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Zhou M, Li R, Lian G, Yang M, Li L, Yin Z, Li G, Zhao J, Tan R. Tetrahydrocurcumin alleviates colorectal tumorigenesis by modulating the SPP1/CD44 axis and preventing M2 tumor-associated macrophage polarization. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 141:156674. [PMID: 40220425 DOI: 10.1016/j.phymed.2025.156674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/13/2025] [Accepted: 03/19/2025] [Indexed: 04/14/2025]
Abstract
BACKGROUND Recent studies show that secreted phosphoprotein 1 (SPP1) is linked to the progression of various cancers, including colorectal cancer (CRC). SPP1 also promotes M2 macrophage polarization, contributing to immune evasion in the tumor microenvironment. Tetrahydrocurcumin (THC) has been reported to alleviate CRC, but the mechanism remains unclear. PURPOSE The study aimed to explore how THC modulated the SPP1/CD44 axis to inhibit M2 polarization and suppress CRC development. METHODS Azoxymethane/dextran sulfate sodium (AOM/DSS)-induced mouse model was used to assess the anti-CRC effects of THC. Transcriptome sequencing was conducted to identify the key targets of THC in CRC. The effects of THC on CRC cells were evaluated by CCK-8, colony formation, migration assays, immunofluorescence staining and flow cytometry. Human monocytic cells, THP-1, and colon cancer cell line, HCT116, were co-cultured, both directly or indirectly, to mimic the tumor-macrophage interactions, and investigate the role of SPP1/CD44 axis and the intervention effect of THC. RESULTS THC significantly inhibited CRC carcinogenesis in mice and improved pathologic symptoms, serum inflammatory markers, and intestinal barrier integrity. THC inhibited CRC cell proliferation, migration and colony formation, while promoting apoptosis. Transcriptome analysis identified SPP1 as a key target of THC against CRC. SPP1 facilitated CRC progression by activating the ERK signaling pathway and maintaining the M2-like phenotype of macrophage, which further exacerbated this response. THC inhibited CRC development by targeting the SPP1/CD44 axis, rather than the integrin pathway. CONCLUSIONS SPP1 played a crucial role in maintaining the M2 phenotype of macrophage and promoting CRC cells proliferation. THC inhibited the activation of ERK signals in CRC cells and phenotypic transformation of M2-like macrophages through the SPP1/CD44 axis, thereby regulating the tumor immune microenvironment to exert anti-CRC effect.
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Affiliation(s)
- Mengting Zhou
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Translational Chinese Medicine Key Laboratory of Sichuan, Sichuan-Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese Medicine, Sichuan Institute for Translational Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610041, China; Translational Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Rui Li
- Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610000, China.
| | - Guiyun Lian
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
| | - Mengni Yang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Translational Chinese Medicine Key Laboratory of Sichuan, Sichuan-Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese Medicine, Sichuan Institute for Translational Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610041, China; Translational Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Li Li
- Translational Chinese Medicine Key Laboratory of Sichuan, Sichuan-Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese Medicine, Sichuan Institute for Translational Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610041, China
| | - Zhujun Yin
- Translational Chinese Medicine Key Laboratory of Sichuan, Sichuan-Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese Medicine, Sichuan Institute for Translational Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610041, China
| | - Guiyu Li
- Translational Chinese Medicine Key Laboratory of Sichuan, Sichuan-Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese Medicine, Sichuan Institute for Translational Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610041, China
| | - Junning Zhao
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Translational Chinese Medicine Key Laboratory of Sichuan, Sichuan-Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese Medicine, Sichuan Institute for Translational Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610041, China; National Key Laboratory of Drug Regulatory Science, National Medical Products Administration (NMPA), Beijing 100038, China; National Center for Nanoscience and Technology, Beijing 100190, China.
| | - Ruirong Tan
- Translational Chinese Medicine Key Laboratory of Sichuan, Sichuan-Chongqing Joint Key Laboratory of Innovation of New Drugs of Traditional Chinese Medicine, Sichuan Institute for Translational Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610041, China; Translational Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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Yang Y, Li S, To KKW, Zhu S, Wang F, Fu L. Tumor-associated macrophages remodel the suppressive tumor immune microenvironment and targeted therapy for immunotherapy. J Exp Clin Cancer Res 2025; 44:145. [PMID: 40380196 DOI: 10.1186/s13046-025-03377-9] [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: 01/17/2025] [Accepted: 03/27/2025] [Indexed: 05/19/2025] Open
Abstract
Despite the significant advances in the development of immune checkpoint inhibitors (ICI), primary and acquired ICI resistance remains the primary impediment to effective cancer immunotherapy. Residing in the tumor microenvironment (TME), tumor-associated macrophages (TAMs) play a pivotal role in tumor progression by regulating diverse signaling pathways. Notably, accumulating evidence has confirmed that TAMs interplay with various cellular components within the TME directly or indirectly to maintain the dynamic balance of the M1/M2 ratio and shape an immunosuppressive TME, consequently conferring immune evasion and immunotherapy tolerance. Detailed investigation of the communication network around TAMs could provide potential molecular targets and optimize ICI therapies. In this review, we systematically summarize the latest advances in understanding the origin and functional plasticity of TAMs, with a focus on the key signaling pathways driving macrophage polarization and the diverse stimuli that regulate this dynamic process. Moreover, we elaborate on the intricate interplay between TAMs and other cellular constituents within the TME, that is driving tumor initiation, progression and immune evasion, exploring novel targets for cancer immunotherapy. We further discuss current challenges and future research directions, emphasizing the need to decode TAM-TME interactions and translate preclinical findings into clinical breakthroughs. In conclusion, while TAM-targeted therapies hold significant promise for enhancing immunotherapy outcomes, addressing key challenges-such as TAM heterogeneity, context-dependent plasticity, and therapeutic resistance-remains critical to achieving optimal clinical efficacy.
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Affiliation(s)
- Yan Yang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Sijia Li
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Kenneth K W To
- School of Pharmacy, The Chinese University of Hong Kong, Hong Kong, 999077, P.R. China
| | - Shuangli Zhu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Fang Wang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China
| | - Liwu Fu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
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Zhou Z, Li Y, Wu D, Xiao Y, Zeng S, Xiao Q, Chen S, Ma J, Yuan X, Chen J, Peng H. Presence of LILRB4 SNP rs1048801 modulates acute myeloid leukemia progression and inhibits CD4+ T cells proliferation. J Leukoc Biol 2025; 117:qiaf052. [PMID: 40275747 DOI: 10.1093/jleuko/qiaf052] [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: 12/06/2024] [Revised: 02/28/2025] [Accepted: 04/24/2025] [Indexed: 04/26/2025] Open
Abstract
Leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4), an emerging immune checkpoint molecule, exhibits therapeutic potential in acute myeloid leukemia (AML). While single nucleotide polymorphisms (SNPs) of immune checkpoint genes have been extensively investigated in AML, the association between LILRB4 genetic polymorphisms and clinical outcomes remains unexplored. We investigated SNPs within the LILRB4 immunoglobulin domain and immunoreceptor tyrosine-based inhibitory motif regions in 151 AML patients and 203 controls. The rs1048801 G allele was significantly associated with increased LILRB4 mRNA expression, higher disease susceptibility, and reduced overall survival. Functional studies revealed that the G allele enhanced AML cell proliferation and colony formation. Furthermore, protein-protein interaction network analysis identified CD4 as a pivotal downstream mediator of LILRB4. Flow cytometry revealed elevated LILRB4 expression in CD45+ leukocytes and CD45+ CD33+ CD14+ monocytic AML cells from G allele carriers, concomitant with reduced CD3+ CD4+ T cell populations and impaired proliferation. Collectively, these findings establish rs1048801 as a critical modulator of AML progression through LILRB4-mediated CD4+ T cell suppression, providing new insights for personalized therapeutic strategies.
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Affiliation(s)
- Zhiyong Zhou
- Center for Molecular Diagnosis and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang 330209, China
- Jiangxi Provincial Center for Advanced Diagnostic Technology and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang 330209, China
| | - Yi Li
- Center for Molecular Diagnosis and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang 330209, China
| | - Di Wu
- Center for Molecular Diagnosis and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang 330209, China
| | - Yiliang Xiao
- Center for Molecular Diagnosis and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang 330209, China
- Jiangxi Provincial Center for Advanced Diagnostic Technology and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang 330209, China
| | - Shuyan Zeng
- Center for Molecular Diagnosis and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang 330209, China
- Huankui Academy, Nanchang University, Nanchang, 1519 Dongyue Dadao, Nanchang 330209, China
| | - Qiuyun Xiao
- Center for Molecular Diagnosis and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang 330209, China
- Jiangxi Provincial Center for Advanced Diagnostic Technology and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang 330209, China
| | - Siqi Chen
- Center for Molecular Diagnosis and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang 330209, China
| | - Junpeng Ma
- Center for Molecular Diagnosis and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang 330209, China
- Jiangxi Provincial Center for Advanced Diagnostic Technology and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang 330209, China
| | - Xin Yuan
- Center for Molecular Diagnosis and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang 330209, China
- Jiangxi Provincial Center for Advanced Diagnostic Technology and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang 330209, China
| | - Jin Chen
- Center for Molecular Diagnosis and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang 330209, China
- Jiangxi Provincial Center for Advanced Diagnostic Technology and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang 330209, China
| | - Huiyun Peng
- Center for Molecular Diagnosis and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang 330209, China
- Jiangxi Provincial Center for Advanced Diagnostic Technology and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang 330209, China
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Wang S, Zou F, Xu M, Wu Z, Xia P, Deng F. The YAP/TEAD4 transcriptional complex in intestinal macrophages promotes M2 polarization and alleviates DSS-induced colitis via the regulation of C/EBPβ. Sci Rep 2025; 15:11796. [PMID: 40189621 PMCID: PMC11973227 DOI: 10.1038/s41598-025-95933-8] [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: 11/30/2024] [Accepted: 03/25/2025] [Indexed: 04/09/2025] Open
Abstract
Suppressing inflammation and promoting intestinal epithelial regeneration are the keys to mucosal healing in individuals with ulcerative colitis (UC). The upregulation of epithelial YAP and the induction of macrophages to polarize to the M2 phenotype in the mucosa can promote intestinal epithelial regeneration and alleviate ulcerative colitis. However, the role of YAP in macrophage polarization remains unclear. Here, we explored the effects of YAP on macrophage polarization and its biological role in a mouse DSS-induced colitis model. The results showed that YAP upregulation in macrophages could induce M2 polarization and increase the levels of anti-inflammatory cytokines such as IL-10 and IL-13. In addition, when mice were infused with YAP-overexpressing and empty vector-transfected macrophages, compared with control mice, YAP-overexpressing mice presented slower weight loss, a longer colon length, less intestinal inflammation, and a better arrangement of crypts. Moreover, macrophages in the lamina propria of the mouse colonic mucosa presented mainly the M2 phenotype in YAP-overexpressing macrophage-infused DSS-treated mice. Mechanistically, knockdown of the expression of the transcription factor TEAD4 in YAP-overexpressing macrophages inhibited macrophage M2 polarization and decreased anti-inflammatory cytokine expression, accompanied by the downregulated expression of C/EBPβ. Furthermore, silencing C/EBPβ following YAP overexpression suppressed M2 polarization. Chromatin immunoprecipitation revealed that TEAD4 was enriched at the C/EBPβ promoter region in YAP-overexpressing macrophages. Thus, YAP in macrophages regulates C/EBPβ expression through the transcription factor TEAD4, which mediates macrophage M2 polarization and inhibits the expression of inflammatory cytokines, thereby exerting inhibitory effects on intestinal inflammation and promoting mucosal healing in a colitis model.
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Affiliation(s)
- Su Wang
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, 410011, Hunan, China
- Clinical Research Center for Digestive Diseases in Hunan Province, Changsha, 410011, Hunan, China
| | - Fei Zou
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, 410011, Hunan, China
- Clinical Research Center for Digestive Diseases in Hunan Province, Changsha, 410011, Hunan, China
| | - Mengmeng Xu
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, 410011, Hunan, China
- Clinical Research Center for Digestive Diseases in Hunan Province, Changsha, 410011, Hunan, China
| | - Zengrong Wu
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, 410011, Hunan, China
- Clinical Research Center for Digestive Diseases in Hunan Province, Changsha, 410011, Hunan, China
| | - Pianpian Xia
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Research Center of Digestive Disease, Central South University, Changsha, 410011, Hunan, China
- Clinical Research Center for Digestive Diseases in Hunan Province, Changsha, 410011, Hunan, China
| | - Feihong Deng
- Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
- Research Center of Digestive Disease, Central South University, Changsha, 410011, Hunan, China.
- Clinical Research Center for Digestive Diseases in Hunan Province, Changsha, 410011, Hunan, China.
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Meyiah A, Khan FI, Alfaki DA, Murshed K, Raza A, Elkord E. The colorectal cancer microenvironment: Preclinical progress in identifying targets for cancer therapy. Transl Oncol 2025; 53:102307. [PMID: 39904281 PMCID: PMC11846588 DOI: 10.1016/j.tranon.2025.102307] [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: 11/06/2024] [Revised: 01/29/2025] [Accepted: 01/30/2025] [Indexed: 02/06/2025] Open
Abstract
Colorectal cancer (CRC) is a common cancer with high mortality rates. Despite progress in treatment, it remains an incurable disease for many patients. In CRC, the tumor microenvironment (TME) plays critical roles in tumor growth, progression, patients' prognosis, and response to treatments. Understanding TME complexities is important for developing effective therapies. In vitro and in vivo preclinical models are critical in understanding the disease, discovering potential targets, and developing effective therapeutics. In this review, we focus on preclinical research studies associated with modulation of the TME in CRC. These models give insights into understanding the role of stroma and immune cell components of the TME in CRC and improve clinical responses, providing insights in novel treatment options. Various studies have focused on targeting the TME in CRC to improve responses to different therapeutic approaches. These include identifying targets for cancer therapies, targeting molecular signaling, and enhancing the efficacy of immunotherapeutic modalities. Furthermore, targeting stromal and angiogenic factors in the TME may provide new therapeutic options. Overall, understanding and targeting the TME in CRC is a promising approach for improving therapeutic outcomes.
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Affiliation(s)
- Abdo Meyiah
- Department of Biosciences and Bioinformatics & Suzhou Municipal Key Lab of Biomedical Sciences and Translational Immunology, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Faez Iqbal Khan
- Department of Biosciences and Bioinformatics & Suzhou Municipal Key Lab of Biomedical Sciences and Translational Immunology, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Dia Aldeen Alfaki
- Department of Haematology, Al-Zaeim Al-Azhari University, Khartoum, Sudan
| | - Khaled Murshed
- Department of Pathology, Hamad Medical Corporation, Doha, Qatar
| | - Afsheen Raza
- College of Health Sciences, Abu Dhabi University, Abu Dhabi, United Arab Emirates
| | - Eyad Elkord
- Department of Biosciences and Bioinformatics & Suzhou Municipal Key Lab of Biomedical Sciences and Translational Immunology, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China; College of Health Sciences, Abu Dhabi University, Abu Dhabi, United Arab Emirates; Biomedical Research Center, School of Science, Engineering and Environment, University of Salford, Manchester, UK.
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Zhang W, Li K, Jian A, Zhang G, Zhang X. Prospects for potential therapy targeting immune‑associated factors in endometriosis (Review). Mol Med Rep 2025; 31:57. [PMID: 39717957 PMCID: PMC11715623 DOI: 10.3892/mmr.2024.13422] [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: 09/27/2024] [Accepted: 12/03/2024] [Indexed: 12/25/2024] Open
Abstract
Endometriosis (EM) is a chronic inflammatory disease that is one of the most common causes of gynecological systemic lesions in women before menopause. The most representative histological feature of EM is that the endometrium appears outside of the uterine cavity, often in the ovary. Although it is generally accepted that the epithelial and stromal cells of the ectopic endometrium are not malignant, they still have numerous similarities to malignant tumors, including considerable changes to the immune microenvironment (immune monitoring disorder), the creation of a specific hormone environment, high levels of oxidative stress, chronic inflammation and abnormal immune cell regulation. The pathogenesis of EM is not fully understood, which makes it difficult to identify specific biomarkers and potential therapeutic targets for early disease diagnosis and effective treatment. However, considerable progress has been made in this field over the past few decades. The purpose of the present review is to summarize the confirmed and potential biomarkers for EM, and to identify potential therapeutic targets based on changes in immunological factors (including natural killer cells, macrophages, the complement system, miRNA and P‑selectin) in the ectopic endometrial tissue. It is hoped that this work can be used as the basis for identifying accurate diagnostic markers for EM and developing personalized immune‑targeted therapy.
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Affiliation(s)
- Wenwen Zhang
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Kang Li
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Aiwen Jian
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Guanran Zhang
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Xiaoli Zhang
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China
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Li M, Tian Y, Si L, Fu H, Lai T, Guo R. OTUD4-mediated inhibition of YAP1 signaling pathway in ovarian cancer: Implications for macrophage polarization and recruitment. Int Immunopharmacol 2025; 147:114011. [PMID: 39778277 DOI: 10.1016/j.intimp.2024.114011] [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: 09/29/2024] [Revised: 12/26/2024] [Accepted: 12/31/2024] [Indexed: 01/11/2025]
Abstract
Ovarian cancer is a malignancy gynecologic oncology with high incidence and high mortality rate. M2-like tumor-associated macrophages promote cancer cell migration and metastasis. Ovarian tumor family deubiquitinase 4 (OTUD4) belongs to deubiquitinating enzyme family. The roles of OTUD4 in tumor microenvironments in ovarian cancer remains unknow. In this work, OTUD4 was overexpressed or knocked down in high-grade serous ovarian cancer cells OVCAR8 and CAOV3. Ovarian cells were co-cultured with THP-1 macrophages to simulate the tumor microenvironment. We found that OTUD4-expressed ovarian cells inhibited macrophage chemotaxis and M2 polarization. Besides, in ovarian tumor-bearing mouse model, OTUD4 suppressed tumor metastasis and remodeling tumor-associated macrophages phenotype (pro-tumor M2 to anti-tumor M1). In mechanism, OTUD4 protein bound to YAP1 protein, and downregulation of OTUD4 enhanced K63 ubiquitination and nuclear translocation of YAP1, thus increasing CCL2 transcription and subsequent macrophage recruitment. OTUD4 might inhibit CCL2 expression to regulate tumor-associated macrophages in ovarian tumor microenvironment. Those findings present a potential therapeutic strategy for ovarian cancer.
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Affiliation(s)
- Mingyue Li
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological Tumor, Zhengzhou, Henan Province, China
| | - Yanpeng Tian
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological Tumor, Zhengzhou, Henan Province, China
| | - Lulu Si
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological Tumor, Zhengzhou, Henan Province, China
| | - Hanlin Fu
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological Tumor, Zhengzhou, Henan Province, China
| | - Tianjiao Lai
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological Tumor, Zhengzhou, Henan Province, China
| | - Ruixia Guo
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological Tumor, Zhengzhou, Henan Province, China.
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Saadh MJ, Ghnim ZS, Mahdi MS, Chandra M, Ballal S, Bareja L, Chaudhary K, Sharma RSK, Gupta S, Taher WM, Alwan M, Jawad MJ, Hamad AK. Decoding the Role of Kinesin Superfamily Proteins in Glioma Progression. J Mol Neurosci 2025; 75:10. [PMID: 39847238 DOI: 10.1007/s12031-025-02308-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 01/04/2025] [Indexed: 01/24/2025]
Abstract
Glioma is a highly aggressive and invasive brain tumor with limited treatment options, highlighting the need for novel therapeutic approaches. Kinesin superfamily proteins (KIFs) are a diverse group of motor proteins that play essential roles in cellular processes such as mitosis, intracellular transport, and signal transduction, all of which are crucial for tumorigenesis. This review focuses on the multifaceted role of KIFs in glioma, examining their clinical relevance, contribution to tumor progression, and potential as therapeutic targets. We discuss how KIFs influence key aspects of glioma biology, including cell proliferation, invasion, migration, and metastasis. Furthermore, we explore the regulation of the cell cycle and critical signaling pathways associated with glioma, such as PI3K-Akt, Wnt/β-catenin, and Hedgehog signaling by KIFs. The review also addresses the emerging interplay between KIFs and non-coding RNAs, including circular RNAs (circRNAs) and microRNAs (miRNAs), in glioma progression. Finally, we examine current therapeutic strategies targeting KIFs, including immunotherapy, chemotherapy, and small-molecule inhibitors, and their potential to improve treatment outcomes for glioma patients. By synthesizing these insights, this review underscores the significance of KIFs in glioma pathogenesis and their promise as novel therapeutic targets in the fight against glioma.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan.
| | | | | | - Muktesh Chandra
- Department of Microbiology, Faculty of Science, Marwadi University Research Center, Marwadi University, Rajkot, 360003, Gujarat, India
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Lakshay Bareja
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - Kamlesh Chaudhary
- Department of Neurology, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India
| | - R S K Sharma
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, 531162, India
| | - Sofia Gupta
- Department of Applied Sciences, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India
| | - Waam Mohammed Taher
- College of Nursing, National University of Science and Technology, Dhi Qar, Iraq
| | - Mariem Alwan
- Pharmacy College, Al-Farahidi University, Baghdad, Iraq
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Liu X, Liu D, Tan C, Wang J. Systemic immune profiling analysis identifying M2-TAM related genes predicted colon cancer prognosis and chemotherapy responses. Medicine (Baltimore) 2024; 103:e40979. [PMID: 39969348 PMCID: PMC11688056 DOI: 10.1097/md.0000000000040979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 11/27/2024] [Indexed: 02/20/2025] Open
Abstract
Colon cancer (COAD) poses great challenges to clinical treatment due to its heterogeneity and complex immune microenvironment. M2-like macrophages significantly influence COAD's onset, progression, and treatment. Yet, existing M2-like macrophage markers are limited in prognostic efficacy, prompting the exploration of new M2 signatures. Extensive data analysis aimed to unveil prognosis-associated M2-derived signatures. Bulk transcriptome, single-cell RNA sequencing, and clinical data from The Cancer Genome Atlas and Gene Expression Omnibus databases for patients with COAD were amassed. Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts identified immune cell infiltration, and the Kaplan-Meier test identified crucial immune populations associated with prognosis. Genetic signatures linked to M2 tumor-associated macrophage were crafted utilizing weighted gene coexpression network analysis, least absolute shrinkage and selection operator, and Cox regression. The M2 tumor-associated macrophage gene signature was validated in GSE17536. The expression profile of the M2 gene signature was investigated in single-cell RNA sequencing dataset GSE166555. Systemic immune profile identified that M2-like macrophage has the most significant prognostic significance in The Cancer Genome Atlas-COAD. The core genes related to M2 macrophage infiltration were extracted by weighted gene coexpression network analysis. Least absolute shrinkage and selection operator-stepwise COX regression-derived M2-derived signatures (snail family zinc finger 1, gastrin-releasing peptide, gamma-aminobutyric acid type A receptor delta subunit, cluster of differentiation 1B, poly(A)-binding protein cytoplasmic 2, manic fringe, and death-associated protein kinase 1) as a risk model, which was confirmed as independent prognosis factors, validated by external dataset. This M2-based prognostic model reflected M2 macrophage infiltration. Mendelian randomization established cytotoxic T lymphocyte associate protein-4 and cluster of differentiation 274 immune checkpoints' causality with COAD. In conclusion, our study developed novel markers for discriminating M2-like macrophages and predicting the prognosis of patients with COAD, offering fresh perspectives for clinical interventions.
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Affiliation(s)
- Xiaopei Liu
- School of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Dan Liu
- Department of Anorectal, Xi’an Hospital of Traditional Chinese Medicine, Xianyang, China
| | - Cong’e Tan
- School of Basic Medicine, Shaanxi University of Chinese Medicine, Xianyang, China
| | - Jiehong Wang
- Department of Gastroenterology, Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, China
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10
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Chaudhary A, Patil P, Raina P, Kaul-Ghanekar R. Matairesinol repolarizes M2 macrophages to M1 phenotype to induce apoptosis in triple-negative breast cancer cells. Immunopharmacol Immunotoxicol 2024:1-15. [PMID: 39722605 DOI: 10.1080/08923973.2024.2425028] [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: 06/05/2024] [Accepted: 10/27/2024] [Indexed: 12/28/2024]
Abstract
OBJECTIVE Triple-Negative Breast Cancer (TNBC), the most challenging subtype of Breast Cancer (BC), currently lacks targeted therapy, presenting a significant therapeutic gap in its management. Tumor Associated Macrophages (TAMs) play a significant role in TNBC progression and could be targeted by repolarizing them from M2 to M1 phenotype. Matairesinol (MAT), a plant lignan, has been shown to exhibit anticancer, anti-inflammatory and immunomodulatory activities. In this study, we explored how MAT-induced repolarization of THP-1-derived M2 macrophages towards the M1 phenotype, which could effectively target the TNBC cell line, MDA-MB-231. METHODS The differential expression of genes in THP-1-derived macrophages at mRNA levels was evaluated by RNAseq assay. An inverted microscope equipped with a CMOS camera was utilized to capture the morphological variations in THP-1 cells and THP-1-derived macrophages. Relative mRNA expression of M1 and M2 specific marker genes was quantified by qRT-PCR. Cell viability and induction of apoptosis were evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide (JC-1 dye) assays, respectively. RESULTS MAT reduced the viability of M2a and M2d macrophages and repolarized them to M1 phenotype. Conditioned medium (CM) from MAT-treated M2a and M2d macrophages significantly reduced the viability of TNBC cells by apoptosis. CONCLUSION Targeting M2 macrophages is an important strategy to regulate cancer progression. Our study provides evidence that MAT may be a promising drug candidate for developing novel anti-TNBC therapy. However, further studies are warranted to thoroughly elucidate the molecular mechanism of action of MAT and evaluate its therapeutic potential in TNBC in vitro and in vivo models.
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Affiliation(s)
- Amol Chaudhary
- Cancer Research Lab, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be University), Pune, India
| | - Prajakta Patil
- Cancer Research Lab, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be University), Pune, India
| | - Prerna Raina
- Cancer Research Lab, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be University), Pune, India
- Analytical Department (ADT), Lupin Limited, Pune, India
| | - Ruchika Kaul-Ghanekar
- Cancer Research Lab, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be University), Pune, India
- Symbiosis Centre for Research and Innovation (SCRI); Symbiosis International Deemed University (SIU), Pune, India
- Cancer Research Lab, Symbiosis School of Biological Sciences (SSBS), Symbiosis International Deemed University (SIU), Pune, India
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11
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Yuan W, Zhang J, Chen H, Zhuang Y, Zhou H, Li W, Qiu W, Zhou H. Natural compounds modulate the mechanism of action of tumour-associated macrophages against colorectal cancer: a review. J Cancer Res Clin Oncol 2024; 150:502. [PMID: 39546016 PMCID: PMC11568041 DOI: 10.1007/s00432-024-06022-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 10/28/2024] [Indexed: 11/17/2024]
Abstract
Colorectal cancer (CRC) exhibits a substantial morbidity and mortality rate, with its aetiology and pathogenesis remain elusive. It holds significant importance within the tumour microenvironment (TME) and exerts a crucial regulatory influence on tumorigenesis, progression, and metastasis. TAMs possess the capability to foster CRC pathogenesis, proliferation, invasion, and metastasis, as well as angiogenesis, immune evasion, and tumour resistance. Furthermore, TAMs can mediate the prognosis of CRC. In this paper, we review the mechanisms by which natural compounds target TAMs to exert anti-CRC effects from the perspective of the promotional effects of TAMs on CRC, mainly regulating the polarization of TAMs, reducing the infiltration and recruitment of TAMs, enhancing the phagocytosis of macrophages, and regulating the signalling pathways and cytokines, and discuss the potential value and therapeutic strategies of natural compounds-targeting the TAMs pathway in CRC clinical treatment.
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Affiliation(s)
- Weichen Yuan
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, The First Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jiexiang Zhang
- Urology Centre, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Surgery of Integrated Traditional Chinese and Western Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Haibin Chen
- Science and Technology Department, Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yupei Zhuang
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, The First Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Hongli Zhou
- College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wenting Li
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, The First Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
| | - Wenli Qiu
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
| | - Hongguang Zhou
- Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, The First Clinical College of Nanjing University of Chinese Medicine, Nanjing, China.
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12
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Chen CY, Ye YZ, Huang YH, Tzeng YM, Gurbanov R, Wang WL, Chang WW. Ovatodiolide inhibits endometrial cancer stemness via reactive oxygen species-mediated DNA damage and cell cycle arrest. Chem Biol Interact 2024; 403:111244. [PMID: 39276908 DOI: 10.1016/j.cbi.2024.111244] [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: 06/04/2024] [Revised: 09/01/2024] [Accepted: 09/12/2024] [Indexed: 09/17/2024]
Abstract
Endometrial cancer (EC) is a common gynecological cancer worldwide, often associated with a poor prognosis after recurrence or metastasis. Ovatodiolide (OVA) is a macrocyclic diterpenoid derived from Anisomeles indica that shows anticancer effects in various malignancies. This study aimed to evaluate the cytotoxic effects of OVA on EC cell proliferation and cancer stem cell (CSC) activity and explore its underlying molecular mechanisms. OVA treatment dose-dependently reduced the viability and colony formation of three EC cell lines (AN3CA, HEC-1A, and EMC6). It induced G2/M phase cell cycle arrest, associated with decreased cell division cycle 25C (CDC25C) expression and reduced activation of cyclin-dependent kinases 1 (CDK1) and 2 (CDK2). OVA also increased reactive oxygen species (ROS) production and DNA damage, activating the DNA damage-sensitive cell cycle checkpoint kinases 1 (CHK1) and 2 (CHK2) and upregulating the DNA damage marker γ-H2A.X variant histone (H2AX). It also suppressed the activation of mechanistic target of rapamycin kinase (mTOR) and nuclear factor kappa B (NF-κB) and downregulated glutathione peroxidase 1 (GPX1), an antioxidant enzyme counteracting oxidative stress. Moreover, OVA reduced the self-renewal capacity of CSCs, reducing the expression of key stemness proteins Nanog homeobox (NANOG) and octamer-binding transcription factor 4 (OCT4). The ROS inhibitor N-acetylcysteine attenuated the anti-proliferative and anti-CSC effects of OVA. Our findings suggest that OVA acts via ROS generation, leading to oxidative stress and DNA damage, culminating in cell cycle arrest and the suppression of CSC activity in EC. Therefore, OVA is a promising therapeutic agent for EC, either as a standalone treatment or an adjunct to existing therapies.
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Affiliation(s)
- Chun-Yu Chen
- Department of Emergency Medicine, Tungs' Taichung MetroHarbor Hospital, Taichung, 435403, Taiwan; Department of Nursing, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, 35664, Taiwan.
| | - Yu-Zhen Ye
- Department of Biomedical Sciences, Chung Shan Medical University, No.110, Sec.1, Jianguo N.Rd., Taichung City, 402306, Taiwan.
| | - Yu-Hao Huang
- Department of Biomedical Sciences, Chung Shan Medical University, No.110, Sec.1, Jianguo N.Rd., Taichung City, 402306, Taiwan
| | - Yew-Min Tzeng
- Department of Applied Science, National Taitung University, Sec. 2, University Rd., Taitung, 95092, Taiwan.
| | - Ranal Gurbanov
- School of Medicine, Gazi University, Emniyet Mah., Bandırma Cad., No:6/1, 06560, Yenimahalle, Ankara, Turkey.
| | - Wen-Ling Wang
- Department of Biomedical Sciences, Chung Shan Medical University, No.110, Sec.1, Jianguo N.Rd., Taichung City, 402306, Taiwan.
| | - Wen-Wei Chang
- Department of Biomedical Sciences, Chung Shan Medical University, No.110, Sec.1, Jianguo N.Rd., Taichung City, 402306, Taiwan; Department of Medical Research, Chung Shan Medical University Hospital, No.110, Sec.1, Jianguo N.Rd., Taichung City, 402306, Taiwan.
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13
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Fan Q, Fu ZW, Xu M, Lv F, Shi JS, Zeng QQ, Xiong DH. Research progress of tumor-associated macrophages in immune checkpoint inhibitor tolerance in colorectal cancer. World J Gastrointest Oncol 2024; 16:4064-4079. [DOI: 10.4251/wjgo.v16.i10.4064] [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: 06/05/2024] [Revised: 08/03/2024] [Accepted: 08/16/2024] [Indexed: 09/26/2024] Open
Abstract
The relevant mechanism of tumor-associated macrophages (TAMs) in the treatment of colorectal cancer patients with immune checkpoint inhibitors (ICIs) is discussed, and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies. As a class of drugs widely used in clinical tumor immunotherapy, ICIs can act on regulatory molecules on cells that play an inhibitory role-immune checkpoints-and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system. The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly. The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs. ICIs can regulate the phenotypic function of TAMs, and TAMs can also affect the tolerance of colorectal cancer to ICI therapy. TAMs play an important role in ICI resistance, and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.
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Affiliation(s)
- Qi Fan
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Zheng-Wei Fu
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Ming Xu
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Feng Lv
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Jia-Song Shi
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Qi-Qi Zeng
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - De-Hai Xiong
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
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14
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Chen T, Wang Q, Liu C, Zhang F, Bai Y, Jiao Y, Wang M, Bao S, Liu B, Shao M, Ma S, Ding Y. Ovatodiolide inhibited hepatocellular carcinoma stemness through SP1/MTDH/STAT3 signaling pathway. Chem Biol Interact 2024; 400:111161. [PMID: 39053793 DOI: 10.1016/j.cbi.2024.111161] [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: 04/03/2024] [Revised: 07/12/2024] [Accepted: 07/22/2024] [Indexed: 07/27/2024]
Abstract
Hepatocellular carcinoma (HCC) is characterized with high recurrence and mortality, and the clinical treatments for HCC are very limited. Hepatocellular carcinoma stem cells are the root of HCC progress, recurrence, and multidrug resistance. Ovatodiolide (OVA) is a bioactive diterpenoid served as an inflammatory and immunotherapeutic responses modulator. In this research, we found OVA inhibited HCC stemness through inhibiting MTDH gene transcription. Moreover, we firstly discovered transcription factor SP1 bound to the promoter region of MTDH to transcriptionally regulate MTDH level. Mechanically, we demonstrated OVA decreased SP1 protein stability to transcriptionally inhibit MTDH gene, and inhibited the nuclear translocation of p65, and then diminished IL-6 level to suppress JAK/STAT3 signaling pathway, eventually decreases CD133 level and the stemness of HCC. Furthermore, we demonstrated ACT004, OVA derivative with high metabolic stability towards cytochrome P450 enzymes, showed no genotoxicity and no accumulative or delayed toxicities after long-term administration in rats. And the in vivo efficacy experiments indicated ACT004 inhibited tumor growth of hepatocellular carcinoma. In conclusion, we revealed the mechanism of OVA in regulating HCC stemness, detected the toxicity of OVA derivative and evaluated the in vivo efficacy which lays a foundation for further discovery of anti-HCC stem cell agents and provide a new strategy for the application of OVA in clinical treatment.
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Affiliation(s)
- Tianyang Chen
- College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
| | - Qin Wang
- College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
| | - Can Liu
- College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
| | - Fengyuan Zhang
- College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
| | - Yongping Bai
- College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
| | - Yan Jiao
- College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China
| | | | - Shiqi Bao
- Accendatech Co., Ltd., Tianjin, 300384, China
| | - Baofeng Liu
- Shan Dong Xinbo Pharmaceutical R&D Co., Ltd., Shan Dong, 251500, China
| | - Mingxiang Shao
- Shan Dong Xinbo Pharmaceutical R&D Co., Ltd., Shan Dong, 251500, China
| | - Shuoqian Ma
- College of Chemistry, Nankai University, Tianjin, 300071, China.
| | - Yahui Ding
- College of Chemistry, Nankai University, Tianjin, 300071, China.
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15
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Liu H, Huang M, Xin D, Wang H, Yu H, Pu W. Natural products with anti-tumorigenesis potential targeting macrophage. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 131:155794. [PMID: 38875811 DOI: 10.1016/j.phymed.2024.155794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 05/06/2024] [Accepted: 05/30/2024] [Indexed: 06/16/2024]
Abstract
BACKGROUND Inflammation is a risk factor for tumorigenesis. Macrophage, a subset of immune cells with high plasticity, plays a multifaceted role in this process. Natural products, which are bioactive compounds derived from traditional herbs or foods, have exhibited diverse effects on macrophages and tumorigenesis making them a valuable resource of drug discovery or optimization in tumor prevention. PURPOSE Provide a comprehensive overview of the various roles of macrophages in tumorigenesis, as well as the effects of natural products on tumorigenesis by modulating macrophage function. METHODS A thorough literature search spanning the past two decades was carried out using PubMed, Web of Science, Elsevier, and CNKI following the PRISMA guidelines. The search terms employed included "macrophage and tumorigenesis", "natural products, macrophages and tumorigenesis", "traditional Chinese medicine and tumorigenesis", "natural products and macrophage polarization", "macrophage and tumor related microenvironment", "macrophage and tumor signal pathway", "toxicity of natural products" and combinations thereof. Furthermore, certain articles are identified through the tracking of citations from other publications or by accessing the websites of relevant journals. Studies that meet the following criteria are excluded: (1) Articles not written in English or Chinese; (2) Full texts were not available; (3) Duplicate articles and irrelevant studies. The data collected was organized and summarized based on molecular mechanisms or compound structure. RESULTS This review elucidates the multifaceted effect of macrophages on tumorigenesis, encompassing process such as inflammation, angiogenesis, and tumor cell invasion by regulating metabolism, non-coding RNA, signal transduction and intercellular crosstalk. Natural products, including vitexin, ovatodiolide, ligustilide, and emodin, as well as herbal remedies, have demonstrated efficacy in modulating macrophage function, thereby attenuating tumorigenesis. These interventions mainly focus on mitigating the initial inflammatory response or modifying the inflammatory environment within the precancerous niche. CONCLUSIONS These mechanistic insights of macrophages in tumorigenesis offer valuable ideas for researchers. The identified natural products facilitate the selection of promising candidates for future cancer drug development.
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Affiliation(s)
- Hao Liu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Manru Huang
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Dandan Xin
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Hong Wang
- School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China.
| | - Haiyang Yu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, PR China.
| | - Weiling Pu
- State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China.
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16
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Ashrafizadeh M, Aref AR, Sethi G, Ertas YN, Wang L. Natural product/diet-based regulation of macrophage polarization: Implications in treatment of inflammatory-related diseases and cancer. J Nutr Biochem 2024; 130:109647. [PMID: 38604457 DOI: 10.1016/j.jnutbio.2024.109647] [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: 10/09/2023] [Revised: 03/28/2024] [Accepted: 04/08/2024] [Indexed: 04/13/2024]
Abstract
Macrophages are phagocytic cells with important physiological functions, including the digestion of cellular debris, foreign substances, and microbes, as well as tissue development and homeostasis. The tumor microenvironment (TME) shapes the aggressiveness of cancer, and the biological and cellular interactions in this complicated space can determine carcinogenesis. TME can determine the progression, biological behavior, and therapy resistance of human cancers. The macrophages are among the most abundant cells in the TME, and their functions and secretions can determine tumor progression. The education of macrophages to M2 polarization can accelerate cancer progression, and therefore, the re-education and reprogramming of these cells is promising. Moreover, macrophages can cause inflammation in aggravating pathological events, including cardiovascular diseases, diabetes, and neurological disorders. The natural products are pleiotropic and broad-spectrum functional compounds that have been deployed as ideal alternatives to conventional drugs in the treatment of cancer. The biological and cellular interactions in the TME can be regulated by natural products, and for this purpose, they enhance the M1 polarization of macrophages, and in addition to inhibiting proliferation and invasion, they impair the chemoresistance. Moreover, since macrophages and changes in the molecular pathways in these cells can cause inflammation, the natural products impair the pro-inflammatory function of macrophages to prevent the pathogenesis and progression of diseases. Even a reduction in macrophage-mediated inflammation can prevent organ fibrosis. Therefore, natural product-mediated macrophage targeting can alleviate both cancerous and non-cancerous diseases.
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Affiliation(s)
- Milad Ashrafizadeh
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China; Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA; Department of Translational Sciences, Xsphera Biosciences Inc., Boston, Massachusetts, USA
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
| | - Yavuz Nuri Ertas
- Department of Biomedical Engineering, Erciyes University, Kayseri, Türkiye; ERNAM-Nanotechnology Research and Application Center, Erciyes University, Kayseri, Türkiye.
| | - Lu Wang
- Department of Gastroenterology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
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17
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Ren Y, Zhou L, Li X, Zhu X, Zhang Z, Sun X, Xue X, Dai C. Taz/Tead1 Promotes Alternative Macrophage Activation and Kidney Fibrosis via Transcriptional Upregulation of Smad3. J Immunol Res 2024; 2024:9512251. [PMID: 39108258 PMCID: PMC11303051 DOI: 10.1155/2024/9512251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 07/04/2024] [Accepted: 07/08/2024] [Indexed: 09/17/2024] Open
Abstract
Macrophage alternative activation is involved in kidney fibrosis. Previous researches have documented that the transcriptional regulators Yes-associated protein (Yap)/transcriptional coactivator with PDZ-binding motif (Taz) are linked to organ fibrosis. However, limited knowledge exists regarding the function and mechanisms of their downstream molecules in regulating macrophage activation and kidney fibrosis. In this paper, we observed that the Hippo pathway was suppressed in macrophages derived from fibrotic kidneys in mice. Knockout of Taz or Tead1 in macrophages inhibited the alternative activation of macrophages and reduced kidney fibrosis. Additionally, by using bone marrow-derived macrophages (BMDMs), we investigated that knockout of Taz or Tead1 in macrophages impeded both cell proliferation and migration. Moreover, deletion of Tead1 reduces p-Smad3 and Smad3 abundance in macrophages. And chromatin immunoprecipitation (ChIP) assays showed that Tead1 could directly bind to the promoter region of Smad3. Collectively, these results indicate that Tead1 knockout in macrophages could reduce TGFβ1-induced phosphorylation Smad3 via transcriptional downregulation of Smad3, thus suppressing macrophage alternative activation and IRI-induced kidney fibrosis.
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Affiliation(s)
- Yizhi Ren
- Department of Clinical GeneticsThe 2nd Affiliated HospitalNanjing Medical University, 262 North Zhongshan Road, Nanjing 210003, Jiangsu, China
| | - Lu Zhou
- Center for kidney diseasesThe 2nd Affiliated HospitalNanjing Medical University, 262 North Zhongshan Road, Nanjing 210003, Jiangsu, China
| | - Xinyuan Li
- Center for kidney diseasesThe 2nd Affiliated HospitalNanjing Medical University, 262 North Zhongshan Road, Nanjing 210003, Jiangsu, China
| | - Xingwen Zhu
- Center for kidney diseasesThe 2nd Affiliated HospitalNanjing Medical University, 262 North Zhongshan Road, Nanjing 210003, Jiangsu, China
| | - Zhiheng Zhang
- School of StomatologyXuzhou Medical University, No. 209 Tongshan Road, Xuzhou 221000, Jiangsu, China
| | - Xiaoli Sun
- Department of Clinical GeneticsThe 2nd Affiliated HospitalNanjing Medical University, 262 North Zhongshan Road, Nanjing 210003, Jiangsu, China
| | - Xian Xue
- Department of Clinical GeneticsThe 2nd Affiliated HospitalNanjing Medical University, 262 North Zhongshan Road, Nanjing 210003, Jiangsu, China
| | - Chunsun Dai
- Department of Clinical GeneticsThe 2nd Affiliated HospitalNanjing Medical University, 262 North Zhongshan Road, Nanjing 210003, Jiangsu, China
- Center for kidney diseasesThe 2nd Affiliated HospitalNanjing Medical University, 262 North Zhongshan Road, Nanjing 210003, Jiangsu, China
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18
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Fu D, Shi X, Yi X, Wu D, He H, Zhou W, Cheng W. m6A reader IGF2BP2 promotes M2 macrophage polarization and malignant biological behavior of bladder cancer by stabilizing NRP1 mRNA expression. BMC Urol 2024; 24:147. [PMID: 39014364 PMCID: PMC11251312 DOI: 10.1186/s12894-024-01534-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 07/02/2024] [Indexed: 07/18/2024] Open
Abstract
BACKGROUND Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) has been confirmed to play oncogenic role in many cancers. However, the role and mechanism of IGF2BP2 in bladder cancer (BCa) still deserves to be further revealed. METHODS The mRNA and protein levels of IGF2BP2 and neuronilin-1 (NRP1) were detected by real-time quantitative PCR (RT-qPCR) and western blot. Cell proliferation, apoptosis, migration and invasion were determined using colony formation assay, EdU assay, CCK8 assay, flow cytometry and transwell assay. Xenograft tumor model was conducted to evaluate the role of IGF2BP2 in vivo. THP-1-M0 macrophages were co-cultured with the condition medium (CM) of BCa cells to induce polarization. M2 macrophage polarization was assessed by detecting the mRNA levels of M2 macrophage markers using RT-qPCR and measuring the proportion of M2 macrophage markers using flow cytometry. Moreover, MeRIP and RIP assay were performed to assess m6A level and the interaction between IGF2BP2 and NRP1. RESULTS IGF2BP2 and NRP1 were upregulated in BCa tissues and cells. IGF2BP2 knockdown suppressed BCa cell growth and metastasis, as well as inhibited BCa tumor growth. After THP-1-M0 macrophages were co-cultured with the CM of BCa cells, the levels of M2 macrophage markers were markedly enhanced, while this effect was abolished by IGF2BP2 knockdown. IGF2BP2 level was positively correlated with NRP1 level, and it could increase NRP1 mRNA stability. NRP1 overexpression reversed the suppressive effect of IGF2BP2 knockdown on M2 macrophage polarization and BCa cell progression. CONCLUSION m6A-reader IGF2BP2 enhanced M2 macrophage polarization and BCa cell progression by promoting NRP1 mRNA stability.
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Affiliation(s)
- Dian Fu
- Department of Urology, Jinling College of Clinical Medicine, Nanjing Medical University, No.305, Zhongshandong Road, Xuanwu District, Nanjing, Jiangsu, 210002, China
| | - Xiuquan Shi
- Department of Urology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, No.305, Zhongshandong Road, Xuanwu District, Nanjing, Jiangsu, 210002, China
| | - Xiaoming Yi
- Department of Urology, Jinling College of Clinical Medicine, Nanjing Medical University, No.305, Zhongshandong Road, Xuanwu District, Nanjing, Jiangsu, 210002, China
| | - Ding Wu
- Department of Urology, Jinling College of Clinical Medicine, Nanjing Medical University, No.305, Zhongshandong Road, Xuanwu District, Nanjing, Jiangsu, 210002, China
| | - Haowei He
- Department of Urology, Jinling College of Clinical Medicine, Nanjing Medical University, No.305, Zhongshandong Road, Xuanwu District, Nanjing, Jiangsu, 210002, China
| | - Wenquan Zhou
- Department of Urology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, No.305, Zhongshandong Road, Xuanwu District, Nanjing, Jiangsu, 210002, China.
| | - Wen Cheng
- Department of Urology, Jinling College of Clinical Medicine, Nanjing Medical University, No.305, Zhongshandong Road, Xuanwu District, Nanjing, Jiangsu, 210002, China.
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Xie Q, Zeng Y, Zhang X, Yu F. The significance of lipid metabolism reprogramming of tumor-associated macrophages in hepatocellular carcinoma. Cancer Immunol Immunother 2024; 73:171. [PMID: 38954021 PMCID: PMC11220057 DOI: 10.1007/s00262-024-03748-9] [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: 02/15/2024] [Accepted: 05/28/2024] [Indexed: 07/04/2024]
Abstract
In the intricate landscape of the tumor microenvironment, tumor-associated macrophages (TAMs) emerge as a ubiquitous cellular component that profoundly affects the oncogenic process. The microenvironment of hepatocellular carcinoma (HCC) is characterized by a pronounced infiltration of TAMs, underscoring their pivotal role in modulating the trajectory of the disease. Amidst the evolving therapeutic paradigms for HCC, the strategic reprogramming of metabolic pathways presents a promising avenue for intervention, garnering escalating interest within the scientific community. Previous investigations have predominantly focused on elucidating the mechanisms of metabolic reprogramming in cancer cells without paying sufficient attention to understanding how TAM metabolic reprogramming, particularly lipid metabolism, affects the progression of HCC. In this review article, we intend to elucidate how TAMs exert their regulatory effects via diverse pathways such as E2F1-E2F2-CPT2, LKB1-AMPK, and mTORC1-SREBP, and discuss correlations of TAMs with these processes and the characteristics of relevant pathways in HCC progression by consolidating various studies on TAM lipid uptake, storage, synthesis, and catabolism. It is our hope that our summary could delineate the impact of specific mechanisms underlying TAM lipid metabolic reprogramming on HCC progression and provide useful information for future research on HCC and the development of new treatment strategies.
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Affiliation(s)
- Qingjian Xie
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yuan Zeng
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiangting Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Fujun Yu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
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20
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Lu M, Zhu M, Wu Z, Liu W, Cao C, Shi J. The role of YAP/TAZ on joint and arthritis. FASEB J 2024; 38:e23636. [PMID: 38752683 DOI: 10.1096/fj.202302273rr] [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: 11/03/2023] [Revised: 04/05/2024] [Accepted: 04/16/2024] [Indexed: 05/21/2024]
Abstract
Osteoarthritis (OA) and rheumatoid arthritis (RA) are two common forms of arthritis with undefined etiology and pathogenesis. Yes-associated protein (YAP) and its homolog transcriptional coactivator with PDZ-binding motif (TAZ), which act as sensors for cellular mechanical and inflammatory cues, have been identified as crucial players in the regulation of joint homeostasis. Current studies also reveal a significant association between YAP/TAZ and the pathogenesis of OA and RA. The objective of this review is to elucidate the impact of YAP/TAZ on different joint tissues and to provide inspiration for further studying the potential therapeutic implications of YAP/TAZ on arthritis. Databases, such as PubMed, Cochran Library, and Embase, were searched for all available studies during the past two decades, with keywords "YAP," "TAZ," "OA," and "RA."
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Affiliation(s)
- Mingcheng Lu
- Zhejiang University School of Medicine, Zhejiang, Hangzhou, China
| | - Mengqi Zhu
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, Zhejiang, Hangzhou, China
| | - Zuping Wu
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, Zhejiang, Hangzhou, China
| | - Wei Liu
- Zhejiang University School of Medicine, Zhejiang, Hangzhou, China
| | - Chuwen Cao
- Zhejiang University School of Medicine, Zhejiang, Hangzhou, China
| | - Jiejun Shi
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Zhejiang, Hangzhou, China
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Yu KX, Yuan WJ, Wang HZ, Li YX. Extracellular matrix stiffness and tumor-associated macrophage polarization: new fields affecting immune exclusion. Cancer Immunol Immunother 2024; 73:115. [PMID: 38693304 PMCID: PMC11063025 DOI: 10.1007/s00262-024-03675-9] [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: 11/12/2023] [Accepted: 03/12/2024] [Indexed: 05/03/2024]
Abstract
In the malignant progression of tumors, there is deposition and cross-linking of collagen, as well as an increase in hyaluronic acid content, which can lead to an increase in extracellular matrix stiffness. Recent research evidence have shown that the extracellular matrix plays an important role in angiogenesis, cell proliferation, migration, immunosuppression, apoptosis, metabolism, and resistance to chemotherapeutic by the alterations toward both secretion and degradation. The clinical importance of tumor-associated macrophage is increasingly recognized, and macrophage polarization plays a central role in a series of tumor immune processes through internal signal cascade, thus regulating tumor progression. Immunotherapy has gradually become a reliable potential treatment strategy for conventional chemotherapy resistance and advanced cancer patients, but the presence of immune exclusion has become a major obstacle to treatment effectiveness, and the reasons for their resistance to these approaches remain uncertain. Currently, there is a lack of exact mechanism on the regulation of extracellular matrix stiffness and tumor-associated macrophage polarization on immune exclusion. An in-depth understanding of the relationship between extracellular matrix stiffness, tumor-associated macrophage polarization, and immune exclusion will help reveal new therapeutic targets and guide the development of clinical treatment methods for advanced cancer patients. This review summarized the different pathways and potential molecular mechanisms of extracellular matrix stiffness and tumor-associated macrophage polarization involved in immune exclusion and provided available strategies to address immune exclusion.
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Affiliation(s)
- Ke-Xun Yu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Wei-Jie Yuan
- Department of Gastrointestinal Surgery, Xiangya Hospital of Central South University, Changsha, China
| | - Hui-Zhen Wang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Yong-Xiang Li
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
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Tang X, Luo X, Wang X, Zhang Y, Xie J, Niu X, Lu X, Deng X, Xu Z, Wu F. Chrysin Inhibits TAMs-Mediated Autophagy Activation via CDK1/ULK1 Pathway and Reverses TAMs-Mediated Growth-Promoting Effects in Non-Small Cell Lung Cancer. Pharmaceuticals (Basel) 2024; 17:515. [PMID: 38675475 PMCID: PMC11055150 DOI: 10.3390/ph17040515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 04/05/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
The natural flavonoid compound chrysin has promising anti-tumor effects. In this study, we aimed to investigate the mechanism by which chrysin inhibits the growth of non-small cell lung cancer (NSCLC). Through in vitro cell culture and animal models, we explored the impact of chrysin on the growth of NSCLC cells and the pro-cancer effects of tumor-associated macrophages (TAMs) and their mechanisms. We observed that M2-TAMs significantly promoted the growth and migration of NSCLC cells, while also markedly activating the autophagy level of these cells. Chrysin displayed a significant inhibitory effect on the growth of NSCLC cells, and it could also suppress the pro-cancer effects of M2-TAMs and inhibit their mediated autophagy. Furthermore, combining network pharmacology, we found that chrysin inhibited TAMs-mediated autophagy activation in NSCLC cells through the regulation of the CDK1/ULK1 signaling pathway, rather than the classical mTOR/ULK1 signaling pathway. Our study reveals a novel mechanism by which chrysin inhibits TAMs-mediated autophagy activation in NSCLC cells through the regulation of the CDK1/ULK1 pathway, thereby suppressing NSCLC growth. This discovery not only provides new therapeutic strategies for NSCLC but also opens up new avenues for further research on chrysin.
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Affiliation(s)
- Xinglinzi Tang
- Central Lab, The Seventh Clinical Medicial College of Guangzhou University of Chinese Medicine, Shenzhen 518000, China
| | - Xiaoru Luo
- Central Lab, The Seventh Clinical Medicial College of Guangzhou University of Chinese Medicine, Shenzhen 518000, China
| | - Xiao Wang
- Department of Basic Theory of TCM, Guangzhou University of Chinese Medicine, Guangzhou 510330, China
| | - Yi Zhang
- Department of Psychology, School of Public Health and Management, Guangzhou University of Chinese Medicine, Guangzhou 510330, China
| | - Jiajia Xie
- Department of Classic Traditional Chinese Medicine, The Seventh Clinical Medicial College of Guangzhou University of Chinese Medicine, Shenzhen 518000, China
| | - Xuan Niu
- Department of Classic Traditional Chinese Medicine, The Seventh Clinical Medicial College of Guangzhou University of Chinese Medicine, Shenzhen 518000, China
| | - Xiaopeng Lu
- Department of Classic Traditional Chinese Medicine, The Seventh Clinical Medicial College of Guangzhou University of Chinese Medicine, Shenzhen 518000, China
| | - Xi Deng
- Department of Classic Traditional Chinese Medicine, The Seventh Clinical Medicial College of Guangzhou University of Chinese Medicine, Shenzhen 518000, China
| | - Zheng Xu
- Department of Classic Traditional Chinese Medicine, The Seventh Clinical Medicial College of Guangzhou University of Chinese Medicine, Shenzhen 518000, China
| | - Fanwei Wu
- Department of Classic Traditional Chinese Medicine, The Seventh Clinical Medicial College of Guangzhou University of Chinese Medicine, Shenzhen 518000, China
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Liu X, Xiong H, Lu M, Liu B, Hu C, Liu P. Trans-3, 5, 4'-trimethoxystilbene restrains non-small-cell lung carcinoma progression via suppressing M2 polarization through inhibition of m6A modified circPACRGL-mediated Hippo signaling. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 126:155436. [PMID: 38394728 DOI: 10.1016/j.phymed.2024.155436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 01/17/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024]
Abstract
BACKGROUND Non-small-cell lung carcinoma (NSCLC) accounts for ∼85% of all lung carcinomas. Trans-3,5,4'-trimethoxystilbene (TMS) shows strong anti-tumor activity and induces tumor cell apoptosis. However, its function and mechanism in NSCLC still require investigation. METHODS PMA was used to treated THP-1 cells for macrophage differentiation. The abundance and m6A modification of circPACRGL were examined with qRT-PCR and MeRIP. Colony forming, transwell, wound healing, and Western blotting assays were applied to analyze proliferation, invasion, migration, and EMT. Macrophage polarization was determined through flow cytometry analysis of M1 and M2 markers. The interplay between circPACRGL, IGF2BP2 and YAP1 was validated by RNA pull-down and RIP assays. Mice received subcutaneous injection of NSCLC cells as a mouse model of subcutaneous tumor. RESULTS CircPACRGL was upregulated in NSCLC cells, but it was reduced by TMS treatment. CircPACRGL depletion blocked proliferation, migration, and invasion in H1299 and H1975 cells. TMS suppressed these malignant behaviors, but it was abolished by circPACRGL overexpression. In addition, NSCLC-derived exosomes delivered circPACRGL into THP-1 cells to promote its M2 polarization, but TMS inhibited these effects by downregulating exosomal circPACRGL. Mechanically, exosomal circPACRGL bound to IGF2BP2 to improve the stability of YAP1 mRNA and regulate Hippo signaling in polarized THP-1 cells. TMS inhibited NSCLC growth via suppressing Hippo signaling and M2 polarization in vivo. CONCLUSION TMS restrains M2 polarization and NSCLC progression by reducing circPACRGL and inhibiting exosomal circPACRGL-mediated Hippo signaling. Thus, these findings provide a novel mechanism underlying NSCLC progression and potential therapeutic targets.
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Affiliation(s)
- Xiaoyu Liu
- Department of Oncology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha, Hunan 410011, PR China
| | - Hui Xiong
- Department of Oncology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha, Hunan 410011, PR China
| | - Min Lu
- Department of Oncology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha, Hunan 410011, PR China
| | - Bin Liu
- Department of Oncology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha, Hunan 410011, PR China
| | - Chunhong Hu
- Department of Oncology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha, Hunan 410011, PR China
| | - Ping Liu
- Department of Oncology, The Second Xiangya Hospital of Central South University, 139 Renmin Middle Road, Changsha, Hunan 410011, PR China.
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24
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Fan Z, Cui Y, Chen L, Liu P, Duan W. 23-Hydroxybetulinic acid attenuates 5-fluorouracil resistance of colorectal cancer by modulating M2 macrophage polarization via STAT6 signaling. Cancer Immunol Immunother 2024; 73:83. [PMID: 38554148 PMCID: PMC10981607 DOI: 10.1007/s00262-024-03662-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Accepted: 02/23/2024] [Indexed: 04/01/2024]
Abstract
Macrophage polarization is closely associated with the inflammatory processes involved in the development and chemoresistance of colorectal cancer (CRC). M2 macrophages, the predominant subtype of tumor-associated macrophages (TAMs) in a wide variety of malignancies, have been demonstrated to promote the resistance of CRC to multiple chemotherapeutic drugs, such as 5-fluorouracil (5-FU). In our study, we investigated the potential of 23-Hydroxybetulinic Acid (23-HBA), a significant active component of Pulsatilla chinensis (P. chinensis), to inhibit the polarization of M2 macrophages induced by IL-4. Our results showed that 23-HBA reduced the expression of M2 specific marker CD206, while downregulating the mRNA levels of M2 related genes (CD206, Arg1, IL-10, and CCL2). Additionally, 23-HBA effectively attenuated the inhibitory effects of the conditioned medium from M2 macrophages on apoptosis in colorectal cancer SW480 cells. Mechanistically, 23-HBA prevented the phosphorylation and nuclear translocation of the STAT6 protein, resulting in the inhibition of IL-10 release in M2 macrophages. Moreover, it interfered with the activation of the IL-10/STAT3/Bcl-2 signaling pathway in SW480 cells, ultimately reducing M2 macrophage-induced resistance to 5-FU. Importantly, depleting STAT6 expression in macrophages abolished the suppressive effect of 23-HBA on M2 macrophage polarization, while also eliminating its ability to decrease M2 macrophage-induced 5-FU resistance in cancer cells. Furthermore, 23-HBA significantly diminished the proportion of M2 macrophages in the tumor tissues of colorectal cancer mice, simultaneously enhancing the anti-cancer efficacy of 5-FU. The findings presented in this study highlight the capacity of 23-HBA to inhibit M2 macrophage polarization, a process that contributes to reduced 5-FU resistance in colorectal cancer.
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Affiliation(s)
- Zeping Fan
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330006, Jiangxi, China
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herbal Medicine, Jiangxi University of Chinese Medicine, Nanchang, 330006, Jiangxi, China
| | - Yaru Cui
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330006, Jiangxi, China
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herbal Medicine, Jiangxi University of Chinese Medicine, Nanchang, 330006, Jiangxi, China
- Key Laboratory for Evaluation on Anti-Tumor Effect of Chinese Medicine by Strengthening Body Resistance to Eliminate Pathogenic Factors, Nanchang, 330006, Jiangxi, China
| | - Lanying Chen
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330006, Jiangxi, China.
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herbal Medicine, Jiangxi University of Chinese Medicine, Nanchang, 330006, Jiangxi, China.
- Key Laboratory for Evaluation on Anti-Tumor Effect of Chinese Medicine by Strengthening Body Resistance to Eliminate Pathogenic Factors, Nanchang, 330006, Jiangxi, China.
| | - Peng Liu
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330006, Jiangxi, China
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herbal Medicine, Jiangxi University of Chinese Medicine, Nanchang, 330006, Jiangxi, China
| | - Wenbin Duan
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330006, Jiangxi, China
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herbal Medicine, Jiangxi University of Chinese Medicine, Nanchang, 330006, Jiangxi, China
- Key Laboratory for Evaluation on Anti-Tumor Effect of Chinese Medicine by Strengthening Body Resistance to Eliminate Pathogenic Factors, Nanchang, 330006, Jiangxi, China
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25
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Xu M, Zhao X, Wen T, Qu X. Unveiling the role of KRAS in tumor immune microenvironment. Biomed Pharmacother 2024; 171:116058. [PMID: 38171240 DOI: 10.1016/j.biopha.2023.116058] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 12/03/2023] [Accepted: 12/14/2023] [Indexed: 01/05/2024] Open
Abstract
Kirsten rats sarcoma viral oncogene (KRAS), the first discovered human oncogene, has long been recognized as "undruggable". KRAS mutations frequently occur in multiple human cancers including non-small cell lung cancer(NSCLC), colorectal cancer(CRC) and pancreatic ductal adenocarcinoma(PDAC), functioning as a "molecule switch" determining the activation of various oncogenic signaling pathways. Except for its intrinsic pro-tumorigenic role, KRAS alteration also exhibits an unique immune signature characterized by elevated PD-L1 level and high tumor mutational burden(TMB). KRAS mutation shape an immune suppressive microenvironment by impeding effective T cells infiltration and recruiting suppressive immune cells including myeloid-derived suppressor cells(MDSCs), regulatory T cells(Tregs), cancer associated fibroblasts(CAFs). In immune checkpoint inhibitor(ICI) era, NSCLC patients with mutated KRAS tend to be more responsive to ICI than patients with intact KRAS. The hallmark for KRAS mutation is the existence of multiple kinds of co-mutations. Different types of co-alterations have distinct tumor microenvironment(TME) signatures and responses to ICI. TP53 co-mutation possess a "hot" TME and achieve higher response to immunotherapy while other loss of function mutation correlated with a "colder" TME and a poor outcome to ICI-based therapy. The groundbreaking discovery of KRAS G12C inhibitors significantly improved outcomes for this KRAS subtype even though efficacy was limited to NSCLC patients. KRAS G12C inhibitors also restore the suppressive TME, creating an opportunity for combinations with ICI. However, an inevitable challenge to KRAS inhibitors is drug resistance. Promising combination strategies such as combination with SHP2 is an approach deserve further exploration because of their immune modulatory effect.
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Affiliation(s)
- Miao Xu
- Department of Medical Oncology, the First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Provinces, The First Hospital of China Medical University, Shenyang, Liaoning, China; Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning, China
| | - Xing Zhao
- Department of Pediatrics, the First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, Liaoning, China
| | - Ti Wen
- Department of Medical Oncology, the First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Provinces, The First Hospital of China Medical University, Shenyang, Liaoning, China; Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning, China
| | - Xiujuan Qu
- Department of Medical Oncology, the First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Provinces, The First Hospital of China Medical University, Shenyang, Liaoning, China; Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning, China.
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Liu Y, An Y, Li G, Wang S. Regulatory mechanism of macrophage polarization based on Hippo pathway. Front Immunol 2023; 14:1279591. [PMID: 38090595 PMCID: PMC10715437 DOI: 10.3389/fimmu.2023.1279591] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 11/13/2023] [Indexed: 12/18/2023] Open
Abstract
Macrophages are found to infiltrate and migrate in a large number of Tumor-associated macrophages (TMEs) and other macrophages in the microenvironment of tumors and related diseases, and undergo phenotypic changes in response to a variety of cytokines, mainly including the primary phenotype M2 and the anti-tumor phenotype M1. The Hippo signaling pathway affects the development of cancer and other diseases through various biological processes, such as inhibition of cell growth. In this review, we focus on immune cells within the microenvironment of tumors and other diseases, and the role of the Hippo pathway in tumors on macrophage polarization in the tumor microenvironment (TME) and other diseases.
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Affiliation(s)
- Yuanqing Liu
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Yina An
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Gebin Li
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China
| | - Shuaiyu Wang
- The Clinical Department, College of Veterinary Medicine, China Agricultural University, Beijing, China
- Center of Research and Innovation of Chinese Traditional Veterinary Medicine, China Agricultural University, Beijing, China
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Wang H, Yu H, Huang T, Wang B, Xiang L. Hippo-YAP/TAZ signaling in osteogenesis and macrophage polarization: Therapeutic implications in bone defect repair. Genes Dis 2023; 10:2528-2539. [PMID: 37554194 PMCID: PMC10404961 DOI: 10.1016/j.gendis.2022.12.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 11/16/2022] [Accepted: 12/08/2022] [Indexed: 01/18/2023] Open
Abstract
Bone defects caused by diseases or surgery are a common clinical problem. Researchers are devoted to finding biological mechanisms that accelerate bone defect repair, which is a complex and continuous process controlled by many factors. As members of transcriptional costimulatory molecules, Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) play an important regulatory role in osteogenesis, and they affect cell function by regulating the expression of osteogenic genes in osteogenesis-related cells. Macrophages are an important group of cells whose function is regulated by YAP/TAZ. Currently, the relationship between YAP/TAZ and macrophage polarization has attracted increasing attention. In bone tissue, YAP/TAZ can realize diverse osteogenic regulation by mediating macrophage polarization. Macrophages polarize into M1 and M2 phenotypes under different stimuli. M1 macrophages dominate the inflammatory response by releasing a number of inflammatory mediators in the early phase of bone defect repair, while massive aggregation of M2 macrophages is beneficial for inflammation resolution and tissue repair, as they secrete many anti-inflammatory and osteogenesis-related cytokines. The mechanism of YAP/TAZ-mediated macrophage polarization during osteogenesis warrants further study and it is likely to be a promising strategy for bone defect repair. In this article, we review the effect of Hippo-YAP/TAZ signaling and macrophage polarization on bone defect repair, and highlight the regulation of macrophage polarization by YAP/TAZ.
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Affiliation(s)
- Haochen Wang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Hui Yu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Tianyu Huang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Bin Wang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
| | - Lin Xiang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
- Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China
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Chaterjee O, Sur D. Artificially induced in situ macrophage polarization: An emerging cellular therapy for immuno-inflammatory diseases. Eur J Pharmacol 2023; 957:176006. [PMID: 37611840 DOI: 10.1016/j.ejphar.2023.176006] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 08/10/2023] [Accepted: 08/18/2023] [Indexed: 08/25/2023]
Abstract
Macrophages are the mature form of monocytes that have high plasticity and can shift from one phenotype to another by the process of macrophage polarization. Macrophage has several vital pharmacological tasks like eliminating microorganism invasion, clearing dead cells, causing inflammation, repairing damaged tissues, etc. The function of macrophages is based on their phenotype. M1 macrophages are mostly responsible for the body's immune responses and M2 macrophages have healing properties. Inappropriate activation of any one of the phenotypes often leads to ROS-induced tissue damage and affects wound healing and angiogenesis. Therefore, maintaining tissue macrophage homeostasis is necessary. Studies are being done to find techniques for macrophage polarization. But, the process of macrophage polarization is very complex as it involves multiple signalling pathways involving innate immunity. Thus, identifying the right pathways for macrophage polarization is essential to apply the polarizing technique for the treatment of various inflammatory diseases where macrophage physiology influences the disease pathology. In this review, we highlighted the various techniques so far used to change macrophage plasticity. We believe that soon macrophage targeting therapeutics will hit the market for the management of inflammatory disease. Hence this review will help macrophage researchers choose suitable methods and materials/agents to polarize macrophages artificially in various disease models.
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Affiliation(s)
- Oishani Chaterjee
- Division of Pharmacology, Guru Nanak Institute of Pharmaceutical Science & Technology, Panihati, Kolkata, 700114, India
| | - Debjeet Sur
- Division of Pharmacology, Guru Nanak Institute of Pharmaceutical Science & Technology, Panihati, Kolkata, 700114, India.
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Chen P, Sun C, Wang H, Zhao W, Wu Y, Guo H, Zhou C, He Y. YAP1 expression is associated with survival and immunosuppression in small cell lung cancer. Cell Death Dis 2023; 14:636. [PMID: 37752152 PMCID: PMC10522695 DOI: 10.1038/s41419-023-06053-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 08/08/2023] [Indexed: 09/28/2023]
Abstract
Immunotherapy is considered a major breakthrough in the treatment of small cell lung cancer (SCLC), although its anti-tumor efficacy is limited. With a high degree of malignancy and high heterogeneity, SCLC is difficult to treat in the clinic. A new combination strategy is urgently needed to further improve the efficacy of immunotherapy in patients with SCLC. By immunofluorescence, 100 SCLC patients in a local cohort were classified into the SCLC-A (high ASCL1 expression; n = 36), SCLC-N (high NEUROD1 expression; n = 32), SCLC-P (high POU2F3 expression; n = 14), and SCLC-Y (high YAP1 expression; n = 18) subtypes. Each SCLC molecular subtype represented different prognoses, tumor microenvironment traits, and immunotherapy sensitivities. Analysis of both the local and public cohorts suggested that the SCLC-Y subtype exhibited the worst clinical outcome (p < 0.05) when compared with other subtypes. SCLC with high YAP1 expression was characterized by high PD-L1 expression, high stromal score, T-cell functional impairment, and a close relationship with immune-related pathways. YAP1 upregulated PD-L1 expression and suppressed T cell activation, thus leading to immune evasion. In in vitro experiments, blockade of YAP1 promoted cancer cell apoptosis, immune cell proliferation, T-cell activation, and cytotoxic T-cell infiltration, thus further potentiating the efficacy of immunotherapy in patients with the SCLC-Y subtype.
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Affiliation(s)
- Peixin Chen
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No 507 Zhengmin Road, Shanghai, 200433, People's Republic of China
- Tongji University, No 1239 Siping Road, Shanghai, 200433, People's Republic of China
| | - Chenglong Sun
- Radiotherapy Department, Anhui No. 2 Provincial People's Hospital, Hefei, 230041, Anhui, People's Republic of China
| | - Hao Wang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No 507 Zhengmin Road, Shanghai, 200433, People's Republic of China
- Tongji University, No 1239 Siping Road, Shanghai, 200433, People's Republic of China
| | - Wencheng Zhao
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No 507 Zhengmin Road, Shanghai, 200433, People's Republic of China
- Tongji University, No 1239 Siping Road, Shanghai, 200433, People's Republic of China
| | - Yan Wu
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No 507 Zhengmin Road, Shanghai, 200433, People's Republic of China
| | - Haoyue Guo
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No 507 Zhengmin Road, Shanghai, 200433, People's Republic of China
- Tongji University, No 1239 Siping Road, Shanghai, 200433, People's Republic of China
| | - Caicun Zhou
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No 507 Zhengmin Road, Shanghai, 200433, People's Republic of China.
| | - Yayi He
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No 507 Zhengmin Road, Shanghai, 200433, People's Republic of China.
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Liu C, Song Y, Li D, Wang B. Regulation of the tumor immune microenvironment by the Hippo Pathway: Implications for cancer immunotherapy. Int Immunopharmacol 2023; 122:110586. [PMID: 37393838 DOI: 10.1016/j.intimp.2023.110586] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/26/2023] [Accepted: 06/28/2023] [Indexed: 07/04/2023]
Abstract
The tumor immune microenvironment (TIME) is a dynamic and complex ecosystem consisting of immune cells, stromal cells, and tumor cells. It plays a crucial role in shaping cancer progression and treatment outcomes. Notably, tumor-associated immune cells are key regulators within the TIME, influencing immune responses and therapeutic efficacy. The Hippo pathway is a critical signaling pathway involved in the TIME and cancer progression. In this review, we provide an overview of the Hippo pathway's role in the TIME, focusing on its interactions with immune cells and their implications in cancer biology and therapy. Specifically, we discuss the involvement of the Hippo pathway in regulating T-cell function, macrophage polarization, B-cell differentiation, MDSC activity, and dendritic cell-mediated immune responses. Furthermore, we explore its influence on PD-L1 expression in lymphocytes and its potential as a therapeutic target. While recent progress has been made in understanding the Hippo pathway's molecular mechanisms, challenges remain in deciphering its context-dependent effects in different cancers and identifying predictive biomarkers for targeted therapies. By elucidating the intricate crosstalk between the Hippo pathway and the TME, we aim to contribute to the development of innovative strategies for cancer treatment.
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Affiliation(s)
- Chang Liu
- Department of Radiation Oncology, the First Hospital of China Medical University, Shenyang, Liaoning Province, PR China.
| | - Yang Song
- Geriatrics Center, Fourth People's Hospital of Shenyang, Shenyang, Liaoning Province, P.R. China.
| | - DeMing Li
- Department of Anesthesiology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, PR China.
| | - Biao Wang
- Department of Biochemistry and Molecular Biology, School of Life Sciences of China Medical University, Shenyang, Liaoning Province, PR China.
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31
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Han X, Yan T, Wang L, He B, Yu H. Knockdown of PTEN promotes colon cancer progression and induces M2 macrophage polarization in the colon cancer cell environment. INDIAN J PATHOL MICR 2023; 66:478-487. [PMID: 37530327 DOI: 10.4103/ijpm.ijpm_786_21] [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: 01/15/2023] Open
Abstract
Objective This article aims to study the effect of phosphate and tension homolog deleted on chromosome ten (PTEN) knockdown on colon cancer progression and macrophage polarization in the cancer environment. Materials and Methods and Results The expression of PTEN in colon cancer tissues and colon cancer cells was significantly lower than in precancerous tissues or CCD-18Co cells, and the decrease was most evident in SW620 cells. The expressions of phosphate (p)-p38, c-Jun N-terminal kinase (JNK), activator protein 1 (AP-1), B-cell lymphoma-2 (Bcl-2) protein in colon cancer tissues and cells were significantly higher than in precancerous tissues or CCD-18Co cells (P-values < 0.05). Bcl-2-associated X (Bax) and Caspase-3 expressions in colon cancer tissues and cells were significantly lower than in precancerous tissues or CCD-18Co cells (P-values < 0.05). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was applied to measure cell viability. Transwell evaluated the cell migration and invasion ability. Si-PTEN improved the proliferation, migration, and invasion of SW620 cells (P-values < 0.05). The expression levels of arginase-1 (Arg-1), CD163, CD206 in colon cancer tissues were significantly higher than in precancerous tissues (P-values < 0.05). The cell cycle, the number of M1 and M2 double-positive cells were assessed by flow cytometry. Si-PTEN reduced the expression of tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and inducible nitric oxide synthase (iNOS), which upregulated the expression of Arg-1, CD206, CD163, p-p38, JNK, and AP-1 (P-values < 0.05). Conclusion Si-PTEN promoted colon cancer progression and induced the polarization of M2 tumor-associated macrophages in the colon cancer cell environment.
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Affiliation(s)
- Xu Han
- General Surgery Department, The Fourth Hospital of Changsha, Changsha City, Hunan Province, China
| | - Ting Yan
- General Surgery Department, The Fourth Hospital of Changsha, Changsha City, Hunan Province, China
| | - Lina Wang
- Department of General Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou City, Henan Province, China
| | - Bin He
- General Surgery Department, The Fourth Hospital of Changsha, Changsha City, Hunan Province, China
| | - Huaxu Yu
- General Surgery Department, The Fourth Hospital of Changsha, Changsha City, Hunan Province, China
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Luo J, Deng L, Zou H, Guo Y, Tong T, Huang M, Ling G, Li P. New insights into the ambivalent role of YAP/TAZ in human cancers. J Exp Clin Cancer Res 2023; 42:130. [PMID: 37211598 DOI: 10.1186/s13046-023-02704-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 05/10/2023] [Indexed: 05/23/2023] Open
Abstract
Hippo signaling was first identified in Drosophila as a key controller of organ size by regulating cell proliferation and anti-apoptosis. Subsequent studies have shown that this pathway is highly conserved in mammals, and its dysregulation is implicated in multiple events of cancer development and progression. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) (hereafter YAP/TAZ) are the downstream effectors of the Hippo pathway. YAP/TAZ overexpression or activation is sufficient to induce tumor initiation and progression, as well as recurrence and therapeutic resistance. However, there is growing evidence that YAP/TAZ also exert a tumor-suppressive function in a context-dependent manner. Therefore, caution should be taken when targeting Hippo signaling in clinical trials in the future. In this review article, we will first give an overview of YAP/TAZ and their oncogenic roles in various cancers and then systematically summarize the tumor-suppressive functions of YAP/TAZ in different contexts. Based on these findings, we will further discuss the clinical implications of YAP/TAZ-based tumor targeted therapy and potential future directions.
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Affiliation(s)
- Juan Luo
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Liang Deng
- Department of General Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Hailin Zou
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Yibo Guo
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Tongyu Tong
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China
- Department of Urology, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Mingli Huang
- Department of General Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Gengqiang Ling
- Department of Neurosurgery, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Peng Li
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China.
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China.
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Zhou H, Tan L, Liu B, Guan XY. Cancer stem cells: Recent insights and therapies. Biochem Pharmacol 2023; 209:115441. [PMID: 36720355 DOI: 10.1016/j.bcp.2023.115441] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 12/20/2022] [Accepted: 01/25/2023] [Indexed: 01/31/2023]
Abstract
Tumors are intricate ecosystems containing malignant components that generate adaptive and evolutionarily driven abnormal tissues. Through self-renewal and differentiation, cancers are reconstructed by a dynamic subset of stem-like cells that enforce tumor heterogeneity and remodel the tumor microenvironment (TME). Through recent technology advances, we are now better equipped to investigate the fundamental role of cancer stem cells (CSCs) in cancer biology. In this review, we discuss the latest insights into characteristics, markers and mechanism of CSCs and describe the crosstalk between CSCs and other cells in TME. Additionally, we explore the performance of single-cell sequencing and spatial transcriptome analysis in CSCs studies and summarize the therapeutic strategies to eliminate CSCs, which could broaden the understanding of CSCs and exploit for therapeutic benefit.
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Affiliation(s)
- Hongyu Zhou
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China
| | - Licheng Tan
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China
| | - Beilei Liu
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China; Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, China.
| | - Xin-Yuan Guan
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China; Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, China; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China; MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, Guangdong, China; Advanced Nuclear Energy and Nuclear Technology Research Center, Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, Guangdong, China.
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Sonnemann HM, Pazdrak B, Antunes DA, Roszik J, Lizée G. Vestigial-like 1 (VGLL1): An ancient co-transcriptional activator linking wing, placenta, and tumor development. Biochim Biophys Acta Rev Cancer 2023; 1878:188892. [PMID: 37004960 DOI: 10.1016/j.bbcan.2023.188892] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023]
Abstract
Vestigial-like 1 (VGLL1) is a recently discovered driver of proliferation and invasion that is expressed in many aggressive human malignancies and is strongly associated with poor prognosis. The VGLL1 gene encodes for a co-transcriptional activator that shows intriguing structural similarity to key activators in the hippo pathway, providing important clues to its functional role. VGLL1 binds to TEADs in an analogous fashion to YAP1 but appears to activate a distinct set of downstream gene targets. In mammals, VGLL1 expression is found almost exclusively in placental trophoblasts, cells that share many hallmarks of cancer. Due to its role as a driver of tumor progression, VGLL1 has become a target of interest for potential anticancer therapies. In this review, we discuss VGLL1 from an evolutionary perspective, contrast its role in placental and tumor development, summarize the current knowledge of how signaling pathways can modulate VGLL1 function, and discuss potential approaches for targeting VGLL1 therapeutically.
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35
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Che J, Yu S. Ecological niches for colorectal cancer stem cell survival and thrival. Front Oncol 2023; 13:1135364. [PMID: 37124519 PMCID: PMC10134776 DOI: 10.3389/fonc.2023.1135364] [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: 12/31/2022] [Accepted: 03/17/2023] [Indexed: 05/02/2023] Open
Abstract
To date, colorectal cancer is still ranking top three cancer types severely threatening lives. According to cancer stem cell hypothesis, malignant colorectal lumps are cultivated by a set of abnormal epithelial cells with stem cell-like characteristics. These vicious stem cells are derived from intestinal epithelial stem cells or transformed by terminally differentiated epithelial cells when they accumulate an array of transforming genomic alterations. Colorectal cancer stem cells, whatever cell-of-origin, give rise to all morphologically and functionally heterogenous tumor daughter cells, conferring them with overwhelming resilience to intrinsic and extrinsic stresses. On the other hand, colorectal cancer stem cells and their daughter cells continuously participate in constructing ecological niches for their survival and thrival by communicating with adjacent stromal cells and circulating immune guardians. In this review, we first provide an overview of the normal cell-of-origin populations contributing to colorectal cancer stem cell reservoirs and the niche architecture which cancer stem cells depend on at early stage. Then we survey recent advances on how these aberrant niches are fostered by cancer stem cells and their neighbors. We also discuss recent research on how niche microenvironment affects colorectal cancer stem cell behaviors such as plasticity, metabolism, escape of immune surveillance as well as resistance to clinical therapies, therefore endowing them with competitive advantages compared to their normal partners. In the end, we explore therapeutic strategies available to target malignant stem cells.
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Affiliation(s)
- Jiayun Che
- Shanghai Institute of Precision Medicine, 9 Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shiyan Yu
- Shanghai Institute of Precision Medicine, 9 Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Oncology, 9 Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Shiyan Yu,
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Lee M, Du H, Winer DA, Clemente-Casares X, Tsai S. Mechanosensing in macrophages and dendritic cells in steady-state and disease. Front Cell Dev Biol 2022; 10:1044729. [PMID: 36467420 PMCID: PMC9712790 DOI: 10.3389/fcell.2022.1044729] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 11/01/2022] [Indexed: 11/18/2022] Open
Abstract
Macrophages and dendritic cells are myeloid cells that play critical roles in immune responses. Macrophages help to maintain homeostasis through tissue regeneration and the clearance of dead cells, but also mediate inflammatory processes against invading pathogens. As the most potent antigen-presenting cells, dendritic cells are important in connecting innate to adaptive immune responses via activation of T cells, and inducing tolerance under physiological conditions. While it is known that macrophages and dendritic cells respond to biochemical cues in the microenvironment, the role of extracellular mechanical stimuli is becoming increasingly apparent. Immune cell mechanotransduction is an emerging field, where accumulating evidence suggests a role for extracellular physical cues coming from tissue stiffness in promoting immune cell recruitment, activation, metabolism and inflammatory function. Additionally, many diseases such as pulmonary fibrosis, cardiovascular disease, cancer, and cirrhosis are associated with changes to the tissue biophysical environment. This review will discuss current knowledge about the effects of biophysical cues including matrix stiffness, topography, and mechanical forces on macrophage and dendritic cell behavior under steady-state and pathophysiological conditions. In addition, we will also provide insight on molecular mediators and signaling pathways important in macrophage and dendritic cell mechanotransduction.
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Affiliation(s)
- Megan Lee
- Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Huixun Du
- Buck Institute for Research on Aging, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, United States
| | - Daniel A. Winer
- Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Hospital Research Institute (TGHRI), University Health Network, Toronto, ON, Canada
- Department of Immunology, University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Pathology, University Health Network, Toronto, ON, Canada
- Buck Institute for Research on Aging, Novato, CA, United States
| | - Xavier Clemente-Casares
- Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB, Canada
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada
| | - Sue Tsai
- Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB, Canada
- Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada
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Yang Y, Wang N, Tian X, Wang X, Yang J, Leng X, Zhang H. Synergy of Polydopamine Nanovaccine and Endostar Alginate Hydrogel for Improving Antitumor Immune Responses Against Colon Tumor. Int J Nanomedicine 2022; 17:4791-4805. [PMID: 36246936 PMCID: PMC9554921 DOI: 10.2147/ijn.s372048] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 09/13/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Tumor immunotherapy, a novel type of therapeutic treatment, has a wide range of applications with potentially prolonged benefits. However, current immunotherapy has a low overall response rate in treating a variety of tumors. Combination of immunotherapy with other therapies can improve the therapeutic response rates. The purpose of this work was to explore the potential of anti-angiogenic treatment in combination with tumor cell lysate loaded polydopamine nanoparticle vaccine as a therapeutic strategy for colon tumor. METHODS We grafted tumor cell lysate onto polydopamine nanoparticles as nano-vaccine (TCLN) and fabricated alginate hydrogel loaded with Endostar (EH), then detected characteristics of EH and TCLN. We also estimated the cytotoxicity of EH/TCLN in vitro. In the tumor-bearing mouse model, we evaluated the antitumor effect of EH/TCLN treatment, and developed the animal survival study. After performing the EH/TCLN treatment, we also analyzed T cells and DCs using flow cytometry, and determined T cell responses and tumor microenvironmental cytokines. At last, we assessed the effect of the EH/TCLN treatment on anti-angiogenesis further. RESULTS When applied in combination with TCLN in MC-38 tumor-bearing mice, EH/TCLN significantly suppressed tumor growth with more than half of the mice showing tumor regression. In addition, EH/TCLN treatment resulted in noticeable changes in the tumor microenvironment. As compared with the control group, EH/TCLN treatment led to significantly reduced tumor angiogenesis and expression of tumor microenvironment-related cytokines (TMCs), increased proportion of CD8+ T cells in the spleen, lymph node and tumor, elevated activity of cytotoxic T lymphocytes (CTLs) and tumor cell apoptosis. CONCLUSION The present study demonstrated that the EH/TCLN treatment effectively created a favorable immune microenvironment for the induction of antitumor immunity and improved antitumor immune responses.
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Affiliation(s)
- Ying Yang
- Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Biomaterials, Tianjin, People’s Republic of China
| | - Ning Wang
- Key Laboratory of Colloid and Interface Chemistry of the Ministry of Education, School of Chemistry and Chemical Engineering, Shandong University, Jinan, People’s Republic of China
| | - XinXin Tian
- Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Biomaterials, Tianjin, People’s Republic of China
| | - XiaoLi Wang
- Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Biomaterials, Tianjin, People’s Republic of China
| | - Jing Yang
- Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Biomaterials, Tianjin, People’s Republic of China
| | - XiGang Leng
- Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Biomaterials, Tianjin, People’s Republic of China
| | - HaiLing Zhang
- Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Biomaterials, Tianjin, People’s Republic of China,Correspondence: HaiLing Zhang, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Biomaterials, Tianjin, People’s Republic of China, Tel +86 22 8789 1191, Fax +86 22 8789 0153, Email
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Tubuloside B, isolated from Cistanche tubulosa, a promising agent against M1 macrophage activation via synergistically targeting Mob1 and ERK1/2. Biomed Pharmacother 2022; 153:113414. [DOI: 10.1016/j.biopha.2022.113414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 07/07/2022] [Accepted: 07/11/2022] [Indexed: 11/17/2022] Open
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Fu H, Chu L, Yuan Y, Liao S, Wang G. circACTR2
activates
M2
polarization of macrophages through activating
YAP
signaling and contributes to renal fibrosis. Immunology 2022; 167:606-621. [DOI: 10.1111/imm.13558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 02/09/2022] [Indexed: 11/26/2022] Open
Affiliation(s)
- Hua Fu
- Department of Pathology, Third Xiangya Hospital Central South University Changsha Hunan Province P.R. China
| | - Ling Chu
- Department of Pathology, Third Xiangya Hospital Central South University Changsha Hunan Province P.R. China
| | - Yi‐Shu Yuan
- Department of Pathology, Third Xiangya Hospital Central South University Changsha Hunan Province P.R. China
| | - Shan Liao
- Department of Pathology, Third Xiangya Hospital Central South University Changsha Hunan Province P.R. China
| | - Guo‐Hui Wang
- Gastrointestinal surgery, Third Xiangya Hospital Central South University Changsha Hunan Province P.R. China
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Mia MM, Singh MK. Emerging roles of the Hippo signaling pathway in modulating immune response and inflammation-driven tissue repair and remodeling. FEBS J 2022; 289:4061-4081. [PMID: 35363945 DOI: 10.1111/febs.16449] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 01/17/2022] [Accepted: 03/30/2022] [Indexed: 02/06/2023]
Abstract
Inflammation is an evolutionarily conserved process and part of the body's defense mechanism. Inflammation leads to the activation of immune and non-immune cells that protect the host tissue/organs from injury or intruding pathogens. The Hippo pathway is an evolutionarily conserved kinase cascade with an established role in regulating cell proliferation, survival, and differentiation. It is involved in diverse biological processes, including organ size control and tissue homeostasis. Recent clinical and pre-clinical studies have shown that the Hippo signaling pathway is also associated with injury- and pathogen-induced tissue inflammation and associated immunopathology. In this review, we have summarized the recent findings related to the involvement of the Hippo signaling pathway in modulating the immune response in different acute and chronic inflammatory diseases and its impact on tissue repair and remodeling.
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Affiliation(s)
- Masum M Mia
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore
| | - Manvendra K Singh
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore.,National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore
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Tuo B, Chen Z, Dang Q, Chen C, Zhang H, Hu S, Sun Z. Roles of exosomal circRNAs in tumour immunity and cancer progression. Cell Death Dis 2022; 13:539. [PMID: 35676257 PMCID: PMC9177590 DOI: 10.1038/s41419-022-04949-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 05/06/2022] [Accepted: 05/12/2022] [Indexed: 02/07/2023]
Abstract
Tumour immunity plays an important role in the development of cancer. Tumour immunotherapy is an important component of antitumour therapy. Exosomes, a type of extracellular vesicle, act as mediators of intercellular communication and molecular transfer and play an essential role in tumour immunity. Circular RNAs (circRNAs) are a new type of noncoding RNA that are enriched within exosomes. In this review, we describe the effects of exosomal circRNAs on various immune cells and the mechanisms of these effects, including macrophages, neutrophils, T cells, and Natural killer (NK) cells. Next, we elaborate on the latest progress of exosome extraction. In addition, the function of exosomal circRNAs as a potential prognostic and drug sensitivity marker is described. We present the great promise of exosomal circRNAs in regulating tumour immunity, predicting patient outcomes, and evaluating drug efficacy.
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Affiliation(s)
- Baojing Tuo
- grid.412633.10000 0004 1799 0733Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China ,grid.207374.50000 0001 2189 3846Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Zhuang Chen
- grid.412633.10000 0004 1799 0733Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Qin Dang
- grid.412633.10000 0004 1799 0733Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Chen Chen
- grid.207374.50000 0001 2189 3846School of Life Sciences, Zhengzhou University, Zhengzhou, 450001 Henan China
| | - Hao Zhang
- grid.412633.10000 0004 1799 0733Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Shengyun Hu
- grid.412633.10000 0004 1799 0733Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Zhenqiang Sun
- grid.412633.10000 0004 1799 0733Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
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Wu H, Liu Y, Liao Z, Mo J, Zhang Q, Zhang B, Zhang L. The role of YAP1 in liver cancer stem cells: proven and potential mechanisms. Biomark Res 2022; 10:42. [PMID: 35672802 PMCID: PMC9171972 DOI: 10.1186/s40364-022-00387-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/25/2022] [Indexed: 02/08/2023] Open
Abstract
YAP1 (Yes-associated protein 1) is one of the principal factors that mediates oncogenesis by acting as a driver of gene expression. It has been confirmed to play an important role in organ volume control, stem cell function, tissue regeneration, tumorigenesis and tumor metastasis. Recent research findings show that YAP1 is correlated with the stemness of liver cancer stem cells, and liver cancer stem cells are closely associated with YAP1-induced tumor initiation and progression. This article reviews the advancements made in research on the mechanisms by which YAP1 promotes liver cancer stem cells and discusses some potential mechanisms that require further study.
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Affiliation(s)
- Haofeng Wu
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Yachong Liu
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Zhibin Liao
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Jie Mo
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Qiaofeng Zhang
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Bixiang Zhang
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
| | - Lei Zhang
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Shanxi Medical University; Shanxi Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Taiyuan, 030032, China.
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Yang D, Yang L, Cai J, Li H, Xing Z, Hou Y. Phosphoinositide 3-kinase/Akt and its related signaling pathways in the regulation of tumor-associated macrophages polarization. Mol Cell Biochem 2022; 477:2469-2480. [PMID: 35590082 DOI: 10.1007/s11010-022-04461-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 04/28/2022] [Indexed: 12/24/2022]
Abstract
Tumor-associated macrophages (TAMs) are a type of functionally plastic immune cell population in tumor microenvironment (TME) and mainly polarized into two phenotypes: M2 and M1-like TAMs. The M2-like TAMs could stimulate tumor growth and metastasis, tissue remodeling and immune-suppression, whereas M1-like TAMs could initiate immune response to dampen tumor progression. TAMs with different polarization phenotypes can produce various kinds of cytokines, chemokines and growth factors to regulate immunity and inflammatory responses. It is an effective method to treat cancer through ameliorating TME and modulating TAMs by converting M2 into M1-like phenotype. However, intracellular signaling mechanisms underlying TAMs polarization are largely undefined. Phosphoinositide 3-kinase (PI3K)/Akt is an important signaling pathway participating in M2-like TAMs polarization, survival, growth, proliferation, differentiation, apoptosis and cytoskeleton rearrangement. In the present review, we analyzed the mechanism of TAMs polarization focusing on PI3K/Akt and its downstream mitogen‑activated protein kinase (MAPK) as well as nuclear factor kappa B (NF-κB) signaling pathways, thus provides the first evidence of intracellular targets for cancer immunotherapy.
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Affiliation(s)
- Depeng Yang
- School of Life Sciences and Technology, Harbin Institute of Technology, Harbin, 150001, Heilongjiang, China
| | - Lijun Yang
- School of Life Sciences and Technology, Harbin Institute of Technology, Harbin, 150001, Heilongjiang, China
| | - Jialing Cai
- School of Life Sciences and Technology, Harbin Institute of Technology, Harbin, 150001, Heilongjiang, China
| | - Huaxin Li
- School of Life Sciences and Technology, Harbin Institute of Technology, Harbin, 150001, Heilongjiang, China
| | - Zheng Xing
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beijing Advanced Innovation Centre for Biomedical Engineering, Beihang University, Beijing, 100191, China
| | - Ying Hou
- Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, 710021, Shaanxi, China.
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Lin Q, Liu M, Yue GGL, Cheung MK, Lai Z, Kwok FHF, Lee JKM, Wang Z, Lau CBS, Tan N. Anti-inflammatory activities of natural cyclopeptide RA-XII in colitis-associated colon cancer mouse model and its effect on gut microbiome. Phytother Res 2022; 36:2641-2659. [PMID: 35537703 DOI: 10.1002/ptr.7482] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 04/07/2022] [Accepted: 04/09/2022] [Indexed: 12/19/2022]
Abstract
Colorectal cancer (CRC), the third most common cancer globally, is associated with intestinal inflammation that leads to poor prognosis. RA-XII, a natural cyclopeptide, has previously been reported to possess anti-tumor activities. Here, the anti-inflammatory activities of RA-XII were investigated in colitis-associated colon cancer mice and a co-culture in vitro model, in which colon cancer cells HCT116 and macrophages RAW264.7 were grown together to mimic the inflammatory microenvironment of CRC. Changes of inflammatory-related molecules and protein expressions in cells were evaluated after RA-XII incubation. Besides, azoxymethane and dextran sulfate sodium-induced colitis-associated colon cancer mice were treated with RA-XII for 24 days, inflammatory parameters and gut microbiome alterations were studied. Our results showed that RA-XII reversed the inflammatory responses of RAW264.7 cells induced by LPS and modulated the protein expressions of AKT, STAT3/p-STAT3, P70S6K, NF-κB and GSK3β and suppressed the expression of LC3A/B in HCT116 cells in co-culture system. RA-XII treatment restored the colitis damage in colon, reduced colon tumors numbers and decreased inflammatory factors (IL-6, IL-10 and TNF-α). The role of RA-XII on regulating gut microbiome was also demonstrated for the first time. In conclusion, our findings provided new scientific evidence for developing RA-XII as a potent anti-inflammatory agent for CRC.
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Affiliation(s)
- Qianwen Lin
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Mingyu Liu
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Grace Gar-Lee Yue
- Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Man Kit Cheung
- Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Zhixing Lai
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Frankie Hin-Fai Kwok
- Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Julia Kin-Ming Lee
- Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Zhe Wang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Clara Bik-San Lau
- Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Ninghua Tan
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
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45
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Tao BY, Liu YY, Liu HY, Zhang ZH, Guan YQ, Wang H, Shi Y, Zhang J. Prognostic Biomarker KIF18A and Its Correlations With Immune Infiltrates and Mitosis in Glioma. Front Genet 2022; 13:852049. [PMID: 35591854 PMCID: PMC9110815 DOI: 10.3389/fgene.2022.852049] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 04/13/2022] [Indexed: 11/21/2022] Open
Abstract
Background: Glioma is globally recognised as one of the most frequently occurring primary malignant brain tumours, making the identification of glioma biomarkers critically significant. The protein KIF18A (Kinesin Family Member 18A) is a member of the kinesin superfamily of microtubule-associated molecular motors and has been shown to participate in cell cycle and mitotic metaphase and anaphase. This is the first investigation into the expression of KIF18A and its prognostic value, potential biological functions, and effects on the immune system and mitosis in glioma patients. Methods: Gene expression and clinicopathological analysis, enrichment analysis, and immune infiltration analysis were based on data obtained from The Cancer Genome Atlas (TCGA), with additional bioinformatics analyses performed. Statistical analysis was conducted in R software. Clinical samples were used to evaluate the expression of KIF18A via immunohistochemical staining. In addition, the expression level of KIF18A was validated on U87 cell line. Results: Our results highlighted that KIF18A plays a key role as an independent prognostic factor in patients with glioma. KIF18A was highly expressed in glioma tissues, and KIF18A expression was associated with age, World Health Organization grade, isocitrate dehydrogenase (IDH) status, 1p/19q codeletion, primary therapy outcome, and overall survival (OS). Enrichment analysis revealed that KIF18A is closely correlated with the cell cycle and mitosis. Single sample gene set enrichment analysis (ssGSEA) analysis revealed that KIF18A expression was related to the immune microenvironment. The increased expression of KIF18A in glioma was verified in clinical samples and U87 cell line. Conclusion: The identification of KIF18A as a new biomarker for glioma could help elucidate how changes in the glioma cell and immune microenvironment promote glioma malignancy. With further analysis, KIF18A may serve as an independent prognostic indicator for human glioma.
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Affiliation(s)
- Bing-Yan Tao
- Medical School of Chinese PLA, Beijing, China
- Department of Neurosurgery, The First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Yu-Yang Liu
- Medical School of Chinese PLA, Beijing, China
- Department of Neurosurgery, The First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Hong-Yu Liu
- Medical School of Chinese PLA, Beijing, China
- Department of Neurosurgery, The First Medical Centre, Chinese PLA General Hospital, Beijing, China
- Department of Neurosurgery, Hainan Hospital of Chinese PLA General Hospital, Sanya, China
| | - Ze-Han Zhang
- Medical School of Chinese PLA, Beijing, China
- Department of Neurosurgery, The First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Yun-Qian Guan
- Cell Therapy Center, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Hui Wang
- Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing, China
| | - Ying Shi
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Jun Zhang
- Department of Neurosurgery, The First Medical Centre, Chinese PLA General Hospital, Beijing, China
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46
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Wu D, Liu X, Mu J, Yang J, Wu F, Zhou H. Therapeutic Approaches Targeting Proteins in Tumor-Associated Macrophages and Their Applications in Cancers. Biomolecules 2022; 12:biom12030392. [PMID: 35327584 PMCID: PMC8945446 DOI: 10.3390/biom12030392] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 02/11/2022] [Accepted: 02/28/2022] [Indexed: 02/07/2023] Open
Abstract
Tumor-associated macrophages (TAMs) promote tumor proliferation, invasion, angiogenesis, stemness, therapeutic resistance, and immune tolerance in a protein-dependent manner. Therefore, the traditional target paradigms are often insufficient to exterminate tumor cells. These pro-tumoral functions are mediated by the subsets of macrophages that exhibit canonical protein markers, while simultaneously having unique transcriptional features, which makes the proteins expressed on TAMs promising targets during anti-tumor therapy. Herein, TAM-associated protein-dependent target strategies were developed with the aim of either reducing the numbers of TAMs or inhibiting the pro-tumoral functions of TAMs. Furthermore, the recent advances in TAMs associated with tumor metabolism and immunity were extensively exploited to repolarize these TAMs to become anti-tumor elements and reverse the immunosuppressive tumor microenvironment. In this review, we systematically summarize these current studies to fully illustrate the TAM-associated protein targets and their inhibitors, and we highlight the potential clinical applications of targeting the crosstalk among TAMs, tumor cells, and immune cells in anti-tumor therapy.
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Affiliation(s)
- Deyang Wu
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, Frontier Innovation Center for Dental Medicine Plus, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; (D.W.); (J.M.); (J.Y.)
| | - Xiaowei Liu
- State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu 610041, China;
| | - Jingtian Mu
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, Frontier Innovation Center for Dental Medicine Plus, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; (D.W.); (J.M.); (J.Y.)
| | - Jin Yang
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, Frontier Innovation Center for Dental Medicine Plus, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; (D.W.); (J.M.); (J.Y.)
| | - Fanglong Wu
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, Frontier Innovation Center for Dental Medicine Plus, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; (D.W.); (J.M.); (J.Y.)
- Correspondence: (F.W.); (H.Z.)
| | - Hongmei Zhou
- State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, Frontier Innovation Center for Dental Medicine Plus, Department of Oral Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; (D.W.); (J.M.); (J.Y.)
- Correspondence: (F.W.); (H.Z.)
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47
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Zhang S, Xie F, Li K, Zhang H, Yin Y, Yu Y, Lu G, Zhang S, Wei Y, Xu K, Wu Y, Jin H, Xiao L, Bao L, Xu C, Li Y, Lu Y, Gao J. Gold nanoparticle-directed autophagy intervention for antitumor immunotherapy via inhibiting tumor-associated macrophage M2 polarization. Acta Pharm Sin B 2022; 12:3124-3138. [PMID: 35865102 PMCID: PMC9293675 DOI: 10.1016/j.apsb.2022.02.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 01/05/2022] [Accepted: 01/20/2022] [Indexed: 11/01/2022] Open
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Pan Z, Zhao R, Li B, Qi Y, Qiu W, Guo Q, Zhang S, Zhao S, Xu H, Li M, Gao Z, Fan Y, Xu J, Wang H, Wang S, Qiu J, Wang Q, Guo X, Deng L, Zhang P, Xue H, Li G. EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3. Mol Cancer 2022; 21:16. [PMID: 35031058 PMCID: PMC8759291 DOI: 10.1186/s12943-021-01485-6] [Citation(s) in RCA: 189] [Impact Index Per Article: 63.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 12/20/2021] [Indexed: 12/13/2022] Open
Abstract
Background Gliomas are the most common malignant primary brain tumours with a highly immunosuppressive tumour microenvironment (TME) and poor prognosis. Circular RNAs (circRNA), a newly found type of endogenous noncoding RNA, characterized by high stability, abundance, conservation, have been shown to play an important role in the pathophysiological processes and TME remodelling of various tumours. Methods CircRNA sequencing analysis was performed to explore circRNA expression profiles in normal and glioma tissues. The biological function of a novel circRNA, namely, circNEIL3, in glioma development was confirmed both in vitro and in vivo. Mechanistically, RNA pull-down, mass spectrum, RNA immunoprecipitation (RIP), luciferase reporter, and co-immunoprecipitation assays were conducted. Results We identified circNEIL3, which could be cyclized by EWS RNA-binding protein 1(EWSR1), to be upregulated in glioma tissues and to correlate positively with glioma malignant progression. Functionally, we confirmed that circNEIL3 promotes tumorigenesis and carcinogenic progression of glioma in vitro and in vivo. Mechanistically, circNEIL3 stabilizes IGF2BP3 (insulin-like growth factor 2 mRNA binding protein 3) protein, a known oncogenic protein, by preventing HECTD4-mediated ubiquitination. Moreover, circNEIL3 overexpression glioma cells drives macrophage infiltration into the tumour microenvironment (TME). Finally, circNEIL3 is packaged into exosomes by hnRNPA2B1 and transmitted to infiltrated tumour associated macrophages (TAMs), enabling them to acquire immunosuppressive properties by stabilizing IGF2BP3 and in turn promoting glioma progression. Conclusions This work reveals that circNEIL3 plays a nonnegligible multifaceted role in promoting gliomagenesis, malignant progression and macrophage tumour-promoting phenotypes polarization, highlighting that circNEIL3 is a potential prognostic biomarker and therapeutic target in glioma. Supplementary Information The online version contains supplementary material available at 10.1186/s12943-021-01485-6.
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Affiliation(s)
- Ziwen Pan
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China
| | - Rongrong Zhao
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China
| | - Boyan Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China
| | - Yanhua Qi
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China
| | - Wei Qiu
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China
| | - Qindong Guo
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China
| | - Shouji Zhang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China
| | - Shulin Zhao
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China
| | - Hao Xu
- Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China.,Department of Neurosurgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Ming Li
- Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China.,Department of Neurosurgery, Taian Central Hospital, Taian, Shandong, China
| | - Zijie Gao
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China
| | - Yang Fan
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China
| | - Jianye Xu
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China
| | - Huizhi Wang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China
| | - Shaobo Wang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China
| | - Jiawei Qiu
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China
| | - Qingtong Wang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China
| | - Xing Guo
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China
| | - Lin Deng
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China
| | - Ping Zhang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, 250012, Shandong, China.,Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China
| | - Hao Xue
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, 250012, Shandong, China. .,Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China.
| | - Gang Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, 107 Wenhua Western Road; Jinan, Shandong 250012, China, Jinan, 250012, Shandong, China. .,Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China.
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Wu AT, Yeh YC, Huang YJ, Mokgautsi N, Lawal B, Huang TH. Gamma-mangostin isolated from garcinia mangostana suppresses colon carcinogenesis and stemness by downregulating the GSK3β/β-catenin/CDK6 cancer stem pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 95:153797. [PMID: 34802869 DOI: 10.1016/j.phymed.2021.153797] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 09/24/2021] [Accepted: 10/07/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Despite advances in chemotherapies and targeted drugs, colorectal cancer (CRC) remains challenging to treat due to drug resistance. Emerging evidence indicates that cancer-associated fibroblasts (CAFs) facilitate the generation of cancer stem-like cells (CSCs) and drug resistance. Glycogen synthase kinase-3 (GSK) associated signaling pathways have been implicated in the generation of CSCs and represent a target for therapeutics development. HYPOTHESIS Gamma-mangostin (gMG) isolated from Garcinia mangostana was evaluated for its ability to downregulate GSK3β-associated signaling in CRC cells and overcome CAF-induced 5-fluorouracil resistance and CSC generation. METHODS Bioinformatics analysis, in silico molecular docking, in vitro assays, including cell viability tests, colony- and tumor sphere-formation assays, transwell migration assays, ELISA, SDS-PAGE, Western blotting, miR expression, qPCR, and flow cytometry, as well as in vivo mouse xenograft models were used to evaluate the antitumor effects of gMG. RESULTS Bioinformatics analyses indicated that GSK3β/CDK6/β-catenin mRNA signature was significantly higher in colon cancer patients. Additional algorithms predicted a higher miR-26b level was associated with significantly higher survival in CRC patients and GSK3β and CDK6 as targets of miR-26b-5p. To validate these findings in vitro, we showed that CAF-cocultured CRC cells expressed an increased expression of GSK3β, β-catenin, CDK6, and NF-κB. Therapeutically, we demonstrated that gMG treatment suppressed GSK3β-associated signaling pathways while concomitantly increased the miR-26b-5p level. Using a xenograft mouse model of CAFs cocultured HCT116 tumorspheres, we showed that gMG treatment reduced tumor growth and overcame CAF-induced 5-fluorouracil resistance. CONCLUSIONS Pharmacological intervention with gMG suppressed CRC carcinogenesis and stemness via downregulating GSK3/β-catenin/CDK6 and upregulating the miR-26b-5p tumor suppressor. Thus, gMG represents a potential new CRC therapeutic agent and warrants further investigation.
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Affiliation(s)
- Alexander Th Wu
- The PhD Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; International PhD Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; College of Medical Science and Technology, Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei 11031, Taiwan; Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan
| | - Yuan-Chieh Yeh
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, 20401, Taiwan; Program in Molecular Medicine, School of Life Sciences, National Yang Ming University, Taipei 11221, Taiwan
| | - Yan-Jiun Huang
- Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan; Department of Surgery, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Ntlotlang Mokgautsi
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; College of Medical Science and Technology, Graduate Institute for Cancer Biology & Drug Discovery, Taipei Medical University, Taipei 11031, Taiwan
| | - Bashir Lawal
- PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; College of Medical Science and Technology, Graduate Institute for Cancer Biology & Drug Discovery, Taipei Medical University, Taipei 11031, Taiwan
| | - Tse-Hung Huang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung 20401, Taiwan; School of Traditional Chinese Medicine, Chang Gung University, Taoyuan 333, Taiwan; School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei 112, Taiwan; Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan; Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan; Department & Graduate Institute of Chemical Engineering & Graduate Institute of Biochemical Engineering, Ming Chi University of Technology, New Taipei City 243, Taiwan.
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The YAP/TAZ Signaling Pathway in the Tumor Microenvironment and Carcinogenesis: Current Knowledge and Therapeutic Promises. Int J Mol Sci 2021; 23:ijms23010430. [PMID: 35008857 PMCID: PMC8745604 DOI: 10.3390/ijms23010430] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/23/2021] [Accepted: 12/24/2021] [Indexed: 12/14/2022] Open
Abstract
The yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) are transcriptional coactivators, members of the Hippo signaling pathway, which play a critical role in cell growth regulation, embryonic development, regeneration, proliferation, and cancer origin and progression. The mechanism involves the nuclear binding of the un-phosphorylated YAP/TAZ complex to release the transcriptional enhanced associate domain (TEAD) from its repressors. The active ternary complex is responsible for the aforementioned biological effects. Overexpression of YAP/TAZ has been reported in cancer stem cells and tumor resistance. The resistance involves chemotherapy, targeted therapy, and immunotherapy. This review provides an overview of YAP/TAZ pathways’ role in carcinogenesis and tumor microenvironment. Potential therapeutic alternatives are also discussed.
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