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Zhang S, Du K, Gao S, Liu Z, Chen L, Wu X, Li L. APM-Related gene signature model to predict prognosis and immunotherapy response in hepatocellular carcinoma. Hum Genet 2025:10.1007/s00439-025-02753-x. [PMID: 40423787 DOI: 10.1007/s00439-025-02753-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Accepted: 05/09/2025] [Indexed: 05/28/2025]
Abstract
Hepatocellular carcinoma (HCC) is a primary liver malignancy with a dismal prognosis. This study established and validated a prognostic model based on antigen-processing and presenting machinery (APM)-related genes through Mendelian randomization and publicly available datasets. Systematic analysis revealed CXCL5, SGPP2, and GLP1R as critical prognostic biomarkers, which were subsequently integrated into a risk model. The model demonstrated significant associations with pathways linked to bile acid, fatty acid, and amino acid metabolism, alongside variations in immune cell infiltration and genomic mutations, including TTN, TP53, and MUC16. Patient stratification into high- and low-risk groups indicated that low-risk individuals exhibited reduced immune infiltration, potentially correlating with enhanced immunotherapy sensitivity. These findings offer a robust gene signature for HCC prognosis and a framework for evaluating responses to immunotherapy.
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Affiliation(s)
- Shangdi Zhang
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, China
- Cuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, China
| | - Kewei Du
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, China
- Cuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, China
| | - Shan Gao
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, China
| | - Zejing Liu
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, China
| | - Linmei Chen
- Operating Theatre, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, China
| | - Xue Wu
- Cuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, China
- Department of Cardiovascular Medicine, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, China
| | - Linjing Li
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, China.
- Cuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, China.
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, No. 82, Cuiyingmen Street, Chengguan District, Lanzhou, Gansu Province, 730030, China.
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Masrour M, Moeinafshar A, Poopak A, Razi S, Rezaei N. The role of CXC chemokines and receptors in breast cancer. Clin Exp Med 2025; 25:128. [PMID: 40278951 PMCID: PMC12031896 DOI: 10.1007/s10238-025-01662-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 04/01/2025] [Indexed: 04/26/2025]
Abstract
CXC chemokines are a class of cytokines possessing chemotactic properties. Studies indicate that CXC chemokines exhibit dysregulation in miscellaneous cancer categories and are significantly associated with the advancement of tumors. Breast cancer is a commonly diagnosed and fatal cancer among the female population. Breast cancer pathogenesis and progression involve various mechanisms, including invasion, metastasis, angiogenesis, and inflammation. Chemokines and their receptors are involved in all of these processes. The CXC chemokine receptors (CXCRs) and their related ligands have attracted considerable attention due to their multifaceted functions in facilitating and controlling tumor proliferation. CXCRs are expressed by both cancer cells and immune cells, and they play a crucial role in regulating the tumor microenvironment and the immune response. This review aims to assess the potential of CXCRs and CXC chemokines as therapeutic targets or biomarkers for personalized therapy. Additionally, it provides an overview of the current understanding of the expression, function, and prognostic relevance of CXCRs in breast cancer. Furthermore, the challenges and potential prospects pertaining to CXCR investigation in breast cancer are deliberated.
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Affiliation(s)
- Mahdi Masrour
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
- Center for Orthopedic Trans-Disciplinary Applied Research, Tehran University of Medical Sciences, Tehran, Iran
| | - Aysan Moeinafshar
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Amirhossein Poopak
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Sepideh Razi
- Cancer Immunology Project (CIP), Universal Scientific and Education Network (USERN), Tehran, Iran
- Research Center for Immunodeficiencies, Children's Medical Center Hospital, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center Hospital, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran.
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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Sarkar S. Pathological role of RAGE underlying progression of various diseases: its potential as biomarker and therapeutic target. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:3467-3487. [PMID: 39589529 DOI: 10.1007/s00210-024-03595-6] [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: 08/12/2024] [Accepted: 10/31/2024] [Indexed: 11/27/2024]
Abstract
The receptor for advanced glycation end products (RAGE) is a multi-ligand receptor with several structural types, performing a myriad of molecular mechanisms. The RAGE-ligand interactions play important roles in maintaining latent chronic inflammation, and oxidative damage underlying various pathological conditions like metabolic syndrome (MetS), neurodegenerative diseases, stroke, cardiovascular disorders, pulmonary disorders, cancer and infections. RAGE is thoroughly explored in knockout animals and human trials, targeted by small molecule inhibitors, peptides, diet, and natural compounds. But it is yet to be incorporated in the mainstream management of any ailment. This review performs an appraisal of the pathological mechanisms influenced by RAGE to uncover its prospects as a biomarker while also assessing its power to become a promising therapeutic target.
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Affiliation(s)
- Sinjini Sarkar
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS Deemed-to-be-University, V.L. Mehta Road, Vile Parle (W), Mumbai, 400056, India.
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Coser M, Neamtu BM, Pop B, Cipaian CR, Crisan M. RAGE and its ligands in breast cancer progression and metastasis. Oncol Rev 2025; 18:1507942. [PMID: 39830522 PMCID: PMC11739297 DOI: 10.3389/or.2024.1507942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 12/10/2024] [Indexed: 01/22/2025] Open
Abstract
Introduction Breast cancer is the most common form of cancer diagnosed worldwide and the leading cause of death in women globally, according to Globocan 2020. Hence, investigating novel pathways implicated in cancer progression and metastasis could lead to the development of targeted therapies and new treatment strategies in breast cancer. Recent studies reported an interplay between the receptor for advanced glycation end products (RAGE) and its ligands, S100 protein group, advanced glycation end products (AGEs) and high-mobility group box 1 protein (HMGB1) and breast cancer growth and metastasis. Materials and methods We used articles available in the NCBI website database PubMed to write this scoping review. The search words used were 'RAGE receptor' AND/OR 'breast cancer, RAGE ligands, glycation end products'. A total of 90 articles were included. We conducted a meta-analysis to assess the relationship between the RAGE rs1800624 polymorphism and breast cancer risk using fixed-effect or random-effect models to calculate odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs). Results RAGE upon activation by its ligands enhances downstream signaling pathways, contributing to breast cancer cells migration, growth, angiogenesis, metastasis, and drug resistance. In addition, studies have shown that RAGE and its ligands influence the way breast cancer cells interact with immune cells present in the tumor microenvironment (macrophages, fibroblasts), thus regulating it to promote tumor growth and metastasis. Conclusion Breast cancers with a high expression of RAGE are associated with poor prognosis. Targeting RAGE and its ligands impairs cell invasion and metastasis, showing promising potential for further research as potential prognostic biomarkers or targeted onco-therapeutics.
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Affiliation(s)
- Madalina Coser
- Department of Histology, Doctoral School “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
| | - Bogdan Mihai Neamtu
- Clinical Medical Department, Center for Research in Mathematics and Applications, Faculty of Medicine, “Lucian Blaga” University Sibiu, Sibiu, Romania
- Department of Clinical Research, Pediatric Clinical Hospital Sibiu, Sibiu, Romania
| | - Bogdan Pop
- Department of Pathology, “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
- Department of Pathology, “Prof. Dr. ion Chiricuta” Institute of Oncology Cluj-Napoca, Cluj-Napoca, Romania
| | - Calin Remus Cipaian
- Second Medical Clinic, Sibiu County Clinical Emergency Hospital, Sibiu, Romania
- Clinical Medical Department, Faculty of Medicine, “Lucian Blaga” University Sibiu, Sibiu, Romania
| | - Maria Crisan
- Department of Histology, “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
- Clinic of Dermatology, Emergency Clinical County Hospital, Cluj-Napoca, Romania
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Calaf GM, Ardiles LN, Crispin LA. Role of Calcium in an Experimental Breast Cancer Model Induced by Radiation and Estrogen. Biomedicines 2024; 12:2432. [PMID: 39594999 PMCID: PMC11592107 DOI: 10.3390/biomedicines12112432] [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: 09/27/2024] [Revised: 10/11/2024] [Accepted: 10/18/2024] [Indexed: 11/28/2024] Open
Abstract
Background: Breast cancer, a global health challenge, significantly impacts women worldwide, causing morbidity, disability, and mortality. Objectives: To analyze the role of genes encoding S100 calcium-binding proteins and their relationship with radiation as possible markers in breast carcinogenesis. Methods: The normal MCF-10F cell line was used to study the role of ionizing radiation and estrogen to induce distinct stages of malignancy giving rise to an in vitro experimental breast cancer model. Results: Analysis of an Affymetrix system revealed that the gene expression levels of the S100 calcium-binding protein P (S100P), the S100 calcium-binding protein A14 (S100A14), and the S100 calcium-binding protein A2 (S100A2) were greater in the Tumor2 than the non-tumorigenic Alpha3 or the tumorigenic Alpha5 cell lines; however, the S100 calcium-binding protein A8 (S100A8) and the S100 calcium-binding protein A9 (S100A9) expression levels were higher in A5 than T2 and A3 cell lines. A significant positive association was found between the estrogen receptor alpha gene (ESR1) and S100A14 in Basal and Her2 patients. The association between ESR1 and S100A8 and S100A9 expression levels was positive in Basal patients but negative in Her2, Luminal A, and Luminal B. S100P and S100A14 expression levels were higher in tumor tissues than in normal ones. The estrogen receptor status was positive in patients with high levels of the S10014 gene, but negative in S100A2, S100A8, and S100A9 expression levels. Conclusion: Cell dependence needs to be considered while designing new breast cancer treatments since gene signatures might vary depending on the type of tumor.
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Affiliation(s)
- Gloria M. Calaf
- Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000000, Chile; (L.N.A.); (L.A.C.)
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Jiang C, Luo J, Jiang X, Lv Y, Dou J. Predictive model of gene expression regulating invasion and migration of M2 macrophages in breast cancer: clinical prognosis and therapeutic implications. Transl Cancer Res 2024; 13:4187-4204. [PMID: 39262492 PMCID: PMC11384920 DOI: 10.21037/tcr-24-29] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Accepted: 06/30/2024] [Indexed: 09/13/2024]
Abstract
Background Breast cancer (BRCA) has surpassed lung cancer to become the malignant tumor with the highest incidence in female population. It occurs in malignant cells in breast tissue and is common worldwide. An increasing body of research indicates that M2 macrophages are critical to the occurrence and progression of BRCA. The aim of this work is to build a predictive model of genes related to invasion and migration of M2 macrophages, forecast the prognosis of patients with BRCA, and then evaluate the efficacy of some targeted treatments. Methods The Gene Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geo/) database supplied the GSE20685 dataset, whereas the expression profile a clinical details of BRCA patients were obtained from The Cancer Genome Atlas (TCGA; https://portal.gdc.cancer.gov/) database. The genes linked to M2 macrophages and the differentially elevated genes of invasion and migration were found in GSE20685. To explore the prognosis-related invasion and migration M2 macrophage genes, the TCGA-BRCA dataset was merged with Cox regression and least absolute shrinkage and selection operator (LASSO) regression. GSE58812 was utilized for external validation. After calculating each patient's risk score, the prognostic model was examined by analyses of immune infiltration, medication sensitivity, mutation, and enrichment of the risk score. Results The risk score had a strong correlation with both several immune cells and popular anti-tumor medications. Additionally, it was discovered that the risk score was a separate prognostic factor for BRCA. Conclusions Based on invasion and migration-related M2 macrophage genes, we investigated and validated predictive characteristics in our study that may offer helpful insights into the progression and prognosis of BRCA.
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Affiliation(s)
- Chengjie Jiang
- Key Laboratory of Traditional Chinese Herbs and Prescription Innovation and Transformation of Gansu Province, Laboratory for TCM New Products Development Engineering of Gansu Province, Lanzhou, China
| | - Jinlei Luo
- Key Laboratory of Traditional Chinese Herbs and Prescription Innovation and Transformation of Gansu Province, Laboratory for TCM New Products Development Engineering of Gansu Province, Lanzhou, China
| | - Xiaoxue Jiang
- School of Chinese Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou, China
| | - Yujie Lv
- Key Laboratory of Traditional Chinese Herbs and Prescription Innovation and Transformation of Gansu Province, Laboratory for TCM New Products Development Engineering of Gansu Province, Lanzhou, China
| | - Jianwei Dou
- School of Pharmacy, Xi'an Jiao Tong University, Xi'an, China
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Xue Y, Chen Y, Sun S, Tong X, Chen Y, Tang S, Wang X, Bi S, Qiu Y, Zhao Q, Qin Z, Xu Q, Ai Y, Chen L, Zhang B, Liu Z, Ji M, Lang M, Chen L, Xu G, Hu L, Ye D, Ji H. TET2-STAT3-CXCL5 nexus promotes neutrophil lipid transfer to fuel lung adeno-to-squamous transition. J Exp Med 2024; 221:e20240111. [PMID: 38805014 PMCID: PMC11129275 DOI: 10.1084/jem.20240111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/21/2024] [Accepted: 04/05/2024] [Indexed: 05/29/2024] Open
Abstract
Phenotypic plasticity is a rising cancer hallmark, and lung adeno-to-squamous transition (AST) triggered by LKB1 inactivation is significantly associated with drug resistance. Mechanistic insights into AST are urgently needed to identify therapeutic vulnerability in LKB1-deficient lung cancer. Here, we find that ten-eleven translocation (TET)-mediated DNA demethylation is elevated during AST in KrasLSL-G12D/+; Lkb1L/L (KL) mice, and knockout of individual Tet genes reveals that Tet2 is required for squamous transition. TET2 promotes neutrophil infiltration through STAT3-mediated CXCL5 expression. Targeting the STAT3-CXCL5 nexus effectively inhibits squamous transition through reducing neutrophil infiltration. Interestingly, tumor-infiltrating neutrophils are laden with triglycerides and can transfer the lipid to tumor cells to promote cell proliferation and squamous transition. Pharmacological inhibition of macropinocytosis dramatically inhibits neutrophil-to-cancer cell lipid transfer and blocks squamous transition. These data uncover an epigenetic mechanism orchestrating phenotypic plasticity through regulating immune microenvironment and metabolic communication, and identify therapeutic strategies to inhibit AST.
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Affiliation(s)
- Yun Xue
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yuting Chen
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- School of Life Science and Technology, Shanghai Tech University, Shanghai, China
| | - Sijia Sun
- Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Xinyuan Tong
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Yujia Chen
- Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Shijie Tang
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Xue Wang
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Simin Bi
- Department of Physics, State Key Laboratory of Surface Physics, Academy for Engineering and Technology, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education), Shanghai, China
| | - Yuqin Qiu
- Key Laboratory of Advanced Polymeric Materials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, China
| | - Qiqi Zhao
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- School of Life Science and Technology, Shanghai Tech University, Shanghai, China
| | - Zhen Qin
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Qin Xu
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Yingjie Ai
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Leilei Chen
- Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Beizhen Zhang
- University of Chinese Academy of Sciences, Beijing, China
| | - Zhijie Liu
- Department of Physics, State Key Laboratory of Surface Physics, Academy for Engineering and Technology, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education), Shanghai, China
| | - Minbiao Ji
- Department of Physics, State Key Laboratory of Surface Physics, Academy for Engineering and Technology, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education), Shanghai, China
| | - Meidong Lang
- Key Laboratory of Advanced Polymeric Materials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, China
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Luonan Chen
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- School of Life Science and Technology, Shanghai Tech University, Shanghai, China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China
| | - Guoliang Xu
- State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
- Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Chinese Academy of Medical Sciences (RU069), Shanghai, China
| | - Liang Hu
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Dan Ye
- Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Hongbin Ji
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- School of Life Science and Technology, Shanghai Tech University, Shanghai, China
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Yu L, Chen Y, Chen Y, Luo K. The crosstalk between metabolic reprogramming and epithelial-mesenchymal transition and their synergistic roles in distant metastasis in breast cancer. Medicine (Baltimore) 2024; 103:e38462. [PMID: 38875364 PMCID: PMC11175907 DOI: 10.1097/md.0000000000038462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 03/07/2024] [Accepted: 05/14/2024] [Indexed: 06/16/2024] Open
Abstract
BACKGROUND Metabolic reprogramming (MR) and epithelial-mesenchymal transition (EMT) are crucial phenomena involved in the distant metastasis of breast cancer (BRCA). This study aims to assess the risk of distant metastasis in BRCA patients based on MR and EMT processes and investigate their underlying mechanisms. METHODS Gene sets related to EMT and MR were downloaded. MR-related genes (MRG) and EMT-related genes (ERG) were obtained. Principal Component Analysis method was used to define the EMT Potential Index (EPI) and MR Potential Index (MPI) to quantify the EMT and MR levels in each tumor tissue. A linear scoring model, the Metastasis Score, was derived using the union of MRGs and ERGs to evaluate the risk of distant metastasis/recurrence in BRCA. The Metastasis Score was then validated in multiple datasets. Additionally, our study explored the underlying mechanism of the Metastasis Score and its association with tumor immunity, focusing on HPRT1 gene expression in breast cancer tissues of transfer and untransferred groups using experimental methods. RESULTS A total of 59 MRGs and 30 ERGs were identified in the present study. Stratifying the dataset based on EPI and MPI revealed significantly lower survival rates (P < .05) in the MPI_high and EPI_high groups. Kaplan-Meier analysis indicated the lowest survival rate in the EPI-high + MPI-high group. The Metastasis Score demonstrated its ability to distinguish prognoses in GSE2034, GSE17705, and TCGA-BRCA datasets. Additionally, differences in mutated genes were found between the high- and the low-Metastasis Score groups, displaying significant associations with immune cell infiltration and anti-tumor immune status. Notably, the 13 genes included in the Metastasis Score showed a strong association with prognosis and tumor immunity. Immunohistochemistry and western blot results revealed high expression of the HPRT1 gene in the transfer group. CONCLUSION This study established the Metastasis Score as a reliable tool for evaluating the risk of distant metastasis/recurrence in BRCA patients. Additionally, we identified key genes involved in MR and EMT crosstalk, offering valuable insights into their roles in tumor immunity and other relevant aspects.
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Affiliation(s)
- Liyan Yu
- Department of Breast Surgery, Guangdong Medical University Affiliated Hospital, Zhanjiang, P.R. China
| | - Yongni Chen
- Department of Breast Surgery, Guangdong Medical University Affiliated Hospital, Zhanjiang, P.R. China
| | - Yingyu Chen
- Department of Breast Surgery, Guangdong Medical University Affiliated Hospital, Zhanjiang, P.R. China
| | - Kangwei Luo
- Department of Breast Surgery, Guangdong Medical University Affiliated Hospital, Zhanjiang, P.R. China
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9
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Ma H, Ma X, Qi L, Zhang Q, Wang T, Guo Q, Li P, Zhang S, Liu S. Lysophosphatidic acid promotes ESCC progression by increasing the level of CCL2 secreted by esophageal epithelial cells. J Gene Med 2024; 26:e3708. [PMID: 38837511 DOI: 10.1002/jgm.3708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 01/15/2024] [Accepted: 03/28/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND Lysophosphatidic acid (LPA) is a small bioactive lipid which acts as a potent regulator in various tumor progressions through six G-protein-coupled receptors (LPA1-LPA6). Our previous study demonstrated that the LPA-producing enzyme, autotaxin (ATX), was upregulated in esophageal squamous cell carcinoma (ESCC) and ATX high expression levels indicated a poor prognosis. Esophageal squamous cell carcinoma is a type of malignant tumor which originates from epithelial cells. Its progression can be affected by the interaction between cancer cells and normal cells. However, the impact of LPA on the interaction between esophageal epithelial cells and cancer cells in the development of ESCC remains uncertain. METHODS MTS and Edu assays were performed to determine ESCC cell proliferation in culture medium (CM) derived from LPA-stimulated esophageal epithelial cells (Het-1a). A wound healing assay, transwell migration and an invasion assay were performed to assess the metastatic ability of ESCC cells. Cytokine array analysis was conducted to detect the differentially secreted cytokines in CM. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to uncover the pathways and cytokines that are influenced by LPA in ESCC. Immunohistochemical staining was employed to measure the expression of ATX and CCL2 in early-stage ESCC. Quantitative real-time PCR, western blot, enzyme-linked immunosorbent assay and an antibody neutralization assay were employed to measure the mechanism of LPA-mediated communication between epithelial cells and cancer cells. RESULTS Functional experiments showed that exposing ESCC cancer cells to CM from LPA-treated Het-1a results in promoting proliferation, migration, invasion and epithelial-mesenchymal transition processes. Using cytokine array analysis, we discovered that LPA triggers the release of multiple cytokines from epithelial cells. After screening of the TCGA and GEO databases, CCL2 was identified and found to be correlated with ATX expression in ESCC. Furthermore, CCL2 levels in both mRNA expression and secretion were observed to be upregulated in epithelial cells upon stimulation with LPA. Blocking CCL2 effectively reduced the pro-migration influence of CM derived from LPA-treated Het-1a. Mechanism studies have demonstrated that LPA activated the NF-κB signaling pathway through LPA1/3, ultimately causing an increase in CCL2 expression and secretion in Het-1a. CONCLUSIONS Our findings, taken together, demonstrate that CM from LPA-treated esophageal epithelial cells plays a significant role in promoting the progression of ESCC, with CCL2 acting as the primary regulator.
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Affiliation(s)
- Hui Ma
- State Key Laboratory of Digestive healthy, Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
| | - Xiaoqian Ma
- State Key Laboratory of Digestive healthy, Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
| | - Lingyu Qi
- State Key Laboratory of Digestive healthy, Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
| | - Qian Zhang
- State Key Laboratory of Digestive healthy, Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
| | - Tiange Wang
- State Key Laboratory of Digestive healthy, Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
| | - Qingdong Guo
- State Key Laboratory of Digestive healthy, Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
| | - Peng Li
- State Key Laboratory of Digestive healthy, Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
| | - Shutian Zhang
- State Key Laboratory of Digestive healthy, Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
| | - Si Liu
- State Key Laboratory of Digestive healthy, Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing, P. R. China
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10
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Song N, Shi P, Cui K, Zeng L, Wang Z, Di W, Li J, Fan Y, Li Z, Zhang J, Su W, Wang H. Potential drug targets for tumors identified through Mendelian randomization analysis. Sci Rep 2024; 14:11370. [PMID: 38762700 PMCID: PMC11102463 DOI: 10.1038/s41598-024-62178-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Accepted: 05/14/2024] [Indexed: 05/20/2024] Open
Abstract
According to the latest cancer research data, there are a significant number of new cancer cases and a substantial mortality rate each year. Although a substantial number of clinical patients are treated with existing cancer drugs each year, the efficacy is unsatisfactory. The incidence is still high and the effectiveness of most cancer drugs remains unsatisfactory. Therefore, we evaluated the human proteins for their causal relationship to for cancer risk and therefore also their potential as drug targets. We used summary tumors data from the FinnGen and cis protein quantitative trait loci (cis-pQTL) data from a genome-wide association study, and employed Mendelian randomization (MR) to explore the association between potential drug targets and nine tumors, including breast, colorectal, lung, liver, bladder, prostate, kidney, head and neck, pancreatic caners. Furthermore, we conducted MR analysis on external cohort. Moreover, Bidirectional MR, Steiger filtering, and colocalization were employed to validate the main results. The DrugBank database was used to discover potential drugs of tumors. Under the threshold of False discovery rate (FDR) < 0.05, results showed that S100A16 was protective protein and S100A14 was risk protein for human epidermal growth factor receptor 2-positive (HER-positive) breast cancer, phosphodiesterase 5A (PDE5A) was risk protein for colorectal cancer, and melanoma inhibitory activity (MIA) was protective protein for non-small cell lung carcinoma (NSCLC). And there was no reverse causal association between them. Colocalization analysis showed that S100A14 (PP.H4.abf = 0.920) and S100A16 (PP.H4.abf = 0.932) shared causal variation with HER-positive breast cancer, and PDE5A (PP.H4.abf = 0.857) shared causal variation with colorectal cancer (CRC). The MR results of all pQTL of PDE5A and MIA were consistent with main results. In addition, the MR results of MIA and external outcome cohort were consistent with main results. In this study, genetic predictions indicate that circulating S100 calcium binding protein A14 (S100A14) and S100 calcium binding protein A16 (S100A16) are associated with increase and decrease in the risk of HER-positive breast cancer, respectively. Circulating PDE5A is associated with increased risk of CRC, while circulating MIA is associated with decreased risk of NSCLC. These findings suggest that four proteins may serve as biomarkers for cancer prevention and as potential drug targets that could be expected for approval.
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Affiliation(s)
- Na Song
- Department of Pathology, Xinxiang Key Laboratory of Precision Medicine, The First Affiliated Hospital of Xinxiang Medical University, Jiankang Road No.88, Xinxiang, 453100, China
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Jinsui Road No. 601, Xinxiang, 453000, China
| | - Pingyu Shi
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Jinsui Road No. 601, Xinxiang, 453000, China
| | - Kai Cui
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Jinsui Road No. 601, Xinxiang, 453000, China
| | - Liqun Zeng
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Jinsui Road No. 601, Xinxiang, 453000, China
| | - Ziwei Wang
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Jinsui Road No. 601, Xinxiang, 453000, China
| | - Wenyu Di
- Department of Pathology, Xinxiang Key Laboratory of Precision Medicine, The First Affiliated Hospital of Xinxiang Medical University, Jiankang Road No.88, Xinxiang, 453100, China
| | - Jinsong Li
- Department of Pathology, Xinxiang Key Laboratory of Precision Medicine, The First Affiliated Hospital of Xinxiang Medical University, Jiankang Road No.88, Xinxiang, 453100, China
| | - Yanwu Fan
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Jinsui Road No. 601, Xinxiang, 453000, China
| | - Zhanjun Li
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China
| | - Jinghang Zhang
- Department of Pathology, Xinxiang Key Laboratory of Precision Medicine, The First Affiliated Hospital of Xinxiang Medical University, Jiankang Road No.88, Xinxiang, 453100, China
| | - Wei Su
- Department of Pathology, Xinxiang Key Laboratory of Precision Medicine, The First Affiliated Hospital of Xinxiang Medical University, Jiankang Road No.88, Xinxiang, 453100, China.
| | - Haijun Wang
- Department of Pathology, Xinxiang Key Laboratory of Precision Medicine, The First Affiliated Hospital of Xinxiang Medical University, Jiankang Road No.88, Xinxiang, 453100, China.
- Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Jinsui Road No. 601, Xinxiang, 453000, China.
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11
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Wu G, Dong Z, Dong Y, Chen Y, Zhu H, Ding D, Cui Y, Wang Y, Xu Y, Chen H. LncRNA CTBP1-AS inhibits TP63-mediated activation of S100A14 during prostate cancer progression. Cancer Sci 2024; 115:1492-1504. [PMID: 38476086 PMCID: PMC11093200 DOI: 10.1111/cas.16138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 02/10/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Long noncoding RNAs (lncRNAs) have emerged as important molecules and potential new targets for human cancers. This study investigates the function of lncRNA CTBP1 antisense RNA (CTBP1-AS) in prostate cancer (PCa) and explores the entailed molecular mechanism. Aberrantly expressed genes potentially correlated with PCa progression were probed using integrated bioinformatics analyses. A cohort of 68 patients with PCa was included, and their tumor and para-cancerous tissues were collected. CTBP1-AS was highly expressed in PCa tissues and cells and associated with poor patient prognosis. By contrast, tumor protein p63 (TP63) and S100 calcium binding protein A14 (S100A14) were poorly expressed in the PCa tissues and cells. CTBP1-AS did not affect TP63 expression; however it blocked the TP63-mediated transcriptional activation of S100A14, thereby reducing its expression. CTBP1-AS silencing suppressed proliferation, apoptosis resistance, migration, invasion, and tumorigenicity of PCa cell lines, while its overexpression led to inverse results. The malignant phenotype of cells was further weakened by TP63 overexpression but restored following artificial S100A14 silencing. In conclusion, this study demonstrates that CTBP1-AS plays an oncogenic role in PCa by blocking TP63-mediated transcriptional activation of S100A14. This may provide insight into the management of PCa.
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Affiliation(s)
- Guangzheng Wu
- Department of UrologyHarbin Medical University Cancer HospitalHarbinHeilongjiangChina
| | - Zhenkun Dong
- Department of UrologyHarbin Medical University Cancer HospitalHarbinHeilongjiangChina
| | - Yuhang Dong
- Department of UrologyHarbin Medical University Cancer HospitalHarbinHeilongjiangChina
| | - Yinmei Chen
- Department of UrologyHarbin Medical University Cancer HospitalHarbinHeilongjiangChina
| | - Huan Zhu
- Department of UrologyHarbin Medical University Cancer HospitalHarbinHeilongjiangChina
| | - Dexin Ding
- Department of UrologyHarbin Medical University Cancer HospitalHarbinHeilongjiangChina
| | - Yan Cui
- Department of UrologyHarbin Medical University Cancer HospitalHarbinHeilongjiangChina
| | - Yiwen Wang
- Department of UrologyHarbin Medical University Cancer HospitalHarbinHeilongjiangChina
| | - Yangyang Xu
- Department of UrologyHarbin Medical University Cancer HospitalHarbinHeilongjiangChina
| | - Hui Chen
- Department of UrologyHarbin Medical University Cancer HospitalHarbinHeilongjiangChina
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12
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Guo H, Liu R, Wu J, Li S, Yao W, Xu J, Zheng C, Lu Y, Zhang H. SRPX2 promotes cancer cell proliferation and migration of papillary thyroid cancer. Clin Exp Med 2023; 23:4825-4834. [PMID: 37306872 PMCID: PMC10725347 DOI: 10.1007/s10238-023-01113-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 05/29/2023] [Indexed: 06/13/2023]
Abstract
Thyroid cancer is the endocrine tumor with the highest incidence at present. It originates from the thyroid follicular epithelium or follicular paraepithelial cells. There is an increasing incidence of thyroid cancer all over the world. We found that SRPX2 expression level was higher in papillary thyroid tumors than in normal thyroid tissues, and SRPX2 expression was closely related to tumor grade and clinical prognosis. Previous reports showed that SRPX2 could function by activating PI3K/AKT signaling pathway. In addition, in vitro experiments showed that SRPX2 promoted the proliferation and migration of papillary thyroid cancer (PTC). In conclusion, SRPX2 could promote the malignant development of PTC. This may be a potential treatment target for PTC.
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Affiliation(s)
- Haiwei Guo
- Otolaryngology and Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center for Cancer of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Ruiqi Liu
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Graduate Department, Bengbu Medical College, Bengbu, Anhui, China
| | - Jiajun Wu
- Otolaryngology and Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Graduate Department, Bengbu Medical College, Bengbu, Anhui, China
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center for Cancer of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Shuang Li
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Weiping Yao
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Graduate Department, Bengbu Medical College, Bengbu, Anhui, China
| | - Jiajie Xu
- Otolaryngology and Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center for Cancer of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Chuanming Zheng
- Otolaryngology and Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, Zhejiang, China
- Clinical Research Center for Cancer of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yanwei Lu
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Haibo Zhang
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
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13
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Garza-Campos A, Prieto-Correa JR, Domínguez-Rosales JA, Hernández-Nazará ZH. Implications of receptor for advanced glycation end products for progression from obesity to diabetes and from diabetes to cancer. World J Diabetes 2023; 14:977-994. [PMID: 37547586 PMCID: PMC10401444 DOI: 10.4239/wjd.v14.i7.977] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/31/2023] [Accepted: 04/17/2023] [Indexed: 07/12/2023] Open
Abstract
Obesity and type 2 diabetes mellitus (T2DM) are chronic pathologies with a high incidence worldwide. They share some pathological mechanisms, including hyperinsulinemia, the production and release of hormones, and hyperglycemia. The above, over time, affects other systems of the human body by causing tissue hypoxia, low-grade inflammation, and oxidative stress, which lay the pathophysiological groundwork for cancer. The leading causes of death globally are T2DM and cancer. Other main alterations of this pathological triad include the accumulation of advanced glycation end products and the release of endogenous alarmins due to cell death (i.e., damage-associated molecular patterns) such as the intracellular proteins high-mobility group box protein 1 and protein S100 that bind to the receptor for advanced glycation products (RAGE) - a multiligand receptor involved in inflammatory and metabolic and neoplastic processes. This review analyzes the latest advanced reports on the role of RAGE in the development of obesity, T2DM, and cancer, with an aim to understand the intracellular signaling mechanisms linked with cancer initiation. This review also explores inflammation, oxidative stress, hypoxia, cellular senescence, RAGE ligands, tumor microenvironment changes, and the “cancer hallmarks” of the leading tumors associated with T2DM. The assimilation of this information could aid in the development of diagnostic and therapeutic approaches to lower the morbidity and mortality associated with these diseases.
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Affiliation(s)
- Andrea Garza-Campos
- Programa de Doctorado en Ciencias en Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - José Roberto Prieto-Correa
- Programa de Doctorado en Ciencias en Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - José Alfredo Domínguez-Rosales
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Zamira Helena Hernández-Nazará
- Departamento de Biología Molecular y Genómica, Instituto de Investigación en Enfermedades Crónico-Degenerativas, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico
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14
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Yoshimura T, Li C, Wang Y, Matsukawa A. The chemokine monocyte chemoattractant protein-1/CCL2 is a promoter of breast cancer metastasis. Cell Mol Immunol 2023; 20:714-738. [PMID: 37208442 PMCID: PMC10310763 DOI: 10.1038/s41423-023-01013-0] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 03/17/2023] [Indexed: 05/21/2023] Open
Abstract
Breast cancer is the most prevalent cancer worldwide, and metastasis is the leading cause of death in cancer patients. Human monocyte chemoattractant protein-1 (MCP-1/CCL2) was isolated from the culture supernatants of not only mitogen-activated peripheral blood mononuclear leukocytes but also malignant glioma cells based on its in vitro chemotactic activity toward human monocytes. MCP-1 was subsequently found to be identical to a previously described tumor cell-derived chemotactic factor thought to be responsible for the accumulation of tumor-associated macrophages (TAMs), and it became a candidate target of clinical intervention; however, the role of TAMs in cancer development was still controversial at the time of the discovery of MCP-1. The in vivo role of MCP-1 in cancer progression was first evaluated by examining human cancer tissues, including breast cancers. Positive correlations between the level of MCP-1 production in tumors and the degree of TAM infiltration and cancer progression were established. The contribution of MCP-1 to the growth of primary tumors and metastasis to the lung, bone, and brain was examined in mouse breast cancer models. The results of these studies strongly suggested that MCP-1 is a promoter of breast cancer metastasis to the lung and brain but not bone. Potential mechanisms of MCP-1 production in the breast cancer microenvironment have also been reported. In the present manuscript, we review studies in which the role of MCP-1 in breast cancer development and progression and the mechanisms of its production were examined and attempt to draw a consensus and discuss the potential use of MCP-1 as a biomarker for diagnosis.
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Affiliation(s)
- Teizo Yoshimura
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan.
| | - Chunning Li
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan
| | - Yuze Wang
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan
| | - Akihiro Matsukawa
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan
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15
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Motyka J, Kicman A, Kulesza M, Ławicki S. CXC ELR-Positive Chemokines as Diagnostic and Prognostic Markers for Breast Cancer Patients. Cancers (Basel) 2023; 15:3118. [PMID: 37370728 DOI: 10.3390/cancers15123118] [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: 03/17/2023] [Revised: 06/01/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
As the most common type of malignant lesison, breast cancer is a leading challenge for clinicians. Currently, diagnosis is based on self-examination and imaging studies that require confirmation by tissue biopsy. However, there are no easily accessible diagnostic tools that can serve as diagnostic and prognostic markers for breast cancer patients. One of the possible candidates for such markers is a group of chemokines that are closely implicated in each stage of tumorigenesis. Many researchers have noted the potential of this molecule group to become tumor markers and have tried to establish their clinical utility. In this work, we summarize the results obtained by scientists on the usefulness of the ELR-positive CXC group of chemokines in ancillary diagnosis of breast cancer.
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Affiliation(s)
- Joanna Motyka
- Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, 15-269 Bialystok, Poland
| | - Aleksandra Kicman
- Department of Aesthetic Medicine, Medical University of Bialystok, 15-267 Bialystok, Poland
| | - Monika Kulesza
- Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, 15-269 Bialystok, Poland
| | - Sławomir Ławicki
- Department of Population Medicine and Lifestyle Diseases Prevention, Medical University of Bialystok, 15-269 Bialystok, Poland
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16
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Zhao Y, Li Y, Zhu R, Feng R, Cui H, Yu X, Huang F, Zhang R, Chen X, Li L, Chen Y, Liu Y, Wang J, Du G, Liu Z. RPS15 interacted with IGF2BP1 to promote esophageal squamous cell carcinoma development via recognizing m 6A modification. Signal Transduct Target Ther 2023; 8:224. [PMID: 37264021 DOI: 10.1038/s41392-023-01428-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 02/23/2023] [Accepted: 03/24/2023] [Indexed: 06/03/2023] Open
Abstract
Increased rates of ribosome biogenesis have been recognized as hallmarks of many cancers and are associated with poor prognosis. Using a CRISPR synergistic activation mediator (SAM) system library targeting 89 ribosomal proteins (RPs) to screen for the most oncogenic functional RPs in human esophageal squamous cell carcinoma (ESCC), we found that high expression of RPS15 correlates with malignant phenotype and poor prognosis of ESCC. Gain and loss of function models revealed that RPS15 promotes ESCC cell metastasis and proliferation, both in vitro and in vivo. Mechanistic investigations demonstrated that RPS15 interacts with the K homology domain of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which recognizes and directly binds the 3'-UTR of MKK6 and MAPK14 mRNA in an m6A-dependent manner, and promotes translation of core p38 MAPK pathway proteins. By combining targeted drug virtual screening and functional assays, we found that folic acid showed a therapeutic effect on ESCC by targeting RPS15, which was augmented by the combination with cisplatin. Inhibition of RPS15 by folic acid, IGF2BP1 ablation, or SB203580 treatment were able to suppress ESCC metastasis and proliferation via the p38 MAPK signaling pathway. Thus, RPS15 promotes ESCC progression via the p38 MAPK pathway and RPS15 inhibitors may serve as potential anti-ESCC drugs.
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Affiliation(s)
- Yahui Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yang Li
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Rui Zhu
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Riyue Feng
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Heyang Cui
- Department of Oncology, Cancer Institute, Peking University Shenzhen Hospital, Shenzhen Peking University-Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Shenzhen, 518035, China
| | - Xiao Yu
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Furong Huang
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Ruixiang Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
| | - Xiankai Chen
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
| | - Lei Li
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China
| | - Yinghui Chen
- School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Yuhao Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518116, China
| | - Jinhua Wang
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - Guanhua Du
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - Zhihua Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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17
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Li H, Li J, Bai Z, Yan S, Li J. Collagen-induced DDR1 upregulates CXCL5 to promote neutrophil extracellular traps formation and Treg infiltration in breast cancer. Int Immunopharmacol 2023; 120:110235. [PMID: 37201403 DOI: 10.1016/j.intimp.2023.110235] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 04/18/2023] [Accepted: 04/21/2023] [Indexed: 05/20/2023]
Abstract
Neutrophil extracellular traps (NETs) have been implicated in many cancers, but the regulatory mechanisms in the context of breast cancer have not been thoroughly discussed. This study proposed a mechanism based on collagen-activated DDR1/CXCL5 for NET formation in breast cancer. Through TCGA and GEO-based bioinformatics analysis, we examined the DDR1 expression and the correlation of CXCL5 with immune cell infiltration in breast cancer. It was found that high DDR1 expression was correlated with poor prognosis of patients with breast cancer, and CXCL5 was positively correlated with neutrophil and Treg infiltration. Expression of DDR1 and CXCL5 was determined in collagen-treated breast cancer cells, the malignant phenotypes of which were evaluated by ectopic expression and knockdown methods. Collagen-activated DDR1 upregulated CXCL5 expression, resulting in augmented malignant phenotypes of breast cancer cells in vitro. The formation of NETs caused promotion in the differentiation and immune infiltration of Tregs in breast cancer. A in situ breast cancer mouse model was constructed, where NET formation and lung metastasis of breast cancer cells were observed. The differentiation of CD4+ T cells isolated from the mouse model was induced into Tregs, followed by Treg infiltration assessment. It was further confirmed in vivo that DDR1/CXCL5 induced the formation of NETs to promote immune infiltration of Tregs, driving tumor growth and metastasis. Accordingly, our results provided new mechanistic insights for an understanding of the role of collagen-mediated DDR1/CXCL5 in formation of NETs and Treg infiltration, revealing potential targets for therapeutic intervention of breast cancer.
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Affiliation(s)
- Hong Li
- Department of Surgical Oncology, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia Province, China
| | - Jiayi Li
- Northewest Minzu University, Lanzhou 730030, Gansu Province, China
| | - Zhengyang Bai
- Ningxia Medical University, Yinchuan 750004, Ningxia Province, China
| | - Shuxun Yan
- Ningxia Medical University, Yinchuan 750004, Ningxia Province, China
| | - Jinping Li
- Department of Surgical Oncology, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia Province, China.
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18
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Wang YY, Zhou YN, Jiang L, Wang S, Zhu L, Zhang SS, Yang H, He Q, Liu L, Xie YH, Liang X, Tang J, Chao FL, Tang Y. Long-term voluntary exercise inhibited AGE/RAGE and microglial activation and reduced the loss of dendritic spines in the hippocampi of APP/PS1 transgenic mice. Exp Neurol 2023; 363:114371. [PMID: 36871860 DOI: 10.1016/j.expneurol.2023.114371] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 02/22/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023]
Abstract
Alzheimer's disease (AD) is closely related to hippocampal synapse loss, which can be alleviated by running exercise. However, further studies are needed to determine whether running exercise reduces synapse loss in the hippocampus in an AD model by regulating microglia. Ten-month-old male wild-type mice and APP/PS1 mice were randomly divided into control and running groups. All mice in the running groups were subjected to voluntary running exercise for four months. After the behavioral tests, immunohistochemistry, stereological methods, immunofluorescence staining, 3D reconstruction, western blotting and RNA-Seq were performed. Running exercise improved the spatial learning and memory abilities of APP/PS1 mice and increased the total number of dendritic spines, the levels of the PSD-95 and Synapsin Ia/b proteins, the colocalization of PSD-95 and neuronal dendrites (MAP-2) and the number of PSD-95-contacting astrocytes (GFAP) in the hippocampi of APP/PS1 mice. Moreover, running exercise reduced the relative expression of CD68 and Iba-1, the number of Iba-1+ microglia and the colocalization of PSD-95 and Iba-1+ microglia in the hippocampi of APP/PS1 mice. The RNA-Seq results showed that some differentially expressed genes (DEGs) related to the complement system (Cd59b, Serping1, Cfh, A2m, and Trem2) were upregulated in the hippocampi of APP/PS1 mice, while running exercise downregulated the C3 gene. At the protein level, running exercise also reduced the expression of advanced glycation end products (AGEs), receptor for advanced glycation end products (RAGE), C1q and C3 in the hippocampus and AGEs and RAGE in hippocampal microglia in APP/PS1 mice. Furthermore, the Col6a3, Scn5a, Cxcl5, Tdg and Clec4n genes were upregulated in the hippocampi of APP/PS1 mice but downregulated after running, and these genes were associated with the C3 and RAGE genes according to protein-protein interaction (PPI) analysis. These findings indicate that long-term voluntary exercise might protect hippocampal synapses and affect the function and activation of microglia, the AGE/RAGE signaling pathway in microglia and the C1q/C3 complement system in the hippocampus in APP/PS1 mice, and these effects may be related to the Col6a3, Scn5a, Cxcl5, Tdg and Clec4n genes. The current results provide an important basis for identifying targets for the prevention and treatment of AD.
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Affiliation(s)
- Yi-Ying Wang
- Department of Histology and Embryology, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cell and Tissue Engineering, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China
| | - Yu-Ning Zhou
- Department of Histology and Embryology, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cell and Tissue Engineering, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China
| | - Lin Jiang
- Lab Teaching & Management Center, Chongqing Medical University, Chongqing 400016, PR China
| | - Shun Wang
- Department of Histology and Embryology, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cell and Tissue Engineering, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China
| | - Lin Zhu
- Department of Histology and Embryology, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cell and Tissue Engineering, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China
| | - Shan-Shan Zhang
- Department of Histology and Embryology, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cell and Tissue Engineering, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China
| | - Hao Yang
- Department of Histology and Embryology, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cell and Tissue Engineering, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China
| | - Qi He
- Department of Histology and Embryology, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cell and Tissue Engineering, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China
| | - Li Liu
- Department of Histology and Embryology, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cell and Tissue Engineering, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China
| | - Yu-Han Xie
- Department of Histology and Embryology, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cell and Tissue Engineering, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China
| | - Xin Liang
- Department of Pathophysiology, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China
| | - Jing Tang
- Department of Histology and Embryology, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cell and Tissue Engineering, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China
| | - Feng-Lei Chao
- Department of Histology and Embryology, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cell and Tissue Engineering, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China.
| | - Yong Tang
- Department of Histology and Embryology, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China; Laboratory of Stem Cell and Tissue Engineering, Faculty of Basic Medical College, Chongqing Medical University, Chongqing 400016, PR China.
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19
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Chen J, Luo T, Jiang M, Liu J, Gupta GP, Li Y. Cell composition inference and identification of layer-specific spatial transcriptional profiles with POLARIS. SCIENCE ADVANCES 2023; 9:eadd9818. [PMID: 36857450 PMCID: PMC9977174 DOI: 10.1126/sciadv.add9818] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 01/31/2023] [Indexed: 06/18/2023]
Abstract
Spatial transcriptomics (ST) technology, providing spatially resolved transcriptional profiles, facilitates advanced understanding of key biological processes related to health and disease. Sequencing-based ST technologies provide whole-transcriptome profiles but are limited by the non-single cell-level resolution. Lack of knowledge in the number of cells or cell type composition at each spot can lead to invalid downstream analysis, which is a critical issue recognized in ST data analysis. Methods developed, however, tend to underuse histological images, which conceptually provide important and complementary information including anatomical structure and distribution of cells. To fill in the gaps, we present POLARIS, a versatile ST analysis method that can perform cell type deconvolution, identify anatomical or functional layer-wise differentially expressed (LDE) genes, and enable cell composition inference from histology images. Applied to four tissues, POLARIS demonstrates high deconvolution accuracy, accurately predicts cell composition solely from images, and identifies LDE genes that are biologically relevant and meaningful.
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Affiliation(s)
- Jiawen Chen
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Tianyou Luo
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Minzhi Jiang
- Department of Applied Physical Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Jiandong Liu
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Gaorav P. Gupta
- Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Yun Li
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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20
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Wang ZZ, Li XT, Li QJ, Zhou JX. Targeting CXCL5 in Pancreatic Cancer Cells Inhibits Cancer Xenograft Growth by Reducing Proliferation and Inhibiting EMT Progression. Dig Dis Sci 2023; 68:841-851. [PMID: 35650416 DOI: 10.1007/s10620-022-07529-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 04/18/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Pancreatic cancer (PC) is the most lethal malignant tumor, with average survival period of about 10 months. C-X-C ligand 5 (CXCL5), an important chemokine for immune cell accumulation in tumor tissues, has been reported to be involved in a variety of human cancers. However, the exact role of CXCL5 in PC progression has not been well defined. METHODS The expression of CXCL5 in PC was analyzed based on online databases and clinical specimens immunohistochemical staining, and Western blotting of CXCL5 in PC cell lines and patient samples. The correlation between CXCL5 expression and prognosis in PC was explored. The role of CXCL5 in PC was investigated through in vitro and in vivo experiments. RESULTS The expression of CXCL5 was significantly increased in PC tissues compared with that in pancreas tissues, and CXCL5 high expression predicts poor prognosis in PC patients. Further analyses demonstrated that overexpression of CXCL5 in PC cells was positively related to higher proliferation rate, higher migration ability, and higher EMT markers including SNAI2 and TWIST1 of tumor cells in vitro. Consistently, the knockdown of CXCL5 in PC cells harmed the proliferation rate, migration ability, and expression of EMT indexes of tumor cells in vitro. Importantly, knockdown of CXCL5 inhibited the growth of xenograft tumors in vivo. CONCLUSION CXCL5 high expression predicts poor prognosis in PC patients. CXCL5 promotes PC cell growth and EMT process. Inhibition of CXCL5 may be a potential therapeutic approach for PC.
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Affiliation(s)
- Zheng-Zheng Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Xiao-Ting Li
- Department of Obstetrics and Gynecology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, China
| | - Qing-Jun Li
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Jin-Xue Zhou
- Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008, China.
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21
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Zhou X, Huang F, Ma G, Wei W, Wu N, Liu Z. Dysregulated ceramides metabolism by fatty acid 2-hydroxylase exposes a metabolic vulnerability to target cancer metastasis. Signal Transduct Target Ther 2022; 7:370. [PMID: 36274060 PMCID: PMC9588768 DOI: 10.1038/s41392-022-01199-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 08/16/2022] [Accepted: 09/19/2022] [Indexed: 11/09/2022] Open
Abstract
Whereas it is appreciated that cancer cells rewire lipid metabolism to survive and propagate, the roles of lipid metabolism in metastasis remain largely unknown. In this study, using esophageal squamous cell carcinoma (ESCC) as a pulmonary metastasis model, we find that the enzyme fatty acid 2-hydroxylase (FA2H), which catalyzes the hydroxylation of free fatty acids (FAs), is enriched in a subpopulation of ESCC cells with high metastatic potential, and that FA2H knockdown markedly mitigates metastatic lesions. Moreover, increased FA2H expression is positively associated with poor survival in patients with ESCC. Lipidomics analysis identifies that two dihydroceramides—Cer(d18:0/24:0) and Cer(d18:0/24:1)—are increased in FA2H-depleted metastasizing ESCC cells. Upon administration, Cer(d18:0/24:0) and Cer(d18:0/24:1) impair the formation of overt metastases in a mouse experimental metastasis model. Then, forkhead box protein C2 (FOXC2) and FA2H are found to be co-upregulated in metastatic ESCC cell populations and ESCC specimens, and FA2H expression is further experimentally verified to be transcriptionally induced by FOXC2, which is boosted per se by tumour necrosis factor α (TNFα), a critical pro-metastasis cytokine in the tumour microenvironment, in metastasizing cells. Together, these results demonstrate that TNFα-FOXC2-FA2H is a novel signaling axis to promote metastasis, and its downstream dihydroceramide products could be promising drugs to intervene in metastasis.
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22
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Wang YY, Hung AC, Wu YC, Lo S, Chen HD, Chen YK, Hsieh YC, Hu SCS, Hou MF, Yuan SSF. ADSCs stimulated by resistin promote breast cancer cell malignancy via CXCL5 in a breast cancer coculture model. Sci Rep 2022; 12:15437. [PMID: 36104403 PMCID: PMC9475041 DOI: 10.1038/s41598-022-19290-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/26/2022] [Indexed: 11/25/2022] Open
Abstract
The tumor microenvironment represents one of the main obstacles in breast cancer treatment owing to the presence of heterogeneous stromal cells, such as adipose-derived stem cells (ADSCs), that may interact with breast cancer cells and promote cancer development. Resistin is an adipocytokine associated with adverse breast cancer progression; however, its underlying mechanisms in the context of the breast tumor microenvironment remain largely unidentified. Here, we utilized a transwell co-culture model containing patient-derived ADSCs and breast cancer cell lines to investigate their potential interaction, and observed that breast cancer cells co-cultured with resistin-treated ADSCs (R-ADSCs) showed enhanced cancer cell growth and metastatic ability. Screening by proteome arrays revealed that C-X-C motif chemokine ligand 5 (CXCL5) was released in the conditioned medium of the co-culture system, and phosphorylated ERK was increased in breast cancer cells after co-culture with R-ADSCs. Breast cancer cells treated with the recombinant proteins of CXCL5 showed similarly enhanced cell migration and invasion ability as occurred in the co-culture model, whereas application of neutralizing antibodies against CXCL5 reversed these phenomena. The orthotopic xenograft in mice by breast cancer cells after co-culture with R-ADSCs had a larger tumor growth and more CXCL5 expression than control. In addition, clinical analysis revealed a positive correlation between the expression of resistin and CXCL5 in both tumor tissues and serum specimens of breast cancer patients. The current study suggests that resistin-stimulated ADSCs may interact with breast cancer cells in the tumor microenvironment via CXCL5 secretion, leading to breast cancer cell malignancy.
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Affiliation(s)
- Yen-Yun Wang
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Amos C Hung
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Chia Wu
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Steven Lo
- College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Huan-Da Chen
- Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yuk-Kwan Chen
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Oral Pathology and Maxillofacial Radiology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Oral and Maxillofacial Imaging Center, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ya-Ching Hsieh
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Stephen Chu-Sung Hu
- Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Feng Hou
- Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shyng-Shiou F Yuan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
- Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
- Department of Biological Science and Technology, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
- Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
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LHX2 Enhances the Malignant Phenotype of Esophageal Squamous Cell Carcinoma by Upregulating the Expression of SERPINE2. Genes (Basel) 2022; 13:genes13081457. [PMID: 36011368 PMCID: PMC9408536 DOI: 10.3390/genes13081457] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/13/2022] [Accepted: 08/15/2022] [Indexed: 12/01/2022] Open
Abstract
LHX2 dysregulations have been found to present in cancers, but the function of LHX2 in esophageal squamous cell carcinoma (ESCC) remains unknown. Here, we report that LHX2 was upregulated in ESCC tissues in comparison to the LHX2 levels in adjacent normal tissues. Loss- and gain-of-function experiments demonstrated that the knockdown of LHX2 markedly inhibited ESCC cells’ proliferation, migration, invasion, tumor growth and metastasis, whereas the overexpression of LHX2 had the opposite effects. A mechanistic investigation revealed that LHX2 bound to the promoter of SERPINE2 gene and transcriptionally regulated the expression of SERPINE2. Collectively, LHX2 facilitates ESCC tumor progression, and it could be a potential therapeutic target for ESCC.
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Wang C, Chen Y, Xinpeng Y, Xu R, Song J, Ruze R, Xu Q, Zhao Y. Construction of immune-related signature and identification of S100A14 determining immune-suppressive microenvironment in pancreatic cancer. BMC Cancer 2022; 22:879. [PMID: 35953822 PMCID: PMC9367131 DOI: 10.1186/s12885-022-09927-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 07/20/2022] [Indexed: 11/20/2022] Open
Abstract
Pancreatic cancer (PC) is a highly lethal and aggressive disease with its incidence and mortality quite discouraging. A robust prognostic signature and novel biomarkers are urgently needed for accurate stratification of the patients and optimization of clinical decision-making. Since the critical role of immune microenvironment in the progression of PC, a prognostic signature based on seven immune-related genes was established, which was validated in The Cancer Genome Atlas (TCGA) training set, TCGA testing set, TCGA entire set and GSE71729 set. Furthermore, S100A14 (S100 Calcium Binding Protein A14) was identified as the gene occupying the most paramount position in risk signature. According to the GSEA, CIBERSORT and ESTIMATE algorithm, S100A14 was mainly associated with lower proportion of CD8 + T cells and higher proportion of M0 macrophages in PC tissue. Meanwhile, analysis of single-cell dataset CRA001160 revealed a significant negative correlation between S100A14 expression in PC cells and CD8 + T cell infiltration, which was further confirmed by tissue microenvironment landscape imaging and machine learning-based analysis in our own PUMCH cohort. Additionally, analysis of a pan-pancreatic cancer cell line illustrated that S100A14 might inhibit CD8 + T cell activation via the upregulation of PD-L1 expression in PC cells, which was also verified by the immunohistochemical results of PUMCH cohort. Finally, tumor mutation burden analysis and immunophenoscore algorithm revealed that patients with high S100A14 expression had a higher probability of responding to immunotherapy. In conclusion, our study established an efficient immune-related prediction model and identified the potential role of S100A14 in regulating the immune microenvironment and serving as a biomarker for immunotherapy efficacy prediction.
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Affiliation(s)
- Chengcheng Wang
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100023, PR China
| | - Yuan Chen
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100023, PR China.
| | - Yin Xinpeng
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100023, PR China
| | - Ruiyuan Xu
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100023, PR China
| | - Jianlu Song
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100023, PR China
| | - Rexiati Ruze
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100023, PR China
| | - Qiang Xu
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100023, PR China.
| | - Yupei Zhao
- Department of General Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100023, PR China.
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Deng J, Jiang R, Meng E, Wu H. CXCL5: A coachman to drive cancer progression. Front Oncol 2022; 12:944494. [PMID: 35978824 PMCID: PMC9376318 DOI: 10.3389/fonc.2022.944494] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 07/08/2022] [Indexed: 11/13/2022] Open
Abstract
Chemokines are a class of pro-inflammatory cytokines that can recruit and activate chemotactic cells. C‐X‐C motif chemokine ligand 5 (CXCL5) is a member of the chemokine family binding CXCR2 (C-X-C Motif Chemokine Receptor 2), a G-protein coupled receptor. Accumulated evidence has shown that dysregulated CXCL5 participates in tumor metastasis and angiogenesis in human malignant tumors. In this review, we summarized the advances in research on CXCL5, including its dysregulation in different tumors and the mechanism associated with tumor behavior (formation of the immunosuppressive microenvironment, promotion of tumor angiogenesis, and metastasis). We also summarized and discussed the perspective about the potential application of CXCL5 in tumor therapy targeting the tumor inflammatory microenvironment.
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26
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Disruption of enhancer-driven S100A14 expression promotes esophageal carcinogenesis. Cancer Lett 2022; 545:215833. [DOI: 10.1016/j.canlet.2022.215833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/07/2022] [Accepted: 07/17/2022] [Indexed: 11/18/2022]
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Peng J, Ma Y, Zhao X, Yang X, Wang H. Constitutive β-Catenin Overexpression Represses Lncrna MIR100HG Transcription via HDAC6-Mediated Histone Modification in Colorectal Cancer. Mol Cancer Res 2022; 20:949-959. [PMID: 35247921 DOI: 10.1158/1541-7786.mcr-21-0923] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 01/21/2022] [Accepted: 02/25/2022] [Indexed: 12/13/2022]
Abstract
Wnt/β-catenin signaling plays a critical role in colonic carcinogenesis. However, non-coding RNAs (ncRNA) transcriptionally regulated by β-catenin are largely unknown. Herein, we found that lncRNA MIR100HG (lnc-MIR100HG) negatively correlated with target genes of β-catenin from The Cancer Genome Atlas colorectal carcinoma database, which was verified in 48 paired colorectal carcinoma specimens. In addition, constitutive overexpression of β-catenin decreased primary and mature lnc-MIR100HG levels, whereas blockage of β-catenin activity with siRNA or inhibitors significantly increased their expression. DNA pull-down and chromatin immunoprecipitation revealed the binding of β-catenin/TCF4 to the MIR100HG promoter. Moreover, β-catenin-forced expression reduced the enrichment of H3K27Ac, an active transcription marker, on the promoter, whereas β-catenin inhibition reversed this effect. Furthermore, HDAC6 was recruited to the MIR100HG promoter and downregulated H3K27Ac enrichment in a β-catenin-dependent manner. Besides, HDAC6 was upregulated and negatively correlated with lnc-MIR100HG in colorectal carcinoma specimens. Functional studies showed that lnc-MIR100HG overexpression induced cell-cycle G0-G1 arrest and repressed cell proliferation via p57 upregulation in vitro and in vivo. Taken together, we found that ectopic β-catenin transcriptionally repressed lnc-MIR100HG expression through HDAC6-mediated histone modification in colorectal carcinoma. Lnc-MIR100HG regulates the cell cycle through p57. IMPLICATIONS It provides a novel downstream mechanism highlighting β-catenin action during colon carcinogenesis and may shed light for further therapeutic approaches.
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Affiliation(s)
- Jian Peng
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yiming Ma
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xinhua Zhao
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xu Yang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hongying Wang
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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28
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Li H, Wu M, Zhao X. Role of chemokine systems in cancer and inflammatory diseases. MedComm (Beijing) 2022; 3:e147. [PMID: 35702353 PMCID: PMC9175564 DOI: 10.1002/mco2.147] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/10/2022] [Accepted: 05/11/2022] [Indexed: 12/12/2022] Open
Abstract
Chemokines are a large family of small secreted proteins that have fundamental roles in organ development, normal physiology, and immune responses upon binding to their corresponding receptors. The primary functions of chemokines are to coordinate and recruit immune cells to and from tissues and to participate in regulating interactions between immune cells. In addition to the generally recognized antimicrobial immunity, the chemokine/chemokine receptor axis also exerts a tumorigenic function in many different cancer models and is involved in the formation of immunosuppressive and protective tumor microenvironment (TME), making them potential prognostic markers for various hematologic and solid tumors. In fact, apart from its vital role in tumors, almost all inflammatory diseases involve chemokines and their receptors in one way or another. Modulating the expression of chemokines and/or their corresponding receptors on tumor cells or immune cells provides the basis for the exploitation of new drugs for clinical evaluation in the treatment of related diseases. Here, we summarize recent advances of chemokine systems in protumor and antitumor immune responses and discuss the prevailing understanding of how the chemokine system operates in inflammatory diseases. In this review, we also emphatically highlight the complexity of the chemokine system and explore its potential to guide the treatment of cancer and inflammatory diseases.
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Affiliation(s)
- Hongyi Li
- Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of EducationWest China Second HospitalSichuan UniversityChengduChina
| | - Min Wu
- Department of Biomedical Sciences, School of Medicine and Health SciencesUniversity of North DakotaGrand ForksNorth DakotaUSA
| | - Xia Zhao
- Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of EducationWest China Second HospitalSichuan UniversityChengduChina
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Zhang Y, Sun M, Gao L, Liang X, Ma C, Lu J, Yue X. ZHX2 inhibits thyroid cancer metastasis through transcriptional inhibition of S100A14. Cancer Cell Int 2022; 22:76. [PMID: 35151335 PMCID: PMC8840030 DOI: 10.1186/s12935-022-02499-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 01/30/2022] [Indexed: 12/21/2022] Open
Abstract
Background Thyroid cancer is the most common malignant endocrine tumour, and metastasis has become the main reason for treatment failure. However, the underlying molecular mechanism of thyroid cancer metastasis remains poorly understood. We investigated the role of the tumour suppressor zinc fingers and homeoboxes 2 (ZHX2) in the metastasis of thyroid cancer. Methods To study the role of ZHX2 in thyroid cancer metastasis, we evaluated the EMT process using cell migration, wound healing and lung metastatic tumour formation in vitro and in vivo models. Results ZHX2 expression was significantly decreased in thyroid cancer tissues, which correlated with poor prognosis of thyroid cancer patients. ZHX2 knockdown significantly promoted the migration of thyroid cancer cells. Mechanistically, ZHX2 associated with the S100 calcium binding protein A14 (S100A14) promoter to decrease the transcription of S100A14. Moreover, S100A14 was highly expressed in human thyroid cancer samples, and its expression negatively correlated with ZHX2 expression. Conclusions Inhibition of S100A14 attenuated the ZHX2 knockdown-induced enhanced metastasis of thyroid cancer cells both in vitro and in vivo. The evidence presented here suggests that ZHX2 inhibits the progression of thyroid cancer by blocking S100A14-mediated metastasis. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-022-02499-w.
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Chi X, Gu X, Chen S, Shen X. Circ_0003221 Downregulation Restrains Cervical Cancer Cell Growth, Metastasis and Angiogenesis by Governing the miR-139-3p/S100A14 Pathway. Reprod Sci 2022; 29:1822-1835. [PMID: 35023052 DOI: 10.1007/s43032-021-00815-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 11/25/2021] [Indexed: 11/26/2022]
Abstract
Circular RNA (circRNA) has considerable potency in carcinogenesis, which has aroused much attention. The objective of our study was to disclose the role of circ_0003221 in cervical cancer. Circ_0003221, miR-139-3p, and S100 calcium-binding protein A14 (S100A14) mRNA were quantified by quantitative real-time PCR (qPCR). The proliferation of cancer cells was checked by CCK-8 assay and EdU assay. The migration and invasion of cancer cells were checked by transwell assay. Angiogenesis was determined by tube formation assay. The protein levels of epithelial-mesenchymal transition (EMT)-related markers, angiogenesis-related markers, and S100A14 protein were measured by western blot. The interplays between miR-139-3p and circ_0003221 or S100A14 were ensured by RIP assay and dual-luciferase reporter assay. Further animal study was conducted to verify the role of circ_0003221 in vivo. Circ_0003221 was highly expressed in cancer tissues and cells, and its downregulation suppressed cancer cell proliferation, migration, invasion, and angiogenesis and also delayed tumor growth in vivo. Circ_0003221 bound to miR-139-3p and sequestered miR-139-3p expression. The inhibitory cancer cell biological behaviors by circ_0003221 downregulation were recovered by miR-139-3p suppression. S100A14 was a target gene of miR-139-3p. MiR-139-3p upregulation repressed cancer cell malignant phenotypes by depleting S100A14. Importantly, circ_0003221 positively regulated S100A14 expression by targeting miR-139-3p. Circ_0003221 downregulation restrains cervical cancer cell growth, metastasis, and angiogenesis by governing the miR-139-3p/S100A14 pathway.
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Affiliation(s)
- Xiaoli Chi
- Department of Obstetrics and Gynecology, Suzhou Hospital of Integrated Traditional Chinese and Western Medicine, No.9 Xiangxi East Road, Mudu Town, Wuzhong District, Suzhou City, 215101, Jiangsu, China.
| | - Xiaofeng Gu
- Department of Obstetrics and Gynecology, Suzhou Hospital of Integrated Traditional Chinese and Western Medicine, No.9 Xiangxi East Road, Mudu Town, Wuzhong District, Suzhou City, 215101, Jiangsu, China
| | - Shujing Chen
- Department of Obstetrics and Gynecology, Suzhou Hospital of Integrated Traditional Chinese and Western Medicine, No.9 Xiangxi East Road, Mudu Town, Wuzhong District, Suzhou City, 215101, Jiangsu, China
| | - Xiaojuan Shen
- Department of Obstetrics and Gynecology, Suzhou Hospital of Integrated Traditional Chinese and Western Medicine, No.9 Xiangxi East Road, Mudu Town, Wuzhong District, Suzhou City, 215101, Jiangsu, China
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Liang F, Xu Y, Chen Y, Zhong H, Wang Z, Nong T, Zhong J. Immune Signature-Based Risk Stratification and Prediction of Immunotherapy Efficacy for Bladder Urothelial Carcinoma. Front Mol Biosci 2022; 8:673918. [PMID: 35004839 PMCID: PMC8739239 DOI: 10.3389/fmolb.2021.673918] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022] Open
Abstract
Immune-related genes (IRGs) are closely related to tumor progression and the immune microenvironment. Few studies have investigated the effect of tumor immune microenvironment on the survival and response to immune checkpoint inhibitors of patients with bladder urothelial carcinoma (BLCA). We constructed two IRG-related prognostic signatures based on gene–immune interaction for predicting risk stratification and immunotherapeutic responses. We also verified their predictive ability on internal and overall data sets. Patients with BLCA were divided into high- and low-risk groups. The high-risk group had poor survival, enriched innate immune-related cell subtypes, low tumor mutation burden, and poor response to anti-PD-L1 therapy. Our prognostic signatures can be used as reliable prognostic biomarkers, which may be helpful to screen the people who will benefit from immunotherapy and guide the clinical decision-making of patients with BLCA.
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Affiliation(s)
- Fangfang Liang
- Department of Medical Oncology, Guangxi Medical University First Affiliated Hospital, Nanning, China
| | - Yansong Xu
- Emergency Department, Guangxi Medical University First Affiliated Hospital, Nanning, China
| | - Yi Chen
- College of Oncology, Guangxi Medical University, Nanning, China
| | - Huage Zhong
- College of Oncology, Guangxi Medical University, Nanning, China
| | - Zhen Wang
- College of Oncology, Guangxi Medical University, Nanning, China
| | - Tianwen Nong
- Department of Medical Oncology, Guangxi Medical University First Affiliated Hospital, Nanning, China
| | - Jincai Zhong
- Department of Medical Oncology, Guangxi Medical University First Affiliated Hospital, Nanning, China
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Subhan A, Attia SA, P Torchilin V. Targeted siRNA nanotherapeutics against breast and ovarian metastatic cancer: a comprehensive review of the literature. Nanomedicine (Lond) 2021; 17:41-64. [PMID: 34930021 DOI: 10.2217/nnm-2021-0207] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Metastasis is considered the major cause of unsuccessful cancer therapy. The metastatic development requires tumor cells to leave their initial site, circulate in the blood stream, acclimate to new cellular environments at a remote secondary site and endure there. There are several steps in metastasis, including invasion, intravasation, circulation, extravasation, premetastatic niche formation, micrometastasis and metastatic colonization. siRNA therapeutics are appreciated for their usefulness in treatment of cancer metastasis. However, siRNA therapy as a single therapy may not be a sufficient option for control of metastasis. By combining siRNA with targeting, functional agents or small-molecule drugs have shown potential effects that enhance therapeutic effectiveness. This review addresses multidrug resistance and metastasis in breast and ovarian cancers and highlights drug-delivery strategies using siRNA therapeutics.
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Affiliation(s)
- Abdus Subhan
- Department of Chemistry, ShahJalal University of Science & Technology, Sylhet 3114, Bangladesh
| | - Sara Aly Attia
- Center for Pharmaceutical Biotechnology and Nanomedicine, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA
| | - Vladimir P Torchilin
- Center for Pharmaceutical Biotechnology and Nanomedicine, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.,Department of Oncology, Radiotherapy & Plastic Surgery, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Russia
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Li X, Qiu N, Li Q. Prognostic Values and Clinical Significance of S100 Family Member's Individualized mRNA Expression in Pancreatic Adenocarcinoma. Front Genet 2021; 12:758725. [PMID: 34804125 PMCID: PMC8595214 DOI: 10.3389/fgene.2021.758725] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 10/14/2021] [Indexed: 12/27/2022] Open
Abstract
Objective: Pancreatic adenocarcinoma (PAAD) is a common malignant tumor worldwide. S100 family (S100s) is wildly involved in regulating the occurrence, development, invasion, metastasis, apoptosis, and drug resistance of many malignant tumors. However, the expression pattern, prognostic value, and oncological role of individual S100s members in PAAD need to be elucidated. Methods: The transcriptional expression levels of S100s were analyzed through the Oncomine and GEPIA, respectively. The protein levels of S100s members in PAAD were studied by Human Protein Atlas. The correlation between S100 mRNA expression and overall survival and tumor stage in PAAD patients was studied by GEPIA. The transcriptional expression correlation and gene mutation rate of S100s members in PAAD patients were explored by cBioPortal. The co-expression networks of S100s are identified using STRING and Gene MANIA to predict their potential functions. The correlation of S100s expression and tumor-infiltrating immune cells was tested by TIMER. Pathway activity and drug target analyzed by GSCALite. Results: 13 S100s members were upregulated in PAAD tissues. 15 S100s members were associated with TP53 mutation. Expression levels of S100A3/A5/A6/A10/A11/A14/A16/B/P/Z were significantly correlated with the pathological stage. Prognosis analysis demonstrated that PAAD patients with low mRNA levels of S100A1/B/Z or high levels of S100A2/A3/A5/A10/A11/A14/A16 had a poor prognosis. Immuno-infiltration analysis showed that the mRNA levels of S100A10/A11/A14/A16 were correlated with the infiltration degree of macrophages in PAAD. Drug sensitivity analysis showed that PAAD expressing high levels of S100A2/A6/A10/A11/A13/A14/A16 maybe resistant to small molecule drugs. Conclusion: This study identifies the clinical significance and biological functions of the S100s in PAAD, which may provide novel insights for the selection of prognostic biomarkers.
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Affiliation(s)
- Xiaomin Li
- Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Ning Qiu
- Key Laboratory of Ocean and Marginal Sea Geology, Guangdong Southern Marine Science & Engineering Laboratory (Guangzhou), South China Sea Institute of Oceanology, Innovation Academy of South China Sea Ecology and Environmental Engineering, Chinese Academy of Sciences, Guangzhou, China
| | - Qijuan Li
- Department of Clinical Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
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Sionov RV. Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled. Cells 2021; 10:cells10092486. [PMID: 34572138 PMCID: PMC8465406 DOI: 10.3390/cells10092486] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 09/12/2021] [Accepted: 09/15/2021] [Indexed: 12/13/2022] Open
Abstract
Neutrophils are the most abundant immune cell in the circulation of human and act as gatekeepers to discard foreign elements that have entered the body. They are essential in initiating immune responses for eliminating invaders, such as microorganisms and alien particles, as well as to act as immune surveyors of cancer cells, especially during the initial stages of carcinogenesis and for eliminating single metastatic cells in the circulation and in the premetastatic organs. Since neutrophils can secrete a whole range of factors stored in their many granules as well as produce reactive oxygen and nitrogen species upon stimulation, neutrophils may directly or indirectly affect carcinogenesis in both the positive and negative directions. An intricate crosstalk between tumor cells, neutrophils, other immune cells and stromal cells in the microenvironment modulates neutrophil function resulting in both anti- and pro-tumor activities. Both the anti-tumor and pro-tumor activities require chemoattraction towards the tumor cells, neutrophil activation and ROS production. Divergence is seen in other neutrophil properties, including differential secretory repertoire and membrane receptor display. Many of the direct effects of neutrophils on tumor growth and metastases are dependent on tight neutrophil–tumor cell interactions. Among them, the neutrophil Mac-1 interaction with tumor ICAM-1 and the neutrophil L-selectin interaction with tumor-cell sialomucins were found to be involved in the neutrophil-mediated capturing of circulating tumor cells resulting in increased metastatic seeding. On the other hand, the anti-tumor function of neutrophils was found to rely on the interaction between tumor-surface-expressed receptor for advanced glycation end products (RAGE) and Cathepsin G expressed on the neutrophil surface. Intriguingly, these two molecules are also involved in the promotion of tumor growth and metastases. RAGE is upregulated during early inflammation-induced carcinogenesis and was found to be important for sustaining tumor growth and homing at metastatic sites. Cathepsin G was found to be essential for neutrophil-supported lung colonization of cancer cells. These data level up the complexity of the dual role of neutrophils in cancer.
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Affiliation(s)
- Ronit Vogt Sionov
- Hadassah Medical School, The Hebrew University of Jerusalem, Ein Kerem Campus, P.O.B. 12272, Jerusalem 9112102, Israel
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35
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Wang X, Wang C, Guan J, Chen B, Xu L, Chen C. Progress of Breast Cancer basic research in China. Int J Biol Sci 2021; 17:2069-2079. [PMID: 34131406 PMCID: PMC8193257 DOI: 10.7150/ijbs.60631] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 04/28/2021] [Indexed: 12/15/2022] Open
Abstract
Breast cancer is the most commonly diagnosed and the most lethal cancer in females both in China and worldwide. Currently, the origin of cancer stem cells, the heterogeneity of cancer cells, the mechanism of cancer metastasis and drug resistance are the most important issues that need to be addressed. Chinese investigators have recently made new discoveries in basic breast cancer researches, especially regarding cancer stem cells, cancer metabolism, and microenvironments. These efforts have led to a deeper understanding of drug resistance and metastasis and have also indicated new biomarkers and therapeutic targets. These findings emphasized the importance of the cancer stem cells for targeted therapy. In this review, we summarized the latest important findings in this field in China.
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Affiliation(s)
- Xuerong Wang
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Chao Wang
- Department of Thoracic Surgery, Jiangsu Cancer Hospital, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210009, China
| | - Jiaheng Guan
- Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Baoan Chen
- Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Lin Xu
- Department of Thoracic Surgery, Jiangsu Cancer Hospital, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210009, China
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
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Liu MJ, Guo H, Jiang LL, Jiao M, Wang SH, Tian T, Fu X, Wang WJ. Elevated RBP-Jκ and CXCL11 Expression in Colon Cancer is Associated with an Unfavorable Clinical Outcome. Cancer Manag Res 2021; 13:3651-3661. [PMID: 33981164 PMCID: PMC8107007 DOI: 10.2147/cmar.s298580] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 04/14/2021] [Indexed: 01/05/2023] Open
Abstract
Introduction This study aims at exploring the expression and significance of recombination signal-binding protein for immunoglobulin kappa J region (RBP-Jκ) and C-X-C motif chemokine 11 (CXCL11) in human colon cancer tissues. Methods The RBP-Jκ and CXCL11 expression levels were assessed by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR) in patients with colon cancer, and their prognostic significance was evaluated. Results Through analyzing 342 samples of colon cancer patients treated at our institution, increased expression of RBP-Jκ and CXCL11 was found in human colon cancer specimens compared with matched paratumorous normal specimens (P<0.001). A positive correlation was found between RBP-Jκ expression and CXCL11 expression (P<0.001). High RBP-Jκ expression was significantly associated with poorly differentiated tumors (P=0.005), invasion beyond propria muscularis (P=0.025), lymph node metastases (P=0.005), distant metastasis (P<0.001), advanced tumor-node-metastasis (TNM) stage (P=0.004), and a shorter overall survival (P<0.001). An increase in CXCL11 protein expression was associated with poorly differentiated tumors (P=0.015), invasion beyond propria muscularis (P=0.029), lymph node metastases (P=0.031), distant metastasis (P=0.045), advanced TNM stage (P=0.026), and a shorter overall survival of patients (P<0.001). In multivariate Cox regression analysis, RBP-Jκ protein expression (P=0.036), CXCL11 protein expression (P=0.001), differentiation (P<0.001), depth of invasion (P=0.009), distant metastasis (P<0.001), and TNM stage (P<0.001) were independent prognostic indicators of colon cancer. Conclusion High expression of RBP-Jκ is closely associated with high CXCL11 expression, which represents a risk factor for the poor overall survival of colon cancer patients.
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Affiliation(s)
- Meng-Jie Liu
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Hui Guo
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Li-Li Jiang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Min Jiao
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Shu-Hong Wang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Tao Tian
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Xiao Fu
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
| | - Wen-Juan Wang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China
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Jiang S, Zhu Y, Chen Z, Huang Z, Liu B, Xu Y, Li Z, Lin Z, Li M. S100A14 inhibits cell growth and epithelial-mesenchymal transition (EMT) in prostate cancer through FAT1-mediated Hippo signaling pathway. Hum Cell 2021; 34:1215-1226. [PMID: 33890248 DOI: 10.1007/s13577-021-00538-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 04/16/2021] [Indexed: 11/30/2022]
Abstract
Prostate cancer (PCA) is an epithelial malignant tumor occurring in the prostate gland. It is the second most common male cancer in the world and one of the top five cancer deaths in men. To combat this disease, it is needed to identify important tumor suppressor genes and elucidate the molecular mechanisms. S100 calcium-binding protein A14 (S100A14), a member of the S100 family, is located on chromosome 1q21.3 and contains an EF-hand motif that binds calcium. S100A14 is involved in a variety of tumor biological processes in several types of cancers. Its expression level and related biological functions are tissue or tumor specific. However, its possible effects on prostate cancer are still unclear. Herein, we found the low expression of S100A14 in human prostate cancer tissues and cell lines. S100A14 suppressed the proliferation of prostate cancer cells and promoted cell apoptosis. Additionally, S100A14 suppressed the motility and EMT processes of prostate cancer cells. We further found S100A14 promoted the expression of FAT1 and activated the Hippo pathway, which, therefore, suppressed the prostate cancer progression. The in vivo assays confirmed that S100A14 suppressed tumor growth of prostate cancer cells through FAT1-mediated Hippo pathway in mice. In conclusion, we clarified the mechanism underlying S100A14 suppressing prostate cancer progression and, therefore, we thought S100A14 could serve as a tumor suppressor protein.
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Affiliation(s)
- Shaoqin Jiang
- Department of Urology, Fujian Medical University Union Hospital, No. 29, Xinquan Road, Gulou District, Fuzhou, 350001, Fujian, China
| | - Yaru Zhu
- Intensive Care Unit, Fujian Provincial Governmental Hospital, Fuzhou, 350001, Fujian, China
| | - Zhenlin Chen
- Department of Urology, Fujian Medical University Union Hospital, No. 29, Xinquan Road, Gulou District, Fuzhou, 350001, Fujian, China
| | - Zhangcheng Huang
- Department of Urology, Fujian Medical University Union Hospital, No. 29, Xinquan Road, Gulou District, Fuzhou, 350001, Fujian, China
| | - Bingqiao Liu
- Department of Urology, Fujian Medical University Union Hospital, No. 29, Xinquan Road, Gulou District, Fuzhou, 350001, Fujian, China
| | - Yue Xu
- Department of Urology, Fujian Medical University Union Hospital, No. 29, Xinquan Road, Gulou District, Fuzhou, 350001, Fujian, China
| | - Zhihao Li
- Department of Urology, Fujian Medical University Union Hospital, No. 29, Xinquan Road, Gulou District, Fuzhou, 350001, Fujian, China
| | - Zequn Lin
- Department of Urology, Fujian Medical University Union Hospital, No. 29, Xinquan Road, Gulou District, Fuzhou, 350001, Fujian, China
| | - Mengqiang Li
- Department of Urology, Fujian Medical University Union Hospital, No. 29, Xinquan Road, Gulou District, Fuzhou, 350001, Fujian, China.
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Li B, Qi ZP, He DL, Chen ZH, Liu JY, Wong MW, Zhang JW, Xu EP, Shi Q, Cai SL, Sun D, Yao LQ, Zhou PH, Zhong YS. NLRP7 deubiquitination by USP10 promotes tumor progression and tumor-associated macrophage polarization in colorectal cancer. J Exp Clin Cancer Res 2021; 40:126. [PMID: 33838681 PMCID: PMC8035766 DOI: 10.1186/s13046-021-01920-y] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 03/21/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND NOD-like receptors affect multiple stages of cancer progression in many malignancies. NACHT, LRR, and PYD domain-containing protein 7 (NLRP7) is a member of the NOD-like receptor family, although its role in tumorigenesis remains unclear. By analyzing clinical samples, we found that NLRP7 protein levels were upregulated in colorectal cancer (CRC). We proposed the hypothesis that a high level of NLRP7 in CRC may promote tumor progression. Here, we further investigated the role of NLRP7 in CRC and the underlying mechanism. METHODS NLRP7 expression in human CRC and adjacent non-tumorous tissues was examined by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry. The effect of NLRP7 in CRC progression was investigated in vitro and in vivo. Proteins interacting with NLRP7 were identified by immunoprecipitation and mass spectrometry analysis while immunofluorescence staining revealed the cellular location of the proteins. Cellular ubiquitination and protein stability assays were applied to demonstrate the ubiquitination effect on NLRP7. Cloning and mutagenesis were used to identify a lysine acceptor site that mediates NLRP7 ubiquitination. Cytokines/chemokines affected by NLRP7 were identified by RNA sequencing, qRT-PCR, and enzyme-linked immunosorbent assay. Macrophage phenotypes were determined using qRT-PCR, flow cytometry, and immunohistochemistry. RESULTS NLRP7 protein levels, but not mRNA levels, were upregulated in CRC, and increased NLRP7 protein expression was associated with poor survival. NLRP7 promoted tumor cell proliferation and metastasis in vivo and in vitro and interacted with ubiquitin-specific protease 10, which catalyzed its deubiquitination in CRC cells. NLRP7 stability and protein levels in CRC cells were modulated by ubiquitination and deubiquitination, and NLRP7 was involved in the ubiquitin-specific protease 10 promotion of tumor progression and metastasis in CRC. K379 was an important lysine acceptor site that mediates NLRP7 ubiquitination in CRC cells. In CRC, NLRP7 promoted the polarization of pro-tumor M2-like macrophages by inducing the secretion of C-C motif chemokine ligand 2. Furthermore, NLRP7 promoted NF-κB nuclear translocation and activation of C-C motif chemokine ligand 2 transcription. CONCLUSIONS We showed that NLRP7 promotes CRC progression and revealed an as-yet-unidentified mechanism by which NLRP7 induces the polarization of pro-tumor M2-like macrophages. These results suggest that NLRP7 could serve as a biomarker and novel therapeutic target for the treatment of CRC.
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Affiliation(s)
- Bing Li
- Endoscopy Center, Zhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai, 20032, People's Republic of China
- Endoscopy Research Institute of Fudan University, Shanghai, 20032, People's Republic of China
| | - Zhi-Peng Qi
- Endoscopy Center, Zhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai, 20032, People's Republic of China
- Endoscopy Research Institute of Fudan University, Shanghai, 20032, People's Republic of China
| | - Dong-Li He
- Endoscopy Center, Xuhui Hospital, Zhongshan Hospital of Fudan University, Shanghai, 20031, People's Republic of China
- Department of Gastroenterology, Xuhui Hospital, Zhongshan Hospital of Fudan University, Shanghai, 20031, People's Republic of China
| | - Zhang-Han Chen
- Endoscopy Center, Zhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai, 20032, People's Republic of China
- Endoscopy Research Institute of Fudan University, Shanghai, 20032, People's Republic of China
| | - Jing-Yi Liu
- Endoscopy Center, Zhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai, 20032, People's Republic of China
- Endoscopy Research Institute of Fudan University, Shanghai, 20032, People's Republic of China
| | - Meng-Wai Wong
- Endoscopy Center, Xuhui Hospital, Zhongshan Hospital of Fudan University, Shanghai, 20031, People's Republic of China
| | - Jia-Wei Zhang
- Department of Gastroenterology, Xuhui Hospital, Zhongshan Hospital of Fudan University, Shanghai, 20031, People's Republic of China
| | - En-Pan Xu
- Endoscopy Center, Zhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai, 20032, People's Republic of China
- Endoscopy Research Institute of Fudan University, Shanghai, 20032, People's Republic of China
| | - Qiang Shi
- Endoscopy Center, Zhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai, 20032, People's Republic of China
- Endoscopy Research Institute of Fudan University, Shanghai, 20032, People's Republic of China
| | - Shi-Lun Cai
- Endoscopy Center, Zhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai, 20032, People's Republic of China
- Endoscopy Research Institute of Fudan University, Shanghai, 20032, People's Republic of China
| | - Di Sun
- Endoscopy Center, Zhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai, 20032, People's Republic of China
- Endoscopy Research Institute of Fudan University, Shanghai, 20032, People's Republic of China
| | - Li-Qing Yao
- Endoscopy Center, Zhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai, 20032, People's Republic of China
- Endoscopy Research Institute of Fudan University, Shanghai, 20032, People's Republic of China
| | - Ping-Hong Zhou
- Endoscopy Center, Zhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai, 20032, People's Republic of China.
- Endoscopy Research Institute of Fudan University, Shanghai, 20032, People's Republic of China.
| | - Yun-Shi Zhong
- Endoscopy Center, Zhongshan Hospital of Fudan University, 180 Fenglin Road, Shanghai, 20032, People's Republic of China.
- Endoscopy Research Institute of Fudan University, Shanghai, 20032, People's Republic of China.
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Abstract
Secretory proteins in tumor tissues are important components of the tumor microenvironment. Secretory proteins act on tumor cells or stromal cells or mediate interactions between tumor cells and stromal cells, thereby affecting tumor progression and clinical treatment efficacy. In this paper, recent research advances in secretory proteins in malignant tumors are reviewed.
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Affiliation(s)
- Na Zhang
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jiajie Hao
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yan Cai
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Mingrong Wang
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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40
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Wang Y, Ren S, Wang Z, Wang Z, Zhu N, Cai D, Ye Z, Ruan J. Chemokines in bone-metastatic breast cancer: Therapeutic opportunities. Int Immunopharmacol 2020; 87:106815. [PMID: 32711376 DOI: 10.1016/j.intimp.2020.106815] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 07/13/2020] [Accepted: 07/14/2020] [Indexed: 12/12/2022]
Abstract
Due to non-response to chemotherapy, incomplete surgical resection, and resistance to checkpoint inhibitors, breast cancer with bone metastasis is notoriously difficult to cure. Therefore, the development of novel, efficient strategies to tackle bone metastasis of breast cancer is urgently needed. Chemokines, which induce directed migration of immune cells and act as guide molecules between diverse cells and tissues, are small proteins indispensable in immunity. These complex chemokine networks play pro-tumor roles or anti-tumor roles when produced by breast cancer cells in the tumor microenvironment. Additionally, chemokines have diverse roles when secreted by various immune cells in the tumor microenvironment of breast cancer, which can be roughly divided into immunosuppressive effects and immunostimulatory effects. Recently, targeting chemokine networks has been shown to have potential for use in treatment of metastatic malignancies, including bone-metastatic breast cancer. In this review, we focus on the role of chemokines networks in the biology of breast cancer and metastasis to the bone. We also discuss the therapeutic opportunities and future prospects of targeting chemokine networks, in combination with other current standard therapies, for the treatment of bone-metastatic breast cancer.
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Affiliation(s)
| | - Shihong Ren
- First People's Hospital of Wenling, Wenling, China
| | - Zhan Wang
- Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zenan Wang
- Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ning Zhu
- Hebei North University, Zhangjiakou, China
| | | | - Zhaoming Ye
- Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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