic view of the processes catalysing metastatic progression is needed to identify preventive or therapeutic opportunities.
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Affiliation(s)
- Nicolas Rabas
- Tumour-Host Interaction Laboratory, The Francis Crick Institute, London, UK
| | - Rute M M Ferreira
- Tumour-Host Interaction Laboratory, The Francis Crick Institute, London, UK
| | - Stefania Di Blasio
- Tumour-Host Interaction Laboratory, The Francis Crick Institute, London, UK
| | - Ilaria Malanchi
- Tumour-Host Interaction Laboratory, The Francis Crick Institute, London, UK.
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Hao X, Li P, Wang Y, Zhang Q, Yang F. Mesenchymal Stem Cell-Exosomal miR-99a Attenuate Silica-Induced Lung Fibrosis by Inhibiting Pulmonary Fibroblast Transdifferentiation. Int J Mol Sci 2024; 25:12626. [PMID: 39684337 DOI: 10.3390/ijms252312626] [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: 10/02/2024] [Revised: 11/15/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
Silicosis is one of the most prevalent and fatal occupational diseases worldwide, with unsatisfactory clinical outcomes. This study aimed to investigate the therapeutic effect and related molecular mechanisms of how mesenchymal stem cell (MSC)-secreted exosomes alleviate SiO2-induced pulmonary fibrosis. miR-99a-5p was significantly downregulated in silicosis models via high-throughput miRNA screening, and was overlapped with miRNAs in exosomes from MSCs. miR-99a-5p was significantly downregulated in the lung of a mice silicosis model and in TGFβ1-induced NIH-3T3 cells. In contrast, fibroblast growth factor receptor 3 (FGFR3), a direct target gene of miR-99a-5p, was upregulated in vitro and in vivo. Furthermore, we demonstrated that MSC-derived exosomes deliver enriched miR-99a-5p to target cells and inhibit TGF-β1-induced fibroblast transdifferentiation to reduce collagen protein production. Similarly, in a silicosis mouse model, MSC-derived exosome treatment through the tail veins of the mice counteracted the upregulation of fibrosis-related proteins and collagen deposition in the lung of the mice. By constructing exosomal therapeutic cell models with different miR-99a expressions, we further demonstrated that miR-99a-5p might attenuate pulmonary fibrosis by regulating target protein FGFR3 and downstream mitogen-activated protein kinase (MAPK) signalling pathways. Our study demonstrated that MSC-derived exosomes ameliorate SiO2-induced pulmonary fibrosis by inhibiting fibroblast transdifferentiation and represent an attractive method of pulmonary fibrosis treatment.
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Affiliation(s)
- Xiaohui Hao
- School of Public Health, North China University of Science and Technology, Tangshan 063210, China
- Hebei Key Laboratory of Organ Fibrosis, North China University of Science and Technology, Tangshan 063210, China
- Hebei Coordinated Innovation Center of Occupational Health and Safety, North China University of Science and Technology, Tangshan 063210, China
| | - Peiyuan Li
- School of Public Health, North China University of Science and Technology, Tangshan 063210, China
| | - Yudi Wang
- School of Public Health, North China University of Science and Technology, Tangshan 063210, China
| | - Qinxin Zhang
- School of Public Health, North China University of Science and Technology, Tangshan 063210, China
| | - Fang Yang
- School of Public Health, North China University of Science and Technology, Tangshan 063210, China
- Hebei Key Laboratory of Organ Fibrosis, North China University of Science and Technology, Tangshan 063210, China
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Zhu C, Liao JY, Liu YY, Chen ZY, Chang RZ, Chen XP, Zhang BX, Liang JN. Immune dynamics shaping pre-metastatic and metastatic niches in liver metastases: from molecular mechanisms to therapeutic strategies. Mol Cancer 2024; 23:254. [PMID: 39543660 PMCID: PMC11562679 DOI: 10.1186/s12943-024-02171-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 11/06/2024] [Indexed: 11/17/2024] Open
Abstract
Liver metastases are commonly detected in the advanced stages of various malignant tumors, representing a significant clinical challenge. Throughout the process of liver metastases formation, immune cells play a pivotal role, particularly in the pre-metastatic and metastatic niches within the liver. Immune cells establish extensive and intricate interactions with tumor cells and other components in the liver, collectively promoting and sustaining the growth of liver metastases. Despite the limited efficacy of existing therapeutic modalities against some advanced liver metastases, novel immune-based treatment approaches are continuously being explored and validated. Building on the systematic elucidation of the immunosuppressive characteristics of liver metastases, we explored the potential of novel immunotherapies applicable to patients with liver metastases from multiple dimensions.
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Affiliation(s)
- Chang Zhu
- Hepatic Surgery Center, and Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Jing-Yu Liao
- Hepatic Surgery Center, and Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Yi-Yang Liu
- Hepatic Surgery Center, and Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Ze-Yu Chen
- Hepatic Surgery Center, and Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Rui-Zhi Chang
- Hepatic Surgery Center, and Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Xiao-Ping Chen
- Hepatic Surgery Center, and Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Bi-Xiang Zhang
- Hepatic Surgery Center, and Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.
| | - Jun-Nan Liang
- Hepatic Surgery Center, and Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.
- Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.
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Cao L, Sun K, Zeng R, Yang H. Adipose-derived stem cell exosomal miR-21-5p enhances angiogenesis in endothelial progenitor cells to promote bone repair via the NOTCH1/DLL4/VEGFA signaling pathway. J Transl Med 2024; 22:1009. [PMID: 39516839 PMCID: PMC11549876 DOI: 10.1186/s12967-024-05806-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Angiogenesis is essential for repairing critical-sized bone defects. Although adipose-derived stem cell (ADSC)-derived exosomes have been shown to enhance the angiogenesis of endothelial progenitor cells (EPCs), the underlying mechanisms remain unclear. This study aims to explore the effects and mechanisms of ADSC-derived exosomes in enhancing bone repair by promoting EPC angiogenesis. METHODS Transmission electron microscopy, nanoparticle tracking analysis, and Dil reagent kit were employed to identify ADSC-derived exosomes and their internalization by EPCs. Micro-CT analysis, H&E staining, and Masson staining were used to assess bone mineral density (BMD), bone volume fraction (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N), as well as the pathological changes and fibrosis at defect sites. Cell viability, migration, invasion, and tube formation of EPCs were evaluated using CCK-8, wound healing, Transwell, and tube formation assays. Immunohistochemical staining, RT-PCR, and Western blotting were utilized to measure the gene and protein expression of markers such as CD31, VEGFA, OCN, RUNX2, NOTCH1, and DLL4. Gene sequencing and bioinformatics analyses were conducted to identify the most highly expressed miRNA in exosomes, while miRDB and dual-luciferase reporter assays were used to explore the interaction between miR-21-5p and NOTCH1. RESULTS The ADSC-derived exosomes, averaging 126 nm in diameter, were internalized by EPCs. In vivo, these exosomes promoted new bone formation, increased BMD, BV/TV, Tb.Th, and Tb.N, reduced pathological damage to cranial defect tissues, enhanced vascular and bone tissue regeneration, and upregulated OCN and RUNX2 expression. In vitro, ADSC-derived exosomes enhanced EPC viability, migration, invasion, and tube formation. Both in vivo and in vitro experiments demonstrated that ADSC-derived exosomes upregulated CD31 and VEGFA expression. miR-21-5p, the most highly expressed miRNA in ADSC-derived exosomes, was found to target NOTCH1. Overexpression of miR-21-5p in these exosomes facilitated EPC migration, tube formation, and VEGFA expression while downregulating NOTCH1 and DLL4 expression. Inhibition of miR-21-5p produced opposite effects on EPCs. CONCLUSIONS These findings indicate that miR-21-5p in ADSC-derived exosomes promotes angiogenesis in EPCs to accelerate bone repair by targeting the NOTCH1/DLL4/VEGFA signaling pathway, offering a potential therapeutic strategy for bone defect treatment.
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Affiliation(s)
- Le Cao
- Department of Orthopaedics, Fuyang Hospital of Anhui Medical University, Fuyang, 236000, China
| | - Kai Sun
- Department of Orthopaedics, Fuyang Hospital of Anhui Medical University, Fuyang, 236000, China
| | - Ran Zeng
- Department of Intensive Care Unit, Fuyang Hospital of Anhui Medical University, Fuyang, 236000, China
| | - Haitao Yang
- Department of Orthopaedics, Fuyang Hospital of Anhui Medical University, Fuyang, 236000, China.
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Dong D, Yu X, Xu J, Yu N, Liu Z, Sun Y. Cellular and molecular mechanisms of gastrointestinal cancer liver metastases and drug resistance. Drug Resist Updat 2024; 77:101125. [PMID: 39173439 DOI: 10.1016/j.drup.2024.101125] [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: 04/20/2024] [Revised: 07/30/2024] [Accepted: 08/05/2024] [Indexed: 08/24/2024]
Abstract
Distant metastases and drug resistance account for poor survival of patients with gastrointestinal (GI) malignancies such as gastric cancer, pancreatic cancer, and colorectal cancer. GI cancers most commonly metastasize to the liver, which provides a unique immunosuppressive tumour microenvironment to support the development of a premetastatic niche for tumor cell colonization and metastatic outgrowth. Metastatic tumors often exhibit greater resistance to drugs than primary tumors, posing extra challenges in treatment. The liver metastases and drug resistance of GI cancers are regulated by complex, intertwined, and tumor-dependent cellular and molecular mechanisms that influence tumor cell behavior (e.g. epithelial-to-mesenchymal transition, or EMT), tumor microenvironment (TME) (e.g. the extracellular matrix, cancer-associated fibroblasts, and tumor-infiltrating immune cells), tumor cell-TME interactions (e.g. through cytokines and exosomes), liver microenvironment (e.g. hepatic stellate cells and macrophages), and the route and mechanism of tumor cell dissemination (e.g. circulating tumor cells). This review provides an overview of recent advances in the research on cellular and molecular mechanisms that regulate liver metastases and drug resistance of GI cancers. We also discuss recent advances in the development of mechanism-based therapy for these GI cancers. Targeting these cellular and molecular mechanisms, either alone or in combination, may potentially provide novel approaches to treat metastatic GI malignancies.
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Affiliation(s)
- Daosong Dong
- Department of Pain, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Xue Yu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Key Laboratory of Molecular Pathology and Epidemiology of Gastric Cancer in the Universities of Liaoning Province, Shenyang, Liaoning 110001, China
| | - Jingjing Xu
- Department of Rheumatology and Immunology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Na Yu
- Department of Pulmonary and Critical Care Medicine, Institute of Respiratory Disease, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Zhe Liu
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
| | - Yanbin Sun
- Department of Thoracic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
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Feng H, Liang L, Deng W, Gao J, Li X, Guan F. Sialyl Lewis X decorated integrin α3 on small extracellular vesicles promotes metastasis of bladder cancer via enhancing vascular permeability. Angiogenesis 2024; 27:883-901. [PMID: 39222273 DOI: 10.1007/s10456-024-09947-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024]
Abstract
The permeability of blood vessels plays a crucial role in the spread of cancer cells, facilitating their metastasis at distant sites. Small extracellular vesicles (sEVs) are known to contribute to the metastasis of various cancers by crossing the blood vessel wall. However, the role of abnormal glycoconjugates on sEVs in tumor blood vessels remains unclear. Our study found elevated levels of fucosyltransferase VII (FUT7) and its product sialyl Lewis X (sLeX) in muscle-invasive bladder cancer (BLCA), with high levels of sLeX promoting the growth and invasion of BLCA cells. Further investigation revealed that sLeX was enriched in sEVs derived from BLCA. sLeX-decorated sEVs increased blood vessel permeability by disrupting the tight junctions of human umbilical vein endothelial cells (HUVECs). Using the glycoproteomics approach, we identified integrin α3 (ITGA3) as a sLeX-bearing glycoprotein in BLCA cells and their sEVs. Mechanically, sLeX modification stabilized ITGA3 by preventing its degradation in lysosomes. sEVs carrying sLeX-modified ITGA3 can be effectively internalized by HUVECs, leading to a decrease in the expression of tight junction protein. Conversely, silencing ITGA3 in sLeX-decorated sEVs restored tight junction proteins and reduced blood vessel permeability by inhibiting the MAPK pathway. Moreover, sLeX-modification of ITGA3 at Asn 265 in HUVECs promoted occludin dephosphorylation at Ser/Thr residues, followed by inducing its importin α1-mediated nuclear translocation, which resulted in the disruption of tight junctions. Our findings suggest a potential strategy for disrupting the formation of a metastatic microenvironment and preventing the spread of malignant bladder cancer.
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Affiliation(s)
- Hui Feng
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, 710069, People's Republic of China
| | - Liang Liang
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, People's Republic of China
| | - Wenli Deng
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, 710069, People's Republic of China
| | - Jiaojiao Gao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, 710069, People's Republic of China
| | - Xiang Li
- Institute of Hematology, School of Medicine, Northwest University, Xi'an, 710069, People's Republic of China
| | - Feng Guan
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, 710069, People's Republic of China.
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Gao B, Wang L, Wen T, Xie X, Rui X, Chen Q. Colon Cancer-Derived Exosomal LncRNA-XIST Promotes M2-like Macrophage Polarization by Regulating PDGFRA. Int J Mol Sci 2024; 25:11433. [PMID: 39518984 PMCID: PMC11545876 DOI: 10.3390/ijms252111433] [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: 08/01/2024] [Revised: 10/08/2024] [Accepted: 10/12/2024] [Indexed: 11/16/2024] Open
Abstract
Colon cancer ranks second in overall cancer-related deaths and poses a serious risk to human life and health. In recent years, exosomes are believed to play an important and significant role in cancer, especially tumor-derived exosomes (TDEs). Previous studies have highlighted the pivotal role of exosomes in tumor development, owing to their ability to mediate communication between tumor cells and macrophages, induce macrophage M2 polarization, and facilitate the progression of tumorigenesis. In this study, we revealed that colon cancer-derived exosomes promoted M2-like macrophage polarization. Moreover, exosome-induced M2-like macrophages, in turn, promoted the proliferation, migration, and invasion abilities of colon cancer cells. Specifically, CT26- and HCT116-derived exosomes led to the activation of AKT, ERK, and STAT3/6 signaling pathways in THP-1(Mφ) cells. Furthermore, our findings showed that colon cancer-derived exosomes secreted lncXIST to sponge miR-17-5p, which, in turn, promoted the expression of PDGFRA, a common gene found in all three signaling pathways, to facilitate M2-like macrophage polarization. Dual-luciferase reporter assays confirmed the binding relationship between lncXIST and miR-17-5p, as well as miR-17-5p and PDGFRA. Collectively, our results highlight the novel role of lncXIST in facilitating macrophage polarization by sponging miR-17-5p and regulating PDGFRA expression.
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Affiliation(s)
| | | | | | | | | | - Qiaoyi Chen
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an 710049, China; (B.G.); (L.W.); (T.W.); (X.X.); (X.R.)
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49
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Zhang Y, Zhang C, Wu N, Feng Y, Wang J, Ma L, Chen Y. The role of exosomes in liver cancer: comprehensive insights from biological function to therapeutic applications. Front Immunol 2024; 15:1473030. [PMID: 39497820 PMCID: PMC11532175 DOI: 10.3389/fimmu.2024.1473030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 09/24/2024] [Indexed: 11/07/2024] Open
Abstract
In recent years, cancer, especially primary liver cancer (including hepatocellular carcinoma and intrahepatic cholangiocarcinoma), has posed a serious threat to human health. In the field of liver cancer, exosomes play an important role in liver cancer initiation, metastasis and interaction with the tumor microenvironment. Exosomes are a class of nanoscale extracellular vesicles (EVs)secreted by most cells and rich in bioactive molecules, including RNA, proteins and lipids, that mediate intercellular communication during physiological and pathological processes. This review reviews the multiple roles of exosomes in liver cancer, including the initiation, progression, and metastasis of liver cancer, as well as their effects on angiogenesis, epithelial-mesenchymal transformation (EMT), immune evasion, and drug resistance. Exosomes have great potential as biomarkers for liver cancer diagnosis and prognosis because they carry specific molecular markers that facilitate early detection and evaluation of treatment outcomes. In addition, exosomes, as a new type of drug delivery vector, have unique advantages in the targeted therapy of liver cancer and provide a new strategy for the treatment of liver cancer. The challenges and prospects of exosome-based immunotherapy in the treatment of liver cancer were also discussed. However, challenges such as the standardization of isolation techniques and the scalability of therapeutic applications remain significant hurdles.
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Affiliation(s)
- Yinghui Zhang
- College of Rehabilitation Medicine, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Congcong Zhang
- College of Rehabilitation Medicine, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Nan Wu
- College of Rehabilitation Medicine, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Yuan Feng
- College of Rehabilitation Medicine, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Jiayi Wang
- College of Rehabilitation Medicine, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
| | - Liangliang Ma
- Rehabilitation Center, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yulong Chen
- College of Rehabilitation Medicine, Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, China
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50
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Xue Z, Liu J, Xing W, Mu F, Wu Y, Zhao J, Liu X, Wang D, Wang J, Li X, Wang J, Huang B. Hypoxic glioma-derived exosomal miR-25-3p promotes macrophage M2 polarization by activating the PI3K-AKT-mTOR signaling pathway. J Nanobiotechnology 2024; 22:628. [PMID: 39407269 PMCID: PMC11481566 DOI: 10.1186/s12951-024-02888-5] [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: 04/28/2024] [Accepted: 09/30/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND Exosomes (EXO) play crucial roles in intercellular communication and glioma microenvironment modulation. Tumor-associated macrophages are more likely to become M2-like type macrophages in the immunosuppressive microenvironment. Here, we aimed to investigate the effects and molecular mechanisms of hypoxic glioma-derived exosomes mediated M2-like macrophage polarization. METHODS Highly expressed miRNAs in exosomes derived from glioma cells cultured under hypoxia condition compared to normoxic condition were identified through microRNA sequencing. The polarization status of macrophages was determined using qRT-PCR, Western blotting, flow cytometry, and immunohistochemistry. By using RNA-seq, we aimed to identify the downstream target genes regulated by miR-25-3p in macrophages and investigate the mechanistic pathways through which it exerts its effects. The proliferation and migration capabilities of glioma cells were assessed through EdU, Transwell assays, and in vivo experiments. RESULTS We found that miR-25-3p was upregulated in the exosomes derived from hypoxic glioma cells and can be transferred to the macrophage. In macrophages, miR-25-3p downregulates the expression of PHLPP2, thereby activating the PI3K-AKT-mTOR signaling pathway, ultimately leading to macrophage M2 polarization. As part of a feedback loop, M2-polarized macrophages can, in turn, promote malignant glioma progression. CONCLUSION Our study reveals that miR-25-3p from hypoxic glioma cells is delivered to macrophages via exosomes as a mediator, promoting M2 polarization of macrophages through the miR-25-3p/PHLPP2/PI3K-AKT signaling pathway. This study suggests that targeted interventions to modulate miR-25-3p expression, transmission, or inhibition of PI3K-AKT pathway activation can disrupt the immune-suppressive microenvironment, providing a novel approach for immunotherapy in gliomas.
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Affiliation(s)
- Zhiwei Xue
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
| | - Junzhi Liu
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
| | - Wenchen Xing
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
| | - Feiyu Mu
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
| | - Yanzhao Wu
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
| | - Jiangli Zhao
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
| | - Xuchen Liu
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
| | - Donghai Wang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Department of Neurosurgery, Qilu Hospital of Shandong University Dezhou Hospital, Dezhou, China
| | - Jian Wang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, Bergen, 5009, Norway
| | - Xingang Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China.
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Health and Function Remodeling, Jinan, China.
| | - Jiwei Wang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China.
| | - Bin Huang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China.
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Health and Function Remodeling, Jinan, China.
- Department of Neurosurgery, Qilu Hospital of Shandong University Dezhou Hospital, Dezhou, China.
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