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1
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Hu X, Jiang T, Wang J. Molecular subtype characteristics and development of prognostic model based on inflammation-related gene in lung adenocarcinoma. Discov Oncol 2025; 16:875. [PMID: 40407957 DOI: 10.1007/s12672-025-02513-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Accepted: 04/25/2025] [Indexed: 05/26/2025] Open
Abstract
As one of the leading causes of death worldwide, lung adenocarcinoma (LUAD) currently lacks satisfactory treatment outcomes. The inflammatory process, closely associated with the formation of the tumor microenvironment and immune evasion, plays a crucial role in LUAD development. This study utilized data from public databases to analyze inflammation-related genes (INF) associated with prognosis in LUAD. Based on differentially expressed INF, molecular subtypes of LUAD were identified. Subsequently, a novel INF scoring system was developed to establish a prognostic model for LUAD patients, assessing its independence and reliability. Comprehensive evaluations, including immune microenvironment infiltration features, somatic mutation characteristics, and differences in immune therapy responsiveness, were conducted to characterize the prognostic model associated with INF. We further selected MMP14 from the screened INF targets for further in vitro experiments. Experiments such as western blot, qRT-PCR, colony-forming assay and Transwell assay confirmed that downregulation of MMP14 could inhibit the cloning, proliferation and invasion of lung cancer cells, thus confirming the results of bioinformatics. Our findings provide evidence from a new perspective on the role of inflammation in LUAD and offer new insights for clinical precision and personalized therapy.
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Affiliation(s)
- Xuelei Hu
- Department of Thoracic Surgery, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, China
| | - Tengfei Jiang
- Medical Laboratory Center, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, China
| | - Jinxiang Wang
- Department of Respiratory and Critical Care Medicine, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, Shandong, China.
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2
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Li N, Zhang N, Wang G. Overexpression of MMP14 is associated with poor prognosis and immune cell infiltration in colon cancer. Front Oncol 2025; 15:1564375. [PMID: 40352589 PMCID: PMC12062125 DOI: 10.3389/fonc.2025.1564375] [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: 01/21/2025] [Accepted: 03/25/2025] [Indexed: 05/14/2025] Open
Abstract
Introduction Colorectal cancer (CRC) poses a significant risk of recurrence and distant metastases. This study investigated the regulatory role of Matrix metalloproteinase-14 (MMP14) in immune function and its impact on CRC prognosis. Methods we performed transcriptome sequencing on tumor and adjacent non-cancerous samples from four pairs of patients diagnosed with colorectal cancer. Single-cell transcriptome data were analyzed to explore MMP14 expression and immune microenvironment changes. mRNA expression profiles and clinical data were retrieved from public databases (TCGA and GEO). The association between MMP14 and pathways as well as immune regulators was analyzed. Co-expression genes of MMP14 relevant to prognosis were identified. A prognostic model was then constructed. MMP14 expression was examined using real-time fluorescence quantification PCR (qRT-PCR) and Western blotting (WB). Immunofluorescence was utilized to demonstrate MMP14 expression in colon cancer tissues, while Hematoxylin and eosin (HE) staining was employed to observe the histology of normal tissue and colon cancer tissue. Results Machine learning identified MMP14 as a candidate gene. MMP14 was overexpressed in CRC tissues and COLO205 cells. Single-cell transcriptome analysis revealed that MMP14 was highly expressed in fibrocyte cells within the liver metastasis group. Increased MMP14 levels correlated with poor overall survival (OS), progression-free survival (PFS), and advanced TNM stages. Functional assays indicated that silencing MMP14 in COLO205 cells enhanced apoptosis and upregulated the expression of the immune-related cytokine IL-1β. Furthermore, MMP14 exhibited significant correlations with immunomodulators, particularly immunostimulants and immunosuppressants, and was associated with immune cell infiltration within tumor tissues. Additionally, by utilizing co-expressed genes of MMP14 and conducting Cox regression analysis, we developed a risk prediction model comprising three genes (LIMK1, SPOCK3, SLC2A3). The risk scores derived from this model were found to correlate with OS and PFS. Discussion MMP14 plays a crucial role in CRC progression. Its overexpression is related to poor prognosis and immune cell infiltration. The prognostic model based on MMP14 co-expression genes may help predict CRC prognosis. However, further studies are needed to validate these findings, such as more in-vitro and in-vivo experiments. In conclusion, MMP14 can serve as a biomarker for evaluating CRC prognosis and immune cell infiltration.
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Affiliation(s)
- Na Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Xi’an Jiao Tong University, Xi’an, Shaanxi, China
| | - Nan Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Xi’an Jiao Tong University, Xi’an, Shaanxi, China
| | - Guanghui Wang
- Department of General Surgery, The First Affiliated Hospital of Xi’an Jiao Tong University, Xi’an, Shaanxi, China
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3
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Chen M, Qu H, Liang X, Huang Y, Yang Z, Lu P, Shi K, Chen P, Zhang Y, Zhou H, Xia J, Shen J. Brachyury promotes proliferation and migration of colorectal cancer cells by targeting MMP14. Cancer Cell Int 2025; 25:132. [PMID: 40197249 PMCID: PMC11977941 DOI: 10.1186/s12935-025-03726-w] [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: 06/18/2024] [Accepted: 03/03/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND The incidence and mortality rates of colorectal cancer (CRC) are rising, and it is the second most common cause of cancer-related deaths worldwide. Although the transcription factor, Brachyury is intricately linked with various clinical malignancies, the mechanisms by which it influences CRC cell proliferation and migration are inadequately understood. METHODS Tissue microarray was used to evaluate Brachyury expression in CRC and adjacent normal tissues. The effects of Brachyury on HCT116 and SW480 CRC cells were also examined in vitro, including using Cell Counting Kit-8, colony formation, and transwell assays, and in vivo through subcutaneous tumorigenesis assays in a nude mouse xenograft model. Chromatin immunoprecipitation was used to evaluate Brachyury binding to the MMP14 promoter and its impact on MMP14 expression. Rescue experiments were used to elucidate MMP14's role in mediating Brachyury's effect on CRC cell behavior. RESULTS Brachyury expression was significantly higher in CRC tissues than in adjacent normal tissues, and it promotes CRC oncogenesis in vitro and in vivo. Rescue experiments established MMP14 as a direct, downstream Brachyury target, affirming that MMP14 enhanced Brachyury-driven CRC cell proliferation. CONCLUSION Our findings highlight targeting the Brachyury-MMP14 axis as a potential novel approach for CRC clinical therapy.
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Affiliation(s)
- Ming Chen
- Department of Orthopeadic Surgery, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, 214000, China
| | - Huiheng Qu
- Department of General Surgery, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, 214000, China
| | - Xiao Liang
- Department of Anesthesiology, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, 214000, China
| | - Ying Huang
- Department of Ultrasonography, The Fifth People's Hospital of Suzhou, Suzhou, 215002, China
| | - Zhengjie Yang
- Department of Orthopeadic Surgery, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, 214000, China
| | - Pei Lu
- Department of Orthopeadic Surgery, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, 214000, China
| | - Keqin Shi
- Department of Orthopeadic Surgery, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, 214000, China
| | - Peng Chen
- Department of Orthopeadic Surgery, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, 214000, China
| | - Yanjing Zhang
- Department of Orthopeadic Surgery, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, 214000, China
| | - Hui Zhou
- Human Reproductive and Genetic Center, Affiliated Hospital of Jiangnan University, Wuxi, 214122, China.
| | - Jiazeng Xia
- Department of General Surgery, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, 214000, China.
| | - Jun Shen
- Department of Orthopeadic Surgery, Suzhou Municipal Hospital, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, 215002, China.
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Huang Z, Jiang Q, Zhang Q, Lu N, Rui X, Chen R, Wang Y, Wang Y, Xu X, Huang Z. Neoadjuvant Chemotherapy With Cisplatin Up-Regulates GSDMD to Enhance Oral Squamous Cell Carcinoma Metastasis Through MMP14-Mediated EMT Activation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2501149. [PMID: 40178046 DOI: 10.1002/advs.202501149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Revised: 03/04/2025] [Indexed: 04/05/2025]
Abstract
Neoadjuvant chemotherapy has been widely used for the treatment of solid tumors. However, clinical observations have shown that patients with oral squamous cell carcinoma (OSCC) who are receiving neoadjuvant chemotherapy with cisplatin still face issues such as a poor lymph node response and even lymph node progression, but the underlying mechanisms remain unidentified. In this work, it is found that low-dose cisplatin promoted oral squamous cell carcinoma migration, invasion and lymph node metastasis, and gasdermin D (GSDMD) is identified as a potential regulator. GSDMD interacted with MMP14, promoting its expression and epithelial‒mesenchymal transition (EMT) activation without activating pyroptosis. Moreover, pH-responsive nanoparticles (NPs) for the systemic delivery of a GSDMD siRNA (siGSDMD) is developed and showed that this NP-delivered siGSDMD can effectively inhibit OSCC tumor growth and metastasis via the efficient silencing of GSDMD expression in vivo. This findings indicate that GSDMD can be a biomarker to predict the prognosis of OSCC patients receiving neoadjuvant chemotherapy and that NP-mediated GSDMD silencing can be a promising strategy for the treatment of patients with advanced OSCC receiving neoadjuvant chemotherapy with cisplatin.
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Affiliation(s)
- Zixian Huang
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Qiming Jiang
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Qianyu Zhang
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Nan Lu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, China
| | - Xi Rui
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Hospital of stomatology, the First Affiliated Hospital of Jinan University, School of Stomatology, Jinan University, Guangzhou, 510632, China
| | - Rui Chen
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Yan Wang
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Yuepeng Wang
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Xiaoding Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
- Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, China
| | - Zhiquan Huang
- Department of Oral and Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China
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Liu J, Li Y, Lian X, Zhang C, Feng J, Tao H, Wang Z. Potential target within the tumor microenvironment - MT1-MMP. Front Immunol 2025; 16:1517519. [PMID: 40196128 PMCID: PMC11973285 DOI: 10.3389/fimmu.2025.1517519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2024] [Accepted: 03/03/2025] [Indexed: 04/09/2025] Open
Abstract
Matrix metalloproteinases are integral to the modification of the tumor microenvironment and facilitate tumor progression by degrading the extracellular matrix, releasing cytokines, and influencing the recruitment of immune cells. Among the matrix metalloproteinases, membrane-type matrix metalloproteinase 1 (MT1-MMP/MMP14) is the first identified membrane-type MMP and acts as an essential proteolytic enzyme that enables tumor infiltration and metastatic progression. Given the pivotal role of MT1-MMP in tumor progression and the correlation between its overexpression in tumors and unfavorable prognoses across multiple cancer types, a comprehensive understanding of the potential functional mechanisms of MT1-MMP is essential. This knowledge will aid in the advancement of diverse anti-tumor therapies aimed at targeting MT1-MMP. Although contemporary research has highlighted the considerable potential of MT1-MMP in targeted cancer therapy, studies pertaining to its application in cell therapy remain relatively limited. In this review, we delineate the structural characteristics and regulatory mechanisms of MT1-MMP expression, as well as its biological significance in tumorigenesis. Finally, we discussed the current status and prospects of anti-tumor therapies targeting MT1-MMP.
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Affiliation(s)
- Jinlong Liu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Centre for Cell and Gene Therapy, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Yijing Li
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Centre for Cell and Gene Therapy, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Xueqi Lian
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Centre for Cell and Gene Therapy, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Chenglin Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Centre for Cell and Gene Therapy, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Jianing Feng
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Centre for Cell and Gene Therapy, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Hongfei Tao
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
- Centre for Cell and Gene Therapy, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Zhimin Wang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
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Wang J, Hua D, Li M, Liu N, Zhang Y, Zhao Y, Jiang S, Hu X, Wang Y, Zhu H. The Role of Zuo Jin Wan in Modulating the Tumor Microenvironment of Colorectal Cancer. Comb Chem High Throughput Screen 2025; 28:523-532. [PMID: 38284730 DOI: 10.2174/0113862073281374231228041841] [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: 09/11/2023] [Revised: 12/15/2023] [Accepted: 12/19/2023] [Indexed: 01/30/2024]
Abstract
INTRODUCTION Traditional Chinese medicine (TCM) can modulate the immune function of tumor patients in various ways. Zuojin Wan (ZJW, a 6:1 ratio of Huang Lian and Wu Zhu Yu) can modulate the microenvironment of ulcerative colitis, but its role in regulating the colorectal cancer (CRC) microenvironment remains unclear. Exploring the role of ZJW in CRC immunomodulation may improve the antitumor effect of existing immunotherapeutic strategies. MATERIAL AND METHODS The active compounds of each herb in ZJW were obtained from the HIT2.0 database with literature evidence. Single-cell RNA sequencing data of CRC were obtained from published studies (PMID: 32451460, 32103181, and 32561858). Pathway enrichment was analyzed using the reactome database, and intergenic correlation analysis was performed using the corrplot R software package. ZJW-regulated gene expression was verified by RT-qPCR. RESULTS Huang Lian and Wu Zhu Yu contain 19 and 4 compounds, respectively. Huang Lian targets 146 proteins, and Wu Zhu Yu targets 28 proteins based on evidence from the literature. ZJW regulates a range of biological processes associated with immune function, including cytokine signaling and Toll-Like Receptor 4 (TLR4) cascade. ZJW regulates malignant CRC cells, immune cells (including T-cells, B-cells, mast cells, NK/NKT cells, and myeloid cells), and other nonimmune cells (including endothelial cells, enteric glial cells, and pericytes). We confirmed that ZJW significantly downregulated the expression of TIMP1 and MTDHin CRC cell lines. CONCLUSIONS ZJW regulates a range of cells in the CRC microenvironment, including malignant CRC, immune cells, and stromal cells. In CRC cell lines, downregulation of TIMP1 and MTDH by ZJW may play an important role in the immunomodulation in CRC.
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Affiliation(s)
- Jiajia Wang
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Dongming Hua
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Mengyao Li
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ningning Liu
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yingru Zhang
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yiyang Zhao
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Shasha Jiang
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xueqing Hu
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yan Wang
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Huirong Zhu
- Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
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Jamialahmadi K, Noruzi S. Matrix metalloproteinases, chemoresistance and cancer. PATHOPHYSIOLOGICAL ASPECTS OF PROTEASES IN CANCER 2025:385-409. [DOI: 10.1016/b978-0-443-30098-1.00023-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Nerlakanti N, McGuire JJ, Bishop RT, Nasr MM, Li T, Reed DR, Lynch CC. Histone deacetylase upregulation of neuropilin-1 in osteosarcoma is essential for pulmonary metastasis. Cancer Lett 2024; 606:217302. [PMID: 39427726 PMCID: PMC12063772 DOI: 10.1016/j.canlet.2024.217302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 09/25/2024] [Accepted: 10/09/2024] [Indexed: 10/22/2024]
Abstract
The lungs represent the most common site of metastasis for osteosarcoma (OS). Despite our advances in developing targeted therapies for treating solid malignancies, broad acting chemotherapies remain the first line treatment for OS. In assaying the efficacy of approved therapeutics for non-OS malignancies, we previously identified the histone deacetylase 1 and 2 (HDAC1 and 2) inhibitor, romidepsin, as effective for the treatment of established lung metastatic OS. Yet, romidepsin has noted toxicities in humans and so here we aimed to define the primary mechanisms through which HDAC1/2 mediate OS progression to identify more selective druggable targets/pathways. Microarray and proteomics analyses of romidepsin treated OS cells revealed a significant suppression of neuropilin-1 (NRP1), a known regulator of cancer cell migration and invasion. Silencing of NRP1 significantly reduced OS proliferation, migration, invasion and adhesion in vitro. More strikingly, in vivo, reduced NRP1 expression significantly mitigated the lung metastatic potential of OS in two independent models (K7M2 and SAOS-LM7). Mechanistically, our data point to NRP1 mediating this effect via the down regulation of migration machinery, namely SRC, FAK and ROCK1 expression/activity, that is in part, related to NRP1 interaction with integrin beta 1 (ITGB1). In summary, our data indicate that romidepsin down regulation of NRP1 significantly mitigates the ability of OS cells to seed the lung and establish metastases, and that targeting NRP1 or its effectors with selective inhibitors may be a viable means with which to prevent this deadly aspect of the disease.
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Affiliation(s)
- Niveditha Nerlakanti
- Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, 33612, USA; Department of Tumor Microenvironment & Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Jeremy J McGuire
- Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, 33612, USA; Department of Tumor Microenvironment & Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Ryan T Bishop
- Department of Tumor Microenvironment & Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Mostafa M Nasr
- Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, 33612, USA; Department of Tumor Microenvironment & Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Tao Li
- Department of Tumor Microenvironment & Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Damon R Reed
- Sarcoma Department, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA
| | - Conor C Lynch
- Department of Tumor Microenvironment & Metastasis, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.
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Rivas-Santiago C, Gallegos-Bañuelos M, Trejo-Ramos I, Solís-Torres N, Quintana-Belmares R, Macías-Segura N, Gutiérrez-Bañuelos H, Troncoso-Vazquez L, Rivas-Santiago B, Gonzalez-Curiel I. Adverse Health Effects of the Long-Term Simultaneous Exposure to Arsenic and Particulate Matter in a Murine Model. J Toxicol 2024; 2024:5391316. [PMID: 38757141 PMCID: PMC11098611 DOI: 10.1155/2024/5391316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 02/20/2024] [Accepted: 03/27/2024] [Indexed: 05/18/2024] Open
Abstract
PM2.5 and arsenic are two of the most hazardous substances for humans that coexist worldwide. Independently, they might cause multiple organ damage. However, the combined effect of PM2.5 and arsenic has not been studied. Here, we used an animal model of simultaneous exposure to arsenic and PM2.5. Adult Wistar rats were exposed to PM2.5, As, or PM2.5 + As and their corresponding control groups. After 7, 14, and 28 days of exposure, the animals were euthanized and serum, lungs, kidneys, and hearts were collected. Analysis performed showed high levels of lung inflammation in all experimental groups, with an additive effect in the coexposed group. Besides, we observed cartilaginous metaplasia in the hearts of all exposed animals. The levels of creatine kinase, CK-MB, and lactate dehydrogenase increased in experimental groups. Tissue alterations might be related to oxidative stress through increased GPx and NADPH oxidase activity. The findings of this study suggest that exposure to arsenic, PM2.5, or coexposure induces high levels of oxidative stress, which might be associated with lung inflammation and heart damage. These findings highlight the importance of reducing exposure to these pollutants to protect human health.
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Affiliation(s)
- Cesar Rivas-Santiago
- CONAHCYT-Academic Unit of Chemical Sciences, Autonomous University of Zacatecas, Zacatecas 98085, Mexico
| | - Maria Gallegos-Bañuelos
- Sciences and Chemical Technology, Chemistry Sciences School, Autonomous University of Zacatecas, Zacatecas 98085, Mexico
| | - Irving Trejo-Ramos
- Sciences and Chemical Technology, Chemistry Sciences School, Autonomous University of Zacatecas, Zacatecas 98085, Mexico
| | - Nancy Solís-Torres
- Pharmacobiology, Chemistry Sciences School, Autonomous University of San Luis Potosi, San Luis Potosi 78210, Mexico
| | | | - Noé Macías-Segura
- Service and Department of Immunology, Faculty of Medicine and University Hospital, Autonomous University of Nuevo León, Nuevo León, 66450, Mexico
| | - Héctor Gutiérrez-Bañuelos
- Veterinary Medicine and Zootechnics School, Autonomous University of Zacatecas, Zacatecas 98085, Mexico
| | | | - Bruno Rivas-Santiago
- Biomedical Research Unit-Zacatecas-IMSS, Mexican Social Security Institute, Zacatecas 98085, Mexico
| | - Irma Gonzalez-Curiel
- Sciences and Chemical Technology, Chemistry Sciences School, Autonomous University of Zacatecas, Zacatecas 98085, Mexico
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Zhang X, Jia Y, Zhang N, Wu D, Ma H, Ren X, Ju H, Wei Q. Self-Assembly-Induced Enhancement of Cathodic Electrochemiluminescence of Copper Nanoclusters for a Split-Type Matrix Metalloproteinase 14 Sensing Platform. Anal Chem 2024; 96:7265-7273. [PMID: 38649306 DOI: 10.1021/acs.analchem.4c01039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2024]
Abstract
The unique optoelectronic and tunable luminescent characteristics of copper nanoclusters (Cu NCs) make them extremely promising as luminophores. However, the limited luminescence intensity and stability of Cu NCs have restricted their application in the field of electrochemiluminescence (ECL). Herein, a self-assembly-induced enhancement strategy was successfully employed to enhance the cathodic ECL performance of flexible ligand-stabilized Cu NCs. Specifically, Cu NCs form ordered sheetlike structures through intermolecular force. The restriction of ligand torsion in this self-assembled structure leads to a significant improvement in the ECL properties of the Cu NCs. Experimental results demonstrate that the assembled nanoscale Cu NC sheets exhibit an approximately three-fold increase in cathodic ECL emission compared to the dispersed state of Cu NCs. Furthermore, assembled nanoscale Cu NCs sheets were utilized as signal probes in conjunction with a specific short peptide derived from the catalytic structural domain of matrix metalloproteinase 14 (MMP 14) as the identification probe, thereby establishing a split-type ECL sensing platform for the quantification of NMP 14. The investigation has revealed the exceptional performance of assembled nanoscale Cu NCs sheets in ECL analysis, thus positioning them as novel and promising signal probes with significant potential in the field of sensing.
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Affiliation(s)
- Xiaoyue Zhang
- Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, Collaborative Innovation Center for Green Chemical Manufacturing and Accurate Detection, School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, P. R. China
| | - Yue Jia
- Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, Collaborative Innovation Center for Green Chemical Manufacturing and Accurate Detection, School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, P. R. China
| | - Nuo Zhang
- Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, Collaborative Innovation Center for Green Chemical Manufacturing and Accurate Detection, School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, P. R. China
| | - Dan Wu
- Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, Collaborative Innovation Center for Green Chemical Manufacturing and Accurate Detection, School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, P. R. China
| | - Hongmin Ma
- Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, Collaborative Innovation Center for Green Chemical Manufacturing and Accurate Detection, School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, P. R. China
| | - Xiang Ren
- Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, Collaborative Innovation Center for Green Chemical Manufacturing and Accurate Detection, School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, P. R. China
| | - Huangxian Ju
- Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, Collaborative Innovation Center for Green Chemical Manufacturing and Accurate Detection, School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, P. R. China
- State Key Laboratory of Analytical Chemistry for Life Science, Department of Chemistry, Nanjing University, Nanjing 210023, China
| | - Qin Wei
- Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, Collaborative Innovation Center for Green Chemical Manufacturing and Accurate Detection, School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, P. R. China
- Department of Chemistry, Sungkyunkwan University, Suwon 16419, Republic of Korea
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11
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Gonzalez‐Molina J, Hahn P, Falcão RM, Gultekin O, Kokaraki G, Zanfagnin V, Braz Petta T, Lehti K, Carlson JW. MMP14 expression and collagen remodelling support uterine leiomyosarcoma aggressiveness. Mol Oncol 2024; 18:850-865. [PMID: 37078535 PMCID: PMC10994236 DOI: 10.1002/1878-0261.13440] [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: 08/09/2022] [Revised: 03/14/2023] [Accepted: 04/18/2023] [Indexed: 04/21/2023] Open
Abstract
Fibrillar collagen deposition, stiffness and downstream signalling support the development of leiomyomas (LMs), common benign mesenchymal tumours of the uterus, and are associated with aggressiveness in multiple carcinomas. Compared with epithelial carcinomas, however, the impact of fibrillar collagens on malignant mesenchymal tumours, including uterine leiomyosarcoma (uLMS), remains elusive. In this study, we analyse the network morphology and density of fibrillar collagens combined with the gene expression within uLMS, LM and normal myometrium (MM). We find that, in contrast to LM, uLMS tumours present low collagen density and increased expression of collagen-remodelling genes, features associated with tumour aggressiveness. Using collagen-based 3D matrices, we show that matrix metalloproteinase-14 (MMP14), a central protein with collagen-remodelling functions that is particularly overexpressed in uLMS, supports uLMS cell proliferation. In addition, we find that, unlike MM and LM cells, uLMS proliferation and migration are less sensitive to changes in collagen substrate stiffness. We demonstrate that uLMS cell growth in low-stiffness substrates is sustained by an enhanced basal yes-associated protein 1 (YAP) activity. Altogether, our results indicate that uLMS cells acquire increased collagen remodelling capabilities and are adapted to grow and migrate in low collagen and soft microenvironments. These results further suggest that matrix remodelling and YAP are potential therapeutic targets for this deadly disease.
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Affiliation(s)
- Jordi Gonzalez‐Molina
- Department of Microbiology, Tumor and Cell BiologyKarolinska InstitutetStockholmSweden
- Department of Oncology‐PathologyKarolinska InstitutetStockholmSweden
| | - Paula Hahn
- Department of Microbiology, Tumor and Cell BiologyKarolinska InstitutetStockholmSweden
| | - Raul Maia Falcão
- Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
- Department of Cellular Biology and GeneticsFederal University of Rio Grande do NorteNatalBrazil
| | - Okan Gultekin
- Department of Microbiology, Tumor and Cell BiologyKarolinska InstitutetStockholmSweden
| | - Georgia Kokaraki
- Department of Oncology‐PathologyKarolinska InstitutetStockholmSweden
- Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
| | | | - Tirzah Braz Petta
- Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
- Department of Cellular Biology and GeneticsFederal University of Rio Grande do NorteNatalBrazil
| | - Kaisa Lehti
- Department of Microbiology, Tumor and Cell BiologyKarolinska InstitutetStockholmSweden
- Department of Biomedical Laboratory ScienceNorwegian University of Science and TechnologyTrondheimNorway
| | - Joseph W. Carlson
- Department of Oncology‐PathologyKarolinska InstitutetStockholmSweden
- Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA
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12
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Kojima Y, Mii S, Hayashi S, Hirose H, Ishikawa M, Akiyama M, Enomoto A, Shimamura T. Single-cell colocalization analysis using a deep generative model. Cell Syst 2024; 15:180-192.e7. [PMID: 38387441 DOI: 10.1016/j.cels.2024.01.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 03/06/2023] [Accepted: 01/23/2024] [Indexed: 02/24/2024]
Abstract
Analyzing colocalization of single cells with heterogeneous molecular phenotypes is essential for understanding cell-cell interactions, and cellular responses to external stimuli and their biological functions in diseases and tissues. However, existing computational methodologies identified the colocalization patterns between predefined cell populations, which can obscure the molecular signatures arising from intercellular communication. Here, we introduce DeepCOLOR, a computational framework based on a deep generative model that recovers intercellular colocalization networks with single-cell resolution by the integration of single-cell and spatial transcriptomes. Along with colocalized population detection accuracy that is superior to existing methods in simulated dataset, DeepCOLOR identified plausible cell-cell interaction candidates between colocalized single cells and segregated cell populations defined by the colocalization relationships in mouse brain tissues, human squamous cell carcinoma samples, and human lung tissues infected with SARS-CoV-2. DeepCOLOR is applicable to studying cell-cell interactions behind various spatial niches. A record of this paper's transparent peer review process is included in the supplemental information.
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Affiliation(s)
- Yasuhiro Kojima
- Laboratory of Computational Life Science, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan; Department of Computational and Systems Biology, Medical Research Insitute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-0034, Japan; Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
| | - Shinji Mii
- Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Shuto Hayashi
- Department of Computational and Systems Biology, Medical Research Insitute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-0034, Japan; Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Haruka Hirose
- Department of Computational and Systems Biology, Medical Research Insitute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-0034, Japan; Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Masato Ishikawa
- Institute for Life and Medical Sciences, Kyoto University, Kyoto, Kyoto 606-8507, Japan; Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba 277-8561, Japan
| | - Masashi Akiyama
- Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Atsushi Enomoto
- Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Teppei Shimamura
- Department of Computational and Systems Biology, Medical Research Insitute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-0034, Japan; Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
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13
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Lee H, Ibrahimi L, Han KY. Fluorescence-Based Peptidolytic Assay for High-Throughput Screening of MMP14 Inhibitors. Methods Mol Biol 2024; 2747:229-242. [PMID: 38038944 DOI: 10.1007/978-1-0716-3589-6_18] [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] [Indexed: 12/02/2023]
Abstract
The membrane-bound matrix metalloproteinase 14 (MMP14, also known as MT1-MMP) plays important roles in the remodeling of the extracellular matrix during various cellular processes such as cancer metastasis, angiogenesis, and wound healing through its proteolytic activity. There are no known MMP14-specific inhibitors to date, and hence identification of MMP14-specific inhibitors will be beneficial for finding potential therapeutics for various diseases, including cancer and inflammation. High-throughput screening (HTS) assays have become a common way to search for new small compounds, peptides, and natural products. Enzymatic assays are highly amenable to HTS because most enzyme activities are quantifiable with the effect of many small molecules of interest on a specific target enzyme. Here, we describe a fluorescence-based enzymatic assay that can be applied as a large-scale HTS and a follow-up enzyme kinetics assay to find MMP14-specific inhibitors.
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Affiliation(s)
- Hyun Lee
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA
- Biophysics Core at the Research Resources Center, University of Illinois at Chicago, Chicago, IL, USA
| | - Lucas Ibrahimi
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA
| | - Kyu-Yeon Han
- Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
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14
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Su H, Shu S, Tang W, Zheng C, Zhao L, Fan H. ETV4 facilitates angiogenesis in hepatocellular carcinoma by upregulating MMP14 expression. Biochem Biophys Res Commun 2023; 684:149137. [PMID: 37897911 DOI: 10.1016/j.bbrc.2023.149137] [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: 08/31/2023] [Revised: 10/17/2023] [Accepted: 10/18/2023] [Indexed: 10/30/2023]
Abstract
Abnormal vascularization plays a crucial role in cell proliferation, tumor invasion and metastasis of hepatocellular carcinoma (HCC). It has been reported that ETV4 functions as an oncogenic gene in driving the carcinogenesis and progression, and promoting invasion and metastasis of HCC. However, the function of ETV4 on angiogenesis in HCC remains unclear. In the current study, immunohistochemistry showed that knockdown of ETV4 reduced angiogenesis in HCC xenograft tumor tissues. In vitro, tube formation assay verified that ETV4 expression promoted angiogenesis through simulating the angiogenic environment in HCC cells. Transcriptome sequencing indicated that MMP14 was one of the differentially expressed genes enriched in angiogenesis process. Subsequently, it was confirmed that MMP14 was regulated by ETV4 at the transcription level in HCC cells, clinical tissue samples and online databases. Further, we demonstrated that MMP14 induced angiogenesis in ETV4-mediated HCC microenvironment. Collectively, this research further reveals the biological mechanism of ETV4 in promoting the migration and invasion of HCC, and provides novel mechanistic insights and strategic guidance for anti-angiogenic therapy in HCC.
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Affiliation(s)
- Hongmeng Su
- Department of Medical Genetics and Developmental Biology, School of Medicine, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, China.
| | - Shihui Shu
- School of Life Science and Technology, Southeast University, Nanjing, China.
| | - Wenqing Tang
- School of Life Science and Technology, Southeast University, Nanjing, China.
| | - Chuqian Zheng
- Department of Medical Genetics and Developmental Biology, School of Medicine, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, China.
| | - Luyu Zhao
- Department of Medical Genetics and Developmental Biology, School of Medicine, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, China.
| | - Hong Fan
- Department of Medical Genetics and Developmental Biology, School of Medicine, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing, China.
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15
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Balakina A, Gadomsky S, Kokovina T, Sashenkova T, Mishchenko D, Terentiev A. New Derivatives of N-Hydroxybutanamide: Preparation, MMP Inhibition, Cytotoxicity, and Antitumor Activity. Int J Mol Sci 2023; 24:16360. [PMID: 38003553 PMCID: PMC10671431 DOI: 10.3390/ijms242216360] [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: 09/19/2023] [Revised: 11/12/2023] [Accepted: 11/13/2023] [Indexed: 11/26/2023] Open
Abstract
Using a novel method of N-substituted succinimide ring opening, new N-hydroxybutanamide derivatives were synthesized. These compounds were evaluated for their ability to inhibit matrix metalloproteinases (MMPs) and their cytotoxicity. The iodoaniline derivative of N1-hydroxy-N4-phenylbutanediamide showed the inhibition of MMP-2, MMP-9, and MMP-14 with an IC50 of 1-1.5 μM. All the compounds exhibited low toxicity towards carcinoma cell lines HeLa and HepG2. The iodoaniline derivative was also slightly toxic to glioma cell lines A-172 and U-251 MG. Non-cancerous FetMSC and Vero cells were found to be the least sensitive to all the compounds. In vivo studies demonstrated that the iodoaniline derivative of N1-hydroxy-N4-phenylbutanediamide had low acute toxicity. In a mouse model of B16 melanoma, this compound showed both antitumor and antimetastatic effects, with a 61.5% inhibition of tumor growth and an 88.6% inhibition of metastasis. Our findings suggest that the iodoaniline derivative of N1-hydroxy-N4-phenylbutanediamide has potential as a lead structure for the development of new MMP inhibitors. Our new synthetic approach can be a cost-effective method for the synthesis of inhibitors of metalloenzymes with promising antitumor potential.
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Affiliation(s)
- Anastasia Balakina
- Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry RAS, 142432 Chernogolovka, Russia; (A.B.); (S.G.); (T.K.); (T.S.); (D.M.)
| | - Svyatoslav Gadomsky
- Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry RAS, 142432 Chernogolovka, Russia; (A.B.); (S.G.); (T.K.); (T.S.); (D.M.)
| | - Tatyana Kokovina
- Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry RAS, 142432 Chernogolovka, Russia; (A.B.); (S.G.); (T.K.); (T.S.); (D.M.)
- Faculty of Fundamental Physical-Chemical Engineering of M.V. Lomonosov MSU, Leninskie Gory, 119991 Moscow, Russia
| | - Tatyana Sashenkova
- Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry RAS, 142432 Chernogolovka, Russia; (A.B.); (S.G.); (T.K.); (T.S.); (D.M.)
| | - Denis Mishchenko
- Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry RAS, 142432 Chernogolovka, Russia; (A.B.); (S.G.); (T.K.); (T.S.); (D.M.)
- Faculty of Fundamental Physical-Chemical Engineering of M.V. Lomonosov MSU, Leninskie Gory, 119991 Moscow, Russia
- Scientific and Educational Center in Chernogolovka, State University of Education, 141014 Mytishchi, Russia
| | - Alexei Terentiev
- Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry RAS, 142432 Chernogolovka, Russia; (A.B.); (S.G.); (T.K.); (T.S.); (D.M.)
- Faculty of Fundamental Physical-Chemical Engineering of M.V. Lomonosov MSU, Leninskie Gory, 119991 Moscow, Russia
- Scientific and Educational Center in Chernogolovka, State University of Education, 141014 Mytishchi, Russia
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16
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Zhang J, Liu X, Xia Y, Xu S, Liu X, Xiao H, Wang X, Liu C, Liu G. Genetically engineered nano-melittin vesicles for multimodal synergetic cancer therapy. Bioeng Transl Med 2023; 8:e10482. [PMID: 38023709 PMCID: PMC10658496 DOI: 10.1002/btm2.10482] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 11/29/2022] [Accepted: 12/20/2022] [Indexed: 11/30/2023] Open
Abstract
Melittin, the principal constituent in bee venom, is an attractive candidate for cancer therapy. However, its clinical applications are limited by hemolysis, nonspecific cytotoxicity, and rapid metabolism. Herein, a novel genetically engineered vesicular antibody-melittin (VAM) drug delivery platform was proposed and validated for targeted cancer combination therapy. VAM generated from the cellular plasma membrane was bio-synthetically fabricated, with the recombinant protein (hGC33 scFv-melittin) being harbored and displayed on the cell membrane. The bioactive and targetable nanomelittin conjugated by hGC33 scFv could be released in an MMP14-responsive manner at tumor sites, which reduced off-target toxicity, especially the hemolytic activity of melittin. Importantly, VAM could be loaded with small-molecule drugs or nanoparticles for combination therapy. Nanomelittin formed pores in membranes and disturbed phospholipid bilayers, which allowed the anticancer agents (i.e., chemotherapeutic drug doxorubicin and sonosensitizer purpurin 18 nanoparticles) co-delivered by VAM to penetrate deeper tumor sites, leading to synergistic therapeutic effects. In particular, the punching effect generated by sonodynamic therapy further improved the immunomodulatory effect of nanomelittin to activate the immune response. Taken together, our findings indicate that clinically translatable VAM-based strategies represent a universal, promising approach to multimodal synergetic cancer therapy.
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Affiliation(s)
- Jianzhong Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public HealthXiamen UniversityXiamenChina
- Center for Molecular Imaging and Translational Medicine, School of Public HealthXiamen UniversityXiamenChina
| | - Xue Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public HealthXiamen UniversityXiamenChina
- Center for Molecular Imaging and Translational Medicine, School of Public HealthXiamen UniversityXiamenChina
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public HealthXiamen UniversityXiamenChina
| | - Yutian Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public HealthXiamen UniversityXiamenChina
- Center for Molecular Imaging and Translational Medicine, School of Public HealthXiamen UniversityXiamenChina
| | - Shuyu Xu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public HealthXiamen UniversityXiamenChina
- Center for Molecular Imaging and Translational Medicine, School of Public HealthXiamen UniversityXiamenChina
| | - Xuan Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public HealthXiamen UniversityXiamenChina
- Center for Molecular Imaging and Translational Medicine, School of Public HealthXiamen UniversityXiamenChina
| | - Haiqing Xiao
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public HealthXiamen UniversityXiamenChina
- Center for Molecular Imaging and Translational Medicine, School of Public HealthXiamen UniversityXiamenChina
| | - Xiaoyong Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public HealthXiamen UniversityXiamenChina
- Center for Molecular Imaging and Translational Medicine, School of Public HealthXiamen UniversityXiamenChina
| | - Chao Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public HealthXiamen UniversityXiamenChina
- Center for Molecular Imaging and Translational Medicine, School of Public HealthXiamen UniversityXiamenChina
| | - Gang Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public HealthXiamen UniversityXiamenChina
- Center for Molecular Imaging and Translational Medicine, School of Public HealthXiamen UniversityXiamenChina
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life SciencesXiamen UniversityXiamenChina
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17
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Tufail M. Unlocking the potential of the tumor microenvironment for cancer therapy. Pathol Res Pract 2023; 251:154846. [PMID: 37837860 DOI: 10.1016/j.prp.2023.154846] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 09/15/2023] [Accepted: 10/02/2023] [Indexed: 10/16/2023]
Abstract
The tumor microenvironment (TME) holds a crucial role in the progression of cancer. Epithelial-derived tumors share common traits in shaping the TME. The Warburg effect is a notable phenomenon wherein tumor cells exhibit resistance to apoptosis and an increased reliance on anaerobic glycolysis for energy production. Recognizing the pivotal role of the TME in controlling tumor growth and influencing responses to chemotherapy, researchers have focused on developing potential cancer treatment strategies. A wide array of therapies, including immunotherapies, antiangiogenic agents, interventions targeting cancer-associated fibroblasts (CAF), and therapies directed at the extracellular matrix, have been under investigation and have demonstrated efficacy. Additionally, innovative techniques such as tumor tissue explants, "tumor-on-a-chip" models, and multicellular tumor spheres have been explored in laboratory research. This comprehensive review aims to provide insights into the intricate cross-talk between cancer-associated signaling pathways and the TME in cancer progression, current therapeutic approaches targeting the TME, the immune landscape within solid tumors, the role of the viral TME, and cancer cell metabolism.
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Affiliation(s)
- Muhammad Tufail
- Institute of Biomedical Sciences, Shanxi University, Taiyuan 030006, China.
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18
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Closset L, Gultekin O, Salehi S, Sarhan D, Lehti K, Gonzalez-Molina J. The extracellular matrix - immune microenvironment crosstalk in cancer therapy: Challenges and opportunities. Matrix Biol 2023; 121:217-228. [PMID: 37524251 DOI: 10.1016/j.matbio.2023.07.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 07/28/2023] [Accepted: 07/28/2023] [Indexed: 08/02/2023]
Abstract
Targeting the tumour immune microenvironment (TIME) by cancer immunotherapy has led to improved patient outcomes. However, response to these treatments is heterogeneous and cancer-type dependant. The therapeutic activity of classical cancer therapies such as chemotherapy, radiotherapy, and surgical oncology is modulated by alterations of the TIME. A major regulator of immune cell function and resistance to both immune and classical therapies is the extracellular matrix (ECM). Concurrently, cancer therapies reshape the TIME as well as the ECM, causing both pro- and anti-tumour responses. Accordingly, the TIME-ECM crosstalk presents attractive opportunities to improve therapy outcomes. Here, we review the molecular crosstalk between the TIME and the ECM in cancer and its implications in cancer progression and clinical intervention. Additionally, we discuss examples and future directions of ECM and TIME co-targeting in combination with oncological therapies including surgery, chemotherapy, and radiotherapy.
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Affiliation(s)
- Lara Closset
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solnavägen 9, Stockholm 171 65, Sweden; Saint-Antoine Research center (CRSA), UMR_S 938, INSERM, Sorbonne Université, Paris F-75012, France
| | - Okan Gultekin
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solnavägen 9, Stockholm 171 65, Sweden
| | - Sahar Salehi
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solnavägen 9, Stockholm 171 65, Sweden; Department of Women's and Children's Health, Division of Obstetrics and Gynecology, Karolinska Institutet, Stockholm, Sweden; Department of Pelvic Cancer, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden
| | - Dhifaf Sarhan
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Kaisa Lehti
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solnavägen 9, Stockholm 171 65, Sweden; Department of Biomedical Laboratory Science, Norwegian University of Science and Technology, Trondheim, Norway
| | - Jordi Gonzalez-Molina
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solnavägen 9, Stockholm 171 65, Sweden.
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19
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Peng Q, Duan N, Wang X, Wang W. The potential roles of cigarette smoke-induced extracellular vesicles in oral leukoplakia. Eur J Med Res 2023; 28:250. [PMID: 37481562 PMCID: PMC10362576 DOI: 10.1186/s40001-023-01217-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 07/08/2023] [Indexed: 07/24/2023] Open
Abstract
BACKGROUND The onset of oral leukoplakia (OLK), the most common oral lesion with a high risk of malignant transformation, is closely associated with the exposure of cigarette smoke. Cigarette smoke is a complicated mixture of more than 4500 different chemicals including various oxidants and free radical, which contributes to the onset of immune and inflammatory response or even carcinogenesis. Recent studies have proved that the exposure of cigarette smoke leads to the onset and aggravation of many diseases via significantly changed the production and components of extracellular vesicles. The extracellular vesicles are membrane-enclosed nanosized particles secreted by diverse cells and involved in cell-cell communication because of their ability to deliver a number of bioactive molecules including proteins, lipids, DNAs and RNAs. Getting insight into the mechanisms of extracellular vesicles in regulating OLK upon cigarette smoke stimulation contributes to unravel the pathophysiology of OLK in-depth. However, evidence done on the role of extracellular vesicles in cigarette smoke-induced OLK is still in its infancy. MATERIALS AND METHODS Relevant literatures on cigarette smoke, oral leukoplakia and extracellular vesicles were searched in PubMed database. CONCLUSIONS In this review, we summarize the recent findings about the function of extracellular vesicles in the pathogenesis of cigarette smoke-induced diseases, and to infer their potential utilizations as diagnostic biomarkers, prognostic evaluation, and therapeutic targets of OLK in the future.
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Affiliation(s)
- Qiao Peng
- Department of Oral Medicine, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing, 210008, China
| | - Ning Duan
- Department of Oral Medicine, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing, 210008, China
| | - Xiang Wang
- Department of Oral Medicine, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing, 210008, China.
| | - Wenmei Wang
- Department of Oral Medicine, Nanjing Stomatological Hospital, Medical School of Nanjing University, 30 Zhongyang Road, Nanjing, 210008, China.
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20
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Almutairi S, Kalloush HM, Manoon NA, Bardaweel SK. Matrix Metalloproteinases Inhibitors in Cancer Treatment: An Updated Review (2013-2023). Molecules 2023; 28:5567. [PMID: 37513440 PMCID: PMC10384300 DOI: 10.3390/molecules28145567] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 07/09/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Matrix metalloproteinases (MMPs) are identifiable members of proteolytic enzymes that can degrade a wide range of proteins in the extracellular matrix (ECM). MMPs can be categorized into six groups based on their substrate specificity and structural differences: collagenases, gelatinases, stromelysins, matrilysins, metalloelastase, and membrane-type MMPs. MMPs have been linked to a wide variety of biological processes, such as cell transformation and carcinogenesis. Over time, MMPs have been evaluated for their role in cancer progression, migration, and metastasis. Accordingly, various MMPs have become attractive therapeutic targets for anticancer drug development. The first generations of broad-spectrum MMP inhibitors displayed effective inhibitory activities but failed in clinical trials due to poor selectivity. Thanks to the evolution of X-ray crystallography, NMR analysis, and homology modeling studies, it has been possible to characterize the active sites of various MMPs and, consequently, to develop more selective, second-generation MMP inhibitors. In this review, we summarize the computational and synthesis approaches used in the development of MMP inhibitors and their evaluation as potential anticancer agents.
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Affiliation(s)
- Shriefa Almutairi
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942, Jordan
| | - Hanin Moh'd Kalloush
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942, Jordan
- Department of Pharmacy, Al-Zaytoonah University of Jordan, Amman 11733, Jordan
| | - Nour A Manoon
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942, Jordan
| | - Sanaa K Bardaweel
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman 11942, Jordan
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21
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Brookes MJ, Chan CD, Crowley TP, Ragbir M, Beckingsale T, Ghosh KM, Rankin KS. What Is the Significance of Indeterminate Pulmonary Nodules in High-Grade Soft Tissue Sarcomas? A Retrospective Cohort Study. Cancers (Basel) 2023; 15:3531. [PMID: 37444641 DOI: 10.3390/cancers15133531] [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: 04/13/2023] [Revised: 06/29/2023] [Accepted: 07/05/2023] [Indexed: 07/15/2023] Open
Abstract
BACKGROUND Sarcomas are rare, aggressive cancers which frequently metastasise to the lungs. Following diagnosis, patients typically undergo staging by means of a CT scan of their chest. This often identifies indeterminate pulmonary nodules (IPNs), but the significance of these in high-grade soft tissue sarcoma (STS) is unclear. Identifying whether these are benign or malignant is important for clinical decision making. This study analyses the clinical relevance of IPNs in high-grade STS. METHODS All patients treated at our centre for high-grade soft tissue sarcoma between 2010 and 2020 were identified from a prospective database. CT scans and their reports were reviewed, and survival data were collected from patient records. RESULTS 389 suitable patients were identified; 34.4% had IPNs on their CT staging scan and 20.1% progressed into lung metastases. Progression was more likely with IPNs ≥ 5 mm in diameter (p = 0.006), multiple IPNs (p = 0.013) or bilateral IPNs (p = 0.022), as well as in patients with primaries ≥ 5 cm (p = 0.014), grade 3 primaries (p = 0.009) or primaries arising deep to the fascia (p = 0.041). The median time to progression was 143 days. IPNs at diagnosis were associated with an increased risk of developing lung metastases and decreased OS in patients with grade 3 STS (p = 0.0019 and p = 0.0016, respectively); this was not observed in grade 2 patients. CONCLUSIONS IPNs at diagnosis are associated with significantly worse OS in patients with grade 3 STS. It is crucial to consider the primary tumour as well as the IPNs when considering the risk of progression. Surveillance CT scans should be carried out within 6 months.
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Affiliation(s)
- Marcus J Brookes
- North of England Bone and Soft Tissue Tumour Service, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK
| | - Corey D Chan
- North of England Bone and Soft Tissue Tumour Service, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
| | - Timothy P Crowley
- North of England Bone and Soft Tissue Tumour Service, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK
| | - Maniram Ragbir
- North of England Bone and Soft Tissue Tumour Service, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK
| | - Thomas Beckingsale
- North of England Bone and Soft Tissue Tumour Service, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK
| | - Kanishka M Ghosh
- North of England Bone and Soft Tissue Tumour Service, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK
| | - Kenneth S Rankin
- North of England Bone and Soft Tissue Tumour Service, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
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22
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Zare F, Shahbazi N, Faraji N, Goli R, Mostafaei B, Anari S. A cruel invasion of Ewing's sarcoma of the skull: A rare case report. Int J Surg Case Rep 2023; 108:108380. [PMID: 37406533 PMCID: PMC10382727 DOI: 10.1016/j.ijscr.2023.108380] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 05/31/2023] [Accepted: 05/31/2023] [Indexed: 07/07/2023] Open
Abstract
INTRODUCTION AND IMPORTANCE Ewing's sarcoma, a highly malignant bone tumor, typically affects the pelvis and long bones of the lower extremities in children and young adults; primary involvement of the skull is rare. Primary Ewing's sarcoma arising from the skull is very rare. In most cases, this disease is fatal, although the prognosis of Ewing sarcoma improves with radiation and chemotherapy after surgery. CASE PRESENTATION This case is about 25-year-old woman who was referred to Omid Hospital in Urmia because of frequent headaches, where a tumor mass was found according to the results of CT scan. Biopsy confirmed small round cell sarcoma as the diagnosis. Chemotherapy was ineffective and tumor growth was unstoppable, causing the patient to die after 3 months. CLINICAL DISCUSSION Ewing's sarcoma can affect various parts of the human body, including bone and soft tissue, but rarely the skull. Ewing's sarcoma typically grows extradural and often reaches a very large size before invading the skull or being detected clinically. CONCLUSION In most cases, Ewing's sarcoma is fatal, although the prognosis of this disease improves with radiation and chemotherapy after surgery.
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Affiliation(s)
- Farzaneh Zare
- Department of Nursing, School of Nursing and Midwifery, Urmia University of Medical Sciences, Urmia, Iran
| | - Niloofar Shahbazi
- Department of Nursing, School of Nursing and Midwifery, Islamic Azad University Zarand, Kerman, Iran
| | - Navid Faraji
- Department of Medical-Surgical Nursing, School of Nursing and Midwifery, Urmia University of Medical Sciences, Urmia, Iran
| | - Rasoul Goli
- Department of Medical-Surgical Nursing, School of Nursing and Midwifery, Urmia University of Medical Sciences, Urmia, Iran
| | - Behnam Mostafaei
- Department of Medical-Surgical Nursing, School of Nursing and Midwifery, Urmia University of Medical Sciences, Urmia, Iran
| | - Sina Anari
- Department of Nursing, School of Nursing and Midwifery, Islamic Azad University Maragheh Branch, Tabriz, Iran.
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Wu J, Guo Y, Zuo ZF, Zhu ZW, Han L. MMP14 is a diagnostic gene of intrahepatic cholangiocarcinoma associated with immune cell infiltration. World J Gastroenterol 2023; 29:2961-2978. [PMID: 37274806 PMCID: PMC10237093 DOI: 10.3748/wjg.v29.i19.2961] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/24/2023] [Accepted: 04/23/2023] [Indexed: 05/16/2023] Open
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor of the hepatobiliary system with concealed onset, strong invasiveness and poor prognosis.
AIM To explore the disease characteristic genes that may be helpful in the diagnosis of ICC and affect immune cell infiltration.
METHODS We downloaded two ICC-related human gene expression profiles from GEO database as the training group (GSE26566 and GSE32958 datasets) for difference analysis, and performed enrichment analysis on differential genes. The least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE) and random forest (RF), three machine learning algorithms, were used to screen the characteristic genes. Double verification was carried out on GSE107943 and The Cancer Genome Atlas, two verification groups. Receiver operating characteristic curve and area under the curve (AUC) were used to evaluate the diagnostic efficacy of genes for ICC. CIBERSORT and ssGSEA algorithms were used to evaluate the effect of characteristic genes on immune infiltration pattern. Human Protein Atlas (HPA) was used to analyze the protein expression level of the target gene.
RESULTS A total of 1091 differential genes were obtained in the training group. Enrichment analysis showed that the above genes were mainly enriched in small molecular catabolism, complement and coagulation cascade, bile secretion and other functions and pathways. Twenty-five characteristic genes were screened by LASSO regression, 19 by SVM-RFE algorithm, and 30 by RF algorithm. Three algorithms were used in combination to determine the characteristic gene of ICC: MMP14. The verification group confirmed that the genes had a high diagnostic accuracy (AUC values of the training group and the verification group were 0.960, 0.999, and 0.977, respectively). Comprehensive analysis of immune infiltration showed that MMP14 could affect the infiltration of monocytes, activated memory CD4 T cells, resting memory CD4 T cells, and other immune cells, and was closely related to the expression of CD200, cytotoxic T-lymphocyte-associated antigen 4, CD14, CD44, and other immune checkpoints. The results of immunohistochemistry in HPA database showed was indeed overexpressed in ICC.
CONCLUSION MMP14 can be used as a disease characteristic gene of ICC, and may regulate the distribution of immune-infiltrating cells in the ICC tumor microenvironment, which provides a new method for the determination of ICC diagnostic markers and screening of therapeutic targets.
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Affiliation(s)
- Jun Wu
- China Medical University, The General Hospital of Northern Theater Command Training Base for Graduate, Shenyang 110016, Liaoning Province, China
| | - Yang Guo
- Department of Hepatobiliary Surgery, The General Hospital of Northern Theater Command, Shenyang 110016, Liaoning Province, China
| | - Zhi-Fan Zuo
- Gynecological Radiotherapy Ward, Liaoning Provincial Cancer Hospital, Shenyang 110801, Liaoning province, China
| | - Zi-Wei Zhu
- China Medical University, The General Hospital of Northern Theater Command Training Base for Graduate, Shenyang 110016, Liaoning Province, China
| | - Lei Han
- Department of Hepatobiliary Surgery, The General Hospital of Northern Theater Command, Shenyang 110016, Liaoning Province, China
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24
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Du X, Liu H, Tian Z, Zhang S, Shi L, Wang Y, Guo X, Zhang B, Yuan S, Zeng X, Zhang H. PI3K/AKT/mTOR pathway mediated-cell cycle dysregulation contribute to malignant proliferation of mouse spermatogonia induced by microcystin-leucine arginine. ENVIRONMENTAL TOXICOLOGY 2023; 38:343-358. [PMID: 36288207 DOI: 10.1002/tox.23691] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 10/09/2022] [Accepted: 10/13/2022] [Indexed: 06/16/2023]
Abstract
Environmental cyanotoxin exposure may be a trigger of testicular cancer. Activation of PI3K/AKT/mTOR signaling pathway is the critical molecular event in testicular carcinogenesis. As a widespread cyanotoxin, microcystin-leucine arginine (MC-LR) is known to induce cell malignant transformation and tumorigenesis. However, the effects of MC-LR on the regulatory mechanism of PI3K/AKT/mTOR pathway in seminoma, the most common testicular tumor, are unknown. In this study, mouse spermatogonia cell line (GC-1) and nude mice were used to investigate the effects and mechanisms of MC-LR on the malignant transformation of spermatogonia by nude mouse tumorigenesis assay, cell migration invasion assay, western blot, and cell cycle assay, and so forth. The results showed that, after continuous exposure to environmentally relevant concentrations of MC-LR (20 nM) for 35 generations, the proliferation, migration, and invasion abilities of GC-1 cells were increased by 120%, 340%, and 370%, respectively. In nude mice, MC-LR-treated GC-1 cells formed tumors with significantly greater volume (0.998 ± 0.768 cm3 ) and weight (0.637 ± 0.406 g) than the control group (0.067 ± 0.039 cm3 ; 0.094 ± 0.087 g) (P < .05). Furthermore, PI3K inhibitor Wortmannin inhibited the PI3K/AKT/mTOR pathway and its downstream proteins (c-MYC, CDK4, CCND1, and MMP14) activated by MC-LR. Blocking PI3K alleviated MC-LR-induced cell cycle disorder and malignant proliferation, migration and invasive of GC-1 cells. Altogether, our findings suggest that MC-LR can induce malignant transformation of mouse spermatogonia, and the PI3K/AKT/mTOR pathway-mediated cell cycle dysregulation may be an important target for malignant proliferation. This study provides clues to further reveal the etiology and pathogenesis of seminoma.
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Affiliation(s)
- Xingde Du
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Haohao Liu
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Zhihui Tian
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Shiyu Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Linjia Shi
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Yongshui Wang
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Xing Guo
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Bingyu Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Shumeng Yuan
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Xin Zeng
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Huizhen Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, China
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25
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Association of SMC4 with prognosis and immune infiltration of sarcoma. Aging (Albany NY) 2023; 15:567-582. [PMID: 36719264 PMCID: PMC9925680 DOI: 10.18632/aging.204503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 01/23/2023] [Indexed: 02/01/2023]
Abstract
OBJECTIVE This study was performed to explore the prognostic relevance of structural maintenance of chromosomes 4 (SMC4) in pan-cancer and explore the association between SMC4 and immune infiltration of sarcoma. RESULTS Elevated expression of SMC4 was detected in cancer tissues compared to normal tissue, which was confirmed in synovial sarcoma tissues with immunohistochemistry (IHC). Additionally, higher expression of SMC4 was connected to worse outcomes of sarcoma, gastric cancer, breast cancer, liver cancer or ovarian cancer. Moreover, SMC4 was positively connected to immune cell infiltrates in sarcoma. In addition, infiltrating immune cell markers including monocyte, TAM, M1 and M2 presented different SMC4-associated immune infiltration patterns. CONCLUSION The results from our study showed that SMC4 was positively related to the prognosis and immunological status of sarcoma. SMC4 could be a potential biomarker for prognosis and immune cell infiltrates in sarcoma. METHODS Several databases including ONCOMINE, GEPIA, and Kaplan-Meier Plotter were adopted to explore the expression pattern of SMC4 in sarcoma, which was confirmed by IHC. The GEPIA and TIMER datasets were adopted to investigate the associations between SMC4 and prognosis in various cancers, especially in sarcoma.
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26
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Dong J, Wang F, Gao X, Zhao H, Zhang J, Wang N, Liu Z, Yan X, Jin J, Ba Y, Ma S, Du J, Ji H, Hu S. Integrated analysis of genome-wide DNA methylation and cancer-associated fibroblasts identified prognostic biomarkers and immune checkpoint blockade in lower grade gliomas. Front Oncol 2023; 12:977251. [PMID: 36727078 PMCID: PMC9885112 DOI: 10.3389/fonc.2022.977251] [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: 06/24/2022] [Accepted: 12/28/2022] [Indexed: 01/18/2023] Open
Abstract
Background Cancer-associated fibroblasts (CAFs) are vital components of prominent cellular components in lower-grade gliomas (LGGs) that contribute to LGGs' progression, treatment resistance, and immunosuppression. Epigenetic modification and immunity have significant implications for tumorigenesis and development. Methods We combined aberrant methylation and CAFs abundances to build a prognostic model and the impact on the biological properties of LGGs. Grouping based on the median CAFs abundances score of samples in the TCGA-LGGs dataset, differentially expressed genes and aberrantly methylated genes were combined for subsequent analysis. Results We identified five differentially methylated and expressed genes (LAT32, SWAP70, GSAP, EMP3, and SLC2A10) and established a prognostic gene signature validated in the CGGA-LGGs dataset. Immunohistochemistry (IHC) and in vitro tests were performed to verify these expressions. The high-risk group increased in tumor-promoting immune cells and tumor mutational burden. Notably, risk stratification had different ICB sensitivities in LGGs, and there were also significant sensitivity differences for temozolomide and the other three novel chemotherapeutic agents. Conclusion Our study reveals characteristics of CAFs in LGGs, refines the direct link between epigenetics and tumor stroma, and might provide clinical implications for guiding tailored anti-CAFs therapy in combination with immunotherapy for LGGs patients.
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Affiliation(s)
- Jiawei Dong
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China,Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Fang Wang
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China,Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xin Gao
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Hongtao Zhao
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China,Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jiheng Zhang
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China,Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Nan Wang
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China,Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhihui Liu
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China,Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiuwei Yan
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China,Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jiaqi Jin
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China,Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yixu Ba
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China,Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shuai Ma
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China,Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jianyang Du
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Hang Ji
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China,Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China,*Correspondence: Shaoshan Hu, ; Hang Ji,
| | - Shaoshan Hu
- Cancer Center, Department of Neurosurgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China,Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China,*Correspondence: Shaoshan Hu, ; Hang Ji,
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27
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Zhang H, Chen B, Waliullah ASM, Aramaki S, Ping Y, Takanashi Y, Zhang C, Zhai Q, Yan J, Oyama S, Kahyo T, Setou M. A New Potential Therapeutic Target for Cancer in Ubiquitin-Like Proteins-UBL3. Int J Mol Sci 2023; 24:ijms24021231. [PMID: 36674743 PMCID: PMC9863382 DOI: 10.3390/ijms24021231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/31/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Ubiquitin-like proteins (Ubls) are involved in a variety of biological processes through the modification of proteins. Dysregulation of Ubl modifications is associated with various diseases, especially cancer. Ubiquitin-like protein 3 (UBL3), a type of Ubl, was revealed to be a key factor in the process of small extracellular vesicle (sEV) protein sorting and major histocompatibility complex class II ubiquitination. A variety of sEV proteins that affects cancer properties has been found to interact with UBL3. An increasing number of studies has implied that UBL3 expression affects cancer cell growth and cancer prognosis. In this review, we provide an overview of the relationship between various Ubls and cancers. We mainly introduce UBL3 and its functions and summarize the current findings of UBL3 and examine its potential as a therapeutic target in cancers.
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Affiliation(s)
- Hengsen Zhang
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Bin Chen
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - A. S. M. Waliullah
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Shuhei Aramaki
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, Shizuoka 431-3192, Japan
- Department of Radiation Oncology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Yashuang Ping
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Yusuke Takanashi
- First Department of Surgery, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Chi Zhang
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, Shizuoka 431-3192, Japan
- Department of Systems Molecular Anatomy, Institute for Medical Photonics Research, Preeminent Medical Photonics, Education & Research Center, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Qing Zhai
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Jing Yan
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Soho Oyama
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Tomoaki Kahyo
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, Shizuoka 431-3192, Japan
- International Mass Imaging Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Mitsutoshi Setou
- Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, Shizuoka 431-3192, Japan
- Department of Systems Molecular Anatomy, Institute for Medical Photonics Research, Preeminent Medical Photonics, Education & Research Center, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, Shizuoka 431-3192, Japan
- International Mass Imaging Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, Shizuoka 431-3192, Japan
- Correspondence: ; Tel.: +81-053-435-2086; Fax: +81-053-435-2468
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28
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Brookes MJ, Roundhill EA, Jeys L, Parry M, Burchill SA, Rankin KS. Membrane-type 1 matrix metalloproteinase as predictor of survival and candidate therapeutic target in Ewing sarcoma. Pediatr Blood Cancer 2022; 69:e29959. [PMID: 36106829 DOI: 10.1002/pbc.29959] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 08/08/2022] [Accepted: 08/09/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND Ewing sarcoma (ES) is the second most common primary bone malignancy, with an urgent need for new treatments. ES is associated with high rates of progression and relapse, driven by drug-resistant cells capable of migration, self-renewal and single-cell tumorigenesis, termed cancer stem-like cells (CSCs). Membrane-type 1 matrix metalloproteinase (MT1-MMP) is a membrane-bound proteolytic enzyme, which, via direct and indirect mechanisms, digests four of the main types of collagen. This can be hijacked in malignancy for invasion and metastasis, with high expression predicting decreased survival in multiple cancers. In this study, we have examined the hypothesis that MT1-MMP is expressed by ES cells and explored the relationship between expression and outcomes. PROCEDURE MT1-MMP expression in ES established cell lines, primary patient-derived cultures and daughter ES-CSCs was characterised by RNA sequencing, Western blotting, immunocytochemistry and flow cytometry. Immunohistochemistry was used to detect MT1-MMP in tumour biopsies, and the relationship between expression, event-free and overall survival examined. RESULTS MT1-MMP was detected at both RNA and protein levels in five of six established cell lines, all primary cultures (n = 25) and all daughter ES-CSCs (n = 7). Immunohistochemistry of treatment-naïve biopsy tissue demonstrated that high MT1-MMP expression predicted decreased event-free and overall survival (p = .017 and .036, respectively; n = 47); this was not significant in multivariate analysis. CONCLUSIONS MT1-MMP is expressed by ES cells, including ES-CSCs, making it a candidate therapeutic target. The level of MT1-MMP expression at diagnosis may be considered as a prognostic biomarker if validated by retrospective analysis of a larger cohort of clinical trial samples.
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Affiliation(s)
- Marcus J Brookes
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.,North of England Bone and Soft Tissue Tumour Service, Royal Victoria Infirmary, Newcastle upon Tyne, UK
| | - Elizabeth A Roundhill
- Children's Cancer Research Group, Leeds Institute of Medical Research, St. James's University Hospital, Leeds, UK
| | - Lee Jeys
- Royal Orthopaedic Hospital NHS Foundation Trust, Northfield, Birmingham, UK
| | - Michael Parry
- Royal Orthopaedic Hospital NHS Foundation Trust, Northfield, Birmingham, UK
| | - Susan A Burchill
- Children's Cancer Research Group, Leeds Institute of Medical Research, St. James's University Hospital, Leeds, UK
| | - Kenneth S Rankin
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.,North of England Bone and Soft Tissue Tumour Service, Royal Victoria Infirmary, Newcastle upon Tyne, UK
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29
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Endogenous stimuli-responsive nanoparticles for cancer therapy: From bench to bedside. Pharmacol Res 2022; 186:106522. [DOI: 10.1016/j.phrs.2022.106522] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 10/17/2022] [Accepted: 10/21/2022] [Indexed: 11/06/2022]
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30
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Gonzalez‐Molina J, Kirchhof KM, Rathod B, Moyano‐Galceran L, Calvo‐Noriega M, Kokaraki G, Bjørkøy A, Ehnman M, Carlson JW, Lehti K. Mechanical Confinement and DDR1 Signaling Synergize to Regulate Collagen-Induced Apoptosis in Rhabdomyosarcoma Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2202552. [PMID: 35957513 PMCID: PMC9534977 DOI: 10.1002/advs.202202552] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/29/2022] [Indexed: 06/15/2023]
Abstract
Fibrillar collagens promote cell proliferation, migration, and survival in various epithelial cancers and are generally associated with tumor aggressiveness. However, the impact of fibrillar collagens on soft tissue sarcoma behavior remains poorly understood. Unexpectedly, this study finds that fibrillar collagen-related gene expression is associated with favorable patient prognosis in rhabdomyosarcoma. By developing and using collagen matrices with distinct stiffness and in vivo-like microarchitectures, this study uncovers that the activation of DDR1 has pro-apoptotic and of integrin β1 pro-survival function, specifically in 3D rhabdomyosarcoma cell cultures. It demonstrates that rhabdomyosarcoma cell-intrinsic or extrinsic matrix remodeling promotes cell survival. Mechanistically, the 3D-specific collagen-induced apoptosis results from a dual DDR1-independent and a synergistic DDR1-dependent TRPV4-mediated response to mechanical confinement. Altogether, these results indicate that dense microfibrillar collagen-rich microenvironments are detrimental to rhabdomyosarcoma cells through an apoptotic response orchestrated by the induction of DDR1 signaling and mechanical confinement. This mechanism helps to explain the preference of rhabdomyosarcoma cells to grow in and metastasize to low fibrillar collagen microenvironments such as the lung.
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Affiliation(s)
- Jordi Gonzalez‐Molina
- Department of MicrobiologyTumor and Cell BiologyKarolinska InstitutetSolnavägen 9Solna17165Sweden
- Department of Oncology‐PathologyKarolinska InstitutetKarolinskavägenSolna17164Sweden
| | - Katharina Miria Kirchhof
- Department of MicrobiologyTumor and Cell BiologyKarolinska InstitutetSolnavägen 9Solna17165Sweden
| | - Bhavik Rathod
- Department of MicrobiologyTumor and Cell BiologyKarolinska InstitutetSolnavägen 9Solna17165Sweden
- Department of Laboratory MedicineDivision of PathologyKarolinska InstitutetAlfred Nobels Allé 8Stockholm14152Sweden
| | - Lidia Moyano‐Galceran
- Department of MicrobiologyTumor and Cell BiologyKarolinska InstitutetSolnavägen 9Solna17165Sweden
| | - Maria Calvo‐Noriega
- Department of MicrobiologyTumor and Cell BiologyKarolinska InstitutetSolnavägen 9Solna17165Sweden
| | - Georgia Kokaraki
- Department of Oncology‐PathologyKarolinska InstitutetKarolinskavägenSolna17164Sweden
- Keck School of MedicineUniversity of Southern California1975 Zonal AveLos AngelesCA90033USA
| | - Astrid Bjørkøy
- Department of PhysicsNorwegian University of Science and TechnologyHøgskoleringen 5TrondheimNO‐7491Norway
| | - Monika Ehnman
- Department of Oncology‐PathologyKarolinska InstitutetKarolinskavägenSolna17164Sweden
| | - Joseph W. Carlson
- Department of Oncology‐PathologyKarolinska InstitutetKarolinskavägenSolna17164Sweden
- Keck School of MedicineUniversity of Southern California1975 Zonal AveLos AngelesCA90033USA
| | - Kaisa Lehti
- Department of MicrobiologyTumor and Cell BiologyKarolinska InstitutetSolnavägen 9Solna17165Sweden
- Department of Biomedical Laboratory ScienceNorwegian University of Science and TechnologyErling Skjalgssons gate 1TrondheimNO‐7491Norway
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Li Y, Tang K, Zhang X, Pan W, Li N, Tang B. Tumor microenvironment responsive nanocarriers for gene therapy. Chem Commun (Camb) 2022; 58:8754-8765. [PMID: 35880654 DOI: 10.1039/d2cc02759c] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Stimuli responsive nanocarriers are important non-viral gene carriers for gene therapy. We discuss the stimulus conditions and then highlight various stimuli responsive nanocarriers in the tumor microenvironment for cancer gene therapy. We hope that this review will inspire readers to develop more effective stimuli responsive nanocarriers for delivering genes.
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Affiliation(s)
- Yanhua Li
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China.
| | - Kun Tang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China.
| | - Xia Zhang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China.
| | - Wei Pan
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China.
| | - Na Li
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China.
| | - Bo Tang
- College of Chemistry, Chemical Engineering and Materials Science, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, P. R. China.
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Pringle TA, Chan CD, Luli S, Blair HJ, Rankin KS, Knight JC. Synthesis and In Vivo Evaluation of a Site-specifically Labeled Radioimmunoconjugate for Dual-Modal (PET/NIRF) Imaging of MT1-MMP in Sarcomas. Bioconjug Chem 2022; 33:1564-1573. [PMID: 35867034 PMCID: PMC9389524 DOI: 10.1021/acs.bioconjchem.2c00306] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
![]()
Bone sarcomas are devastating primary bone cancers that
mostly
affect children, young adults, and the elderly. These aggressive tumors
are associated with poor survival, and surgery remains the mainstay
of treatment. Surgical planning is increasingly informed by positron
emission tomography (PET), and tumor margin identification during
surgery is aided by near-infrared fluorescence (NIRF) imaging, yet
these investigations are confounded by probes that lack specificity
for sarcoma biomarkers. We report the development of a dual-modal
(PET/NIRF) immunoconjugate ([89Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW)
that targets MT1-MMP, a matrix metalloproteinase overexpressed in
high-grade sarcomas. [89Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW
was synthesized via site-specific chemoenzymatic
glycan modification, characterized, and isolated in high specific
activity and radiochemical purity. Saturation binding and immunoreactivity
assays indicated only minor perturbation of binding properties. A
novel mouse model of dedifferentiated chondrosarcoma based on intrafemoral
inoculation of HT1080 WT or KO cells (high and low MT1-MMP expression,
respectively) was used to evaluate target binding and biodistribution.
Fluorescence and Cerenkov luminescence images of [89Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW
showed preferential uptake in HT1080 WT tumors. Ex vivo gamma counting revealed that uptake in MT1-MMP-positive tumors was
significantly higher than that in control groups. Taken together,
[89Zr]Zr-DFO-anti-MT1-MMP-IRDye800CW is a promising dual-modal
sarcoma imaging agent for pre-operative surgical planning and intraoperative
surgical guidance.
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Affiliation(s)
- Toni A Pringle
- School of Natural and Environmental Sciences, Newcastle University, Newcastle Upon Tyne NE1 7RU, U.K
| | - Corey D Chan
- North of England Bone and Soft Tissue Tumour Service, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Road, Newcastle Upon Tyne NE7 7DN, U.K.,Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne NE1 7RU, U.K
| | - Saimir Luli
- Preclinical In Vivo Imaging, Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne NE2 4HH, U.K
| | - Helen J Blair
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne NE1 7RU, U.K.,Wolfson Childhood Cancer Research Centre, Newcastle Upon Tyne NE1 7RY, U.K
| | - Kenneth S Rankin
- North of England Bone and Soft Tissue Tumour Service, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Road, Newcastle Upon Tyne NE7 7DN, U.K.,Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne NE1 7RU, U.K
| | - James C Knight
- School of Natural and Environmental Sciences, Newcastle University, Newcastle Upon Tyne NE1 7RU, U.K.,Newcastle Centre for Cancer, Newcastle University, Newcastle Upon Tyne NE1 7RU, U.K
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Kim J, Park H, Kim H, Kim Y, Oh HJ, Chung S. Microfluidic one-directional interstitial flow generation from cancer to cancer associated fibroblast. Acta Biomater 2022; 144:258-265. [PMID: 35364320 DOI: 10.1016/j.actbio.2022.03.044] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 03/05/2022] [Accepted: 03/24/2022] [Indexed: 11/01/2022]
Abstract
Tumors, unlike normal tissue, have vascular anomalies and create interstitial flow (IF), which allows soluble substances from cancer cells to be transported directionally toward the tumor stroma. In the stroma, IF activates fibroblasts. Cancer-associated fibroblasts (CAFs) are formed from stimulated cells and aid cancer growth. A microfluidic device was designed to generate a one-directional flow of a small volume mimicking IF from donor cells to recipient at steady-state conditions only based on the medium evaporation from reservoirs with different diameter. The IF carried substances from donor cells, which stimulated the activation of fibroblasts on the receiving side, as well as their migration and stellate formation. Matrix metallopeptidases 9 and 14 as well as CAF markers such as fibroblast activation protein alpha, vimentin, and alpha-smooth muscle actin are abundantly expressed in the migrating fibroblasts. The created platform mimicked one-directional delivery in tumor stroma. This will allow researchers to investigate how cancer cells activate and differentiate stromal cells. STATEMENT OF SIGNIFICANCE: We show how to provide continuous one-directional interstitial flow (IF) in a microfluidic device without using any power source and instrumentation. This microfluidic technology was used to simulate the tumor microenvironment. Fibroblasts in the tumor stroma are activated and migrated toward cancer cells, as recapitulated by co-culture of cancer cells as donor and fibroblasts as recipient under the one-directional IF. We believe that soluble substances from cancerous cells delivered by the one-directional IF efficiently regulated the development of cancer-associated fibroblasts (CAFs), as shown by increasing roundness and decreased circularity, taking on a stellate morphology, and by enhanced invasion into a type I collagen hydrogel. Migrating fibroblasts into the hydrogel had significant levels of MMP-9, MMP-14, FAP, vimentin, and αSMA, all of which are CAF markers, bearing a capacity to form hot stroma affecting tumor malignancy.
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Liang Z, Yu J, Gu D, Liu X, Liu J, Wu M, Xu M, Shen M, Duan W, Li W. M2-phenotype tumour-associated macrophages upregulate the expression of prognostic predictors MMP14 and INHBA in pancreatic cancer. J Cell Mol Med 2022; 26:1540-1555. [PMID: 35150061 PMCID: PMC8899166 DOI: 10.1111/jcmm.17191] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 12/11/2021] [Accepted: 12/17/2021] [Indexed: 12/25/2022] Open
Abstract
Pancreatic cancer is one of the most lethal gastrointestinal tumours, the most common pathological type is pancreatic adenocarcinoma (PAAD). In recent year, immune imbalanced in tumour microenvironment has been shown to play an important role in the evolution of tumours progression, and the efficacy of immunotherapy has been gradually demonstrated in clinical practice. In this study, we propose to construct an immune-related prognostic risk model based on immune-related genes MMP14 and INHBA expression that can assess the prognosis of pancreatic cancer patients and identify potential therapeutic targets for pancreatic cancer, to provide new ideas for the treatment of pancreatic cancer. We also investigate the correlation between macrophage infiltration and MMP14 and INHBA expression. First, the gene expression data of pancreatic cancer and normal pancreatic tissue were obtained from The Cancer Genome Atlas Program (TCGA) and The Genotype-Tissue Expression public database (GTEx). The differentially expressed immune-related genes between pancreatic cancer samples and normal sample were screened by R software. Secondly, univariate Cox regression analysis were used to evaluate the relationship between immune-related genes and the prognosis of pancreatic cancer patients. A polygenic risk score model was constructed by Cox regression analysis. The prognostic nomogram was constructed, and its performance was evaluated comprehensively by internal calibration curve and C-index. Using the risk model, each patient gets a risk score, and was divided into high- or low- risk groups. The proportion of 22 types of immune cells infiltration in pancreatic cancer samples was inferred by CIBERSOFT algorithm, correlation analysis (Pearson method) was used to analyse the correlation between the immune-related genes and immunes cells. Then, we applied macrophage conditioned medium to culture pancreatic cancer cell line PANC1, detected the expression of MMP14 and INHBA by qRT-PCR and Western blot methods. Knock-down MMP14 and INHBA in PANC1 cells by transfected with shRNA lentiviruses. Detection of migration ability of pancreatic cells was done by trans-well cell migration assay. A subcutaneous xenograft tumour model of human pancreatic cancer in nude mice was constructed. In conclusion, an immune-related gene prognostic model was constructed, patients with high-risk scores have poorer survival status, M2-phenotype tumour-associated macrophages (TAMs) up-regulate two immune-related genes, MMP14 and INHBA, which were used to establish the prognostic model. Knock-down of MMP14 and INHBA inhibited invasion of pancreatic cancer.
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Affiliation(s)
- Zhan‐Wen Liang
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Jie Yu
- Department of PathologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Dong‐Mei Gu
- Department of PathologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Xiao‐Meng Liu
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Jin Liu
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Meng‐Yao Wu
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Meng‐Dan Xu
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Meng Shen
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Weiming Duan
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Wei Li
- Department of OncologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
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35
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Comprehensive Analysis of Prognostic Value and Immune Infiltration of MMP12 in Esophageal Squamous Cell Carcinoma. JOURNAL OF ONCOLOGY 2022; 2022:4097428. [PMID: 35265129 PMCID: PMC8898792 DOI: 10.1155/2022/4097428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/06/2022] [Accepted: 02/09/2022] [Indexed: 11/17/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a typical neoplastic disease and a frequent cause of death in China. The prognosis of most ESCC patients is still poor. Previous studies demonstrated that MMP12 is involved in tumor metastasis. However, its clinical significance and association with cancer immunity remained largely unclear. In this study, we first analyzed the expressing pattern of MMPs in ESCC from TCGA datasets and found that several MMPs expression was distinctly increased in ESCC. However, only MMP12 expression was associated with five-year survival of ESCC patients. Then, we focused on MMP12 and found its high expression was positively related to advanced clinical stages of ESCC specimens. KEGG assays revealed MMP12 may influence the activity of several tumor-related pathways, such as the Toll-like receptor signaling pathway, TNF signaling pathway, and IL-17 signaling pathway. Then, we sought to determine whether MMP12 expressions were related to immune cell infiltration in ESCC. We observed that increased MMP12 levels were positively associated with the infiltration levels of mast cells activated and macrophages M0. However, eosinophils, B cells naïve, and mast cells resting exhibited an opposite result. Finally, we showed that knockdown of MMP12 suppressed the proliferation of ESCC cells. Overall, our findings proved that high expression of MMP12 may be a novel and valuable prognostic factor in ESCC.
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36
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Matrix Metalloproteinases Shape the Tumor Microenvironment in Cancer Progression. Int J Mol Sci 2021; 23:ijms23010146. [PMID: 35008569 PMCID: PMC8745566 DOI: 10.3390/ijms23010146] [Citation(s) in RCA: 212] [Impact Index Per Article: 53.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer progression with uncontrolled tumor growth, local invasion, and metastasis depends largely on the proteolytic activity of numerous matrix metalloproteinases (MMPs), which affect tissue integrity, immune cell recruitment, and tissue turnover by degrading extracellular matrix (ECM) components and by releasing matrikines, cell surface-bound cytokines, growth factors, or their receptors. Among the MMPs, MMP-14 is the driving force behind extracellular matrix and tissue destruction during cancer invasion and metastasis. MMP-14 also influences both intercellular as well as cell-matrix communication by regulating the activity of many plasma membrane-anchored and extracellular proteins. Cancer cells and other cells of the tumor stroma, embedded in a common extracellular matrix, interact with their matrix by means of various adhesive structures, of which particularly invadopodia are capable to remodel the matrix through spatially and temporally finely tuned proteolysis. As a deeper understanding of the underlying functional mechanisms is beneficial for the development of new prognostic and predictive markers and for targeted therapies, this review examined the current knowledge of the interplay of the various MMPs in the cancer context on the protein, subcellular, and cellular level with a focus on MMP14.
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Comprehensive Analysis of the Immune and Prognostic Implication of MMP14 in Lung Cancer. DISEASE MARKERS 2021; 2021:5917506. [PMID: 34868395 PMCID: PMC8635876 DOI: 10.1155/2021/5917506] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 10/27/2021] [Accepted: 11/01/2021] [Indexed: 12/22/2022]
Abstract
More and more studies have indicated an association between immune infiltration in lung cancer and clinical outcomes. Matrix metalloproteinase 14 (MMP14) has been reported to be dysregulated in many types of tumors and involved in the development and progression of tumors. However, its contribution to cancer immunity was rarely reported. In the study, we found that MMP14 expression was distinctly upregulated in lung cancer specimens compared with nontumor lung specimens. High MMP14 expression predicted a poor prognosis of lung squamous cell carcinoma (LUSC) patients. Increased MMP14 expressions were observed to be positively related to high immune infiltration levels in most of the immune cells. A pathway enrichment analysis of 32 MMP14-associated immunomodulators indicated the involvement of T cell receptor signaling pathway and Toll-like receptor signaling pathway. Based on MMP14-associated immunomodulators, we applied multivariate assays to construct multiple-gene risk prediction signatures. We observed that risk scores were independently associated with overall survival. These data highlighted that MMP14 was involved in tumor immunity, indicating that MMP14 could serve as a novel prognostic biomarker and therapeutic target for lung cancer. Our data suggest that the four genes identified in this study may serve as valuable biomarkers of lung cancer patient outcomes.
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Singh M, Agarwal S, Agarwal V, Mall S, Pancham P, Mani S. Current theranostic approaches for metastatic cancers through hypoxia-induced exosomal packaged cargo. Life Sci 2021; 286:120017. [PMID: 34619169 DOI: 10.1016/j.lfs.2021.120017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/20/2021] [Accepted: 09/29/2021] [Indexed: 12/23/2022]
Abstract
Tumour cells exhibit numerous defence mechanisms against various therapeutic strategies and help in developing drug resistance. These defence strategies help cancer cells prevent their elimination from an organism and prosper at a specific location. In recent times it's been observed that there is a significant contribution of secreted extracellular vesicles (EVs) from such tumorigenic sites in the development and prognosis of cancer. Amongst the various types of EVs, exosomes behave like biological carriers, play a crucial role in transporting the content between different cells, and had such an underrated defence mode by getting induced due to the hypoxia secreted highly specialised double-membrane structures. These small structure vesicles play a critical part in regulating local microenvironment and intracellular communications, cited by many research studies. Exosomes are a potential carrier of several cargo biomolecules like proteins, lipids, miRNAs, mRNAs etc., facilitating better communication within the microenvironment of cancer cells, enhancing the metastatic rate along with cancer progression. Several studies have extensively researched elucidating exosomes mediated radiation-induced bystander effects: multidrug resistance, epithelial-mesenchymal transition, and help cancer cells escape from the immune system apart from playing a critical role in angiogenesis too. Due to its natural tendency to carry different biomolecules, it can also be used to haul chemical drugs and efficiently deliver the drug molecules to the targeted site of cancer. The current review aims to explore the vivid role of hypoxia-induced exosomes in tumour progression along with its application and challenges in cancer therapeutics.
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Affiliation(s)
- Manisha Singh
- Centre for Emerging Diseases (CFED), Department of Biotechnology, Jaypee Institute of Information Technology (JIIT) Noida, U. P., India.
| | - Shriya Agarwal
- Department of Molecular Sciences, Macquarie University, Sydney, Australia.
| | - Vinayak Agarwal
- Centre for Emerging Diseases (CFED), Department of Biotechnology, Jaypee Institute of Information Technology (JIIT) Noida, U. P., India
| | - Shweta Mall
- Department of Animal Genetics and Breeding, Southern Regional Station of Indian Council of Agriculture Research-Research Institute, Bangalore 560030, India
| | - Pranav Pancham
- Centre for Emerging Diseases (CFED), Department of Biotechnology, Jaypee Institute of Information Technology (JIIT) Noida, U. P., India
| | - Shalini Mani
- Centre for Emerging Diseases (CFED), Department of Biotechnology, Jaypee Institute of Information Technology (JIIT) Noida, U. P., India
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Liao Z, Yeo HL, Wong SW, Zhao Y. Cellular Senescence: Mechanisms and Therapeutic Potential. Biomedicines 2021; 9:1769. [PMID: 34944585 PMCID: PMC8698401 DOI: 10.3390/biomedicines9121769] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/15/2021] [Accepted: 11/17/2021] [Indexed: 12/15/2022] Open
Abstract
Cellular senescence is a complex and multistep biological process which cells can undergo in response to different stresses. Referring to a highly stable cell cycle arrest, cellular senescence can influence a multitude of biological processes-both physiologically and pathologically. While phenotypically diverse, characteristics of senescence include the expression of the senescence-associated secretory phenotype, cell cycle arrest factors, senescence-associated β-galactosidase, morphogenesis, and chromatin remodelling. Persistent senescence is associated with pathologies such as aging, while transient senescence is associated with beneficial programmes, such as limb patterning. With these implications, senescence-based translational studies, namely senotherapy and pro-senescence therapy, are well underway to find the cure to complicated diseases such as cancer and atherosclerosis. Being a subject of major interest only in the recent decades, much remains to be studied, such as regarding the identification of unique biomarkers of senescent cells. This review attempts to provide a comprehensive understanding of the diverse literature on senescence, and discuss the knowledge we have on senescence thus far.
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Affiliation(s)
- Zehuan Liao
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore;
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Biomedicum, Solnavägen 9, SE-17177 Stockholm, Sweden
| | - Han Lin Yeo
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore;
| | - Siaw Wen Wong
- School of Chemical and Biomedical Engineering, Nanyang Technological University, 62 Nanyang Drive, Singapore 637459, Singapore;
| | - Yan Zhao
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore;
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MMP14 Contributes to HDAC Inhibition-Induced Radiosensitization of Glioblastoma. Int J Mol Sci 2021; 22:ijms221910403. [PMID: 34638754 PMCID: PMC8508883 DOI: 10.3390/ijms221910403] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/21/2021] [Accepted: 09/22/2021] [Indexed: 11/17/2022] Open
Abstract
Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Radiotherapy has long been an important treatment method of GBM. However, the intrinsic radioresistance of GBM cells is a key reason of poor therapeutic efficiency. Recently, many studies have shown that using the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) in radiotherapy may improve the prognosis of GBM patients, but the underlying molecular mechanisms remain unclear. In this study, Gene Expression Omnibus (GEO) datasets GSE153982 and GSE131956 were analyzed to evaluate radiation-induced changes of gene expression in GBM without or with SAHA treatment, respectively. Additionally, the survival-associated genes of GBM patients were screened using the Chinese Glioma Genome Atlas (CGGA) database. Taking the intersection of these three datasets, 11 survival-associated genes were discovered to be activated by irradiation and regulated by SAHA. The expressions of these genes were further verified in human GBM cell lines U251, T98G, and U251 homologous radioresistant cells (U251R) by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). It was found that MMP14 mRNA was considerably highly expressed in the radioresistant cell lines and was reduced by SAHA treatment. Transfection of MMP14 siRNA (siMMP14) suppressed cell survivals of these GBM cells after irradiation. Taken together, our results reveal for the first time that the MMP14 gene contributed to SAHA-induced radiosensitization of GBM.
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41
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Integrin-α V-mediated activation of TGF-β regulates anti-tumour CD8 T cell immunity and response to PD-1 blockade. Nat Commun 2021; 12:5209. [PMID: 34471106 PMCID: PMC8410945 DOI: 10.1038/s41467-021-25322-y] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 07/29/2021] [Indexed: 12/17/2022] Open
Abstract
TGF-β is secreted in the tumour microenvironment in a latent, inactive form bound to latency associated protein and activated by the integrin αV subunit. The activation of latent TGF-β by cancer-cell-expressed αV re-shapes the tumour microenvironment, and this could affect patient responses to PD-1-targeting therapy. Here we show, using multiplex immunofluorescence staining in cohorts of anti-PD-1 and anti-PD-L1-treated lung cancer patients, that decreased expression of cancer cell αV is associated with improved immunotherapy-related, progression-free survival, as well as with an increased density of CD8+CD103+ tumour-infiltrating lymphocytes. Mechanistically, tumour αV regulates CD8 T cell recruitment, induces CD103 expression on activated CD8+ T cells and promotes their differentiation to granzyme B-producing CD103+CD69+ resident memory T cells via autocrine TGF-β signalling. Thus, our work provides the underlying principle of targeting cancer cell αV for more efficient PD-1 checkpoint blockade therapy. Response to PD-1 checkpoint blockade is unpredictable in lung cancer patients. Here authors show in human lung and mouse tumour models that low or absent αV integrin expression leads to better tumour growth control by anti-PD-1 via reduced TGF-β activation and hence increased infiltration of anti-tumour CD8+ T cells.
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Xiao Y, Xia Y, Wang Y, Xue C. Pathogenic roles of long noncoding RNAs in melanoma: Implications in diagnosis and therapies. Genes Dis 2021; 10:113-125. [PMID: 37013035 PMCID: PMC10066279 DOI: 10.1016/j.gendis.2021.08.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 07/30/2021] [Accepted: 08/20/2021] [Indexed: 12/12/2022] Open
Abstract
Melanoma is one of the most dangerous types of cutaneous neoplasms, which are pigment-producing cells of neuroectodermal origin found all over the body. A great deal of research is focused on the mechanisms of melanoma to promote better diagnostic and treatment options for melanoma in its advanced stages. The progression of melanoma involves alteration in different levels of gene expression. With the successful implementation of next-generation sequencing technology, an increasing number of long noncoding RNAs (lncRNAs) sequences have been discovered, and a significant number of them have phenotypic effects in both in vitro and in vivo studies, implying that they play an important role in the occurrence and progression of human cancers, particularly melanoma. A number of evidence indicated that lncRNAs are important regulators in tumor cell proliferation, invasion, apoptosis, immune escape, energy metabolism, drug resistance, epigenetic regulation. To better understand the role of lncRNAs in melanoma tumorigenesis, we categorize melanoma-associated lncRNAs according to their cellular functions and associations with gene expression and signaling pathways in this review. Based on the mechanisms of lncRNA, we discuss the possibility of lncRNA-target treatments, and the application of liquid biopsies to detect lncRNAs in melanoma diagnosis and prognosis.
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Chen S, Gao C, Yu T, Qu Y, Xiao GG, Huang Z. Bioinformatics Analysis of a Prognostic miRNA Signature and Potential Key Genes in Pancreatic Cancer. Front Oncol 2021; 11:641289. [PMID: 34094925 PMCID: PMC8174116 DOI: 10.3389/fonc.2021.641289] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 03/31/2021] [Indexed: 12/11/2022] Open
Abstract
Background In this study, miRNAs and their critical target genes related to the prognosis of pancreatic cancer were screened based on bioinformatics analysis to provide targets for the prognosis and treatment of pancreatic cancer. Methods R software was used to screen differentially expressed miRNAs (DEMs) and genes (DEGs) downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, respectively. A miRNA Cox proportional hazards regression model was constructed based on the miRNAs, and a miRNA prognostic model was generated. The target genes of the prognostic miRNAs were predicted using TargetScan and miRDB and then intersected with the DEGs to obtain common genes. The functions of the common genes were subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses. A protein-protein interaction (PPI) network of the common genes was constructed with the STRING database and visualized with Cytoscape software. Key genes were also screened with the MCODE and cytoHubba plug-ins of Cytoscape. Finally, a prognostic model formed by the key gene was also established to help evaluate the reliability of this screening process. Results A prognostic model containing four downregulated miRNAs (hsa-mir-424, hsa-mir-3613, hsa-mir-4772 and hsa-mir-126) related to the prognosis of pancreatic cancer was constructed. A total of 118 common genes were enriched in two KEGG pathways and 33 GO functional annotations, including extracellular matrix (ECM)-receptor interaction and cell adhesion. Nine key genes related to pancreatic cancer were also obtained: MMP14, ITGA2, THBS2, COL1A1, COL3A1, COL11A1, COL6A3, COL12A1 and COL5A2. The prognostic model formed by nine key genes also possessed good prognostic ability. Conclusions The prognostic model consisting of four miRNAs can reliably predict the prognosis of patients with pancreatic cancer. In addition, the screened nine key genes, which can also form a reliable prognostic model, are significantly related to the occurrence and development of pancreatic cancer. Among them, one novel miRNA (hsa-mir-4772) and two novel genes (COL12A1 and COL5A2) associated with pancreatic cancer have great potential to be used as prognostic factors and therapeutic targets for this tumor.
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Affiliation(s)
- Shuoling Chen
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, China.,The Second School of Clinical Medicine, Guangdong Medical University, Dongguan, China
| | - Chang Gao
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, China.,Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang, China
| | - Tianyang Yu
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, China.,Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang, China
| | - Yueyang Qu
- School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, China
| | - Gary Guishan Xiao
- School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, China
| | - Zunnan Huang
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, Dongguan, China.,Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang), Zhanjiang, China
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Zheng K, Wang Y. MiR-193a-3p Promotes Fracture Healing via Targeting PTEN Gene. Mol Biotechnol 2021; 63:605-612. [PMID: 33813678 DOI: 10.1007/s12033-021-00322-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 03/20/2021] [Indexed: 10/21/2022]
Abstract
The aim of this study was to investigate the role and potential mechanism of miR-193a-3p in fracture healing. The 70 fragility fracture patients and 45 healthy controls were enrolled in this study. Quantitative real-time PCR (qRT-PCR) was used for the measurement of the expression levels of miR-193a-3p and PTEN. MTT assay and flow cytometry were used to detect cell viability and apoptosis in the mouse osteoblastic cell line MC3T3-E1. Luciferase reporter assay was performed to confirm the correlation of miR-193a-3p with PTEN. The serum expression level of miR-193a-3p showed no significant change in fracture patients 7 days after fixation treatment, but over time, there was a significant decrease in the expression at 14 days and 21 days after treatment (P < 0.01). Overexpression of miR-193a-3p significantly enhanced cell viability and inhibited cell apoptosis in MC3T3-E1 cells (P < 0.001). Serum PTEN level in fracture patients was increased gradually during the fracture healing process (P < 0.01). PTEN was demonstrated to be a target gene of miR-9-5p and reversed the effect of miR-193a-3p on cell viability and apoptosis (P < 0.001). miR-193a-3p promoted fracture healing via regulating PTEN and may serve as a novel potential target for enhancing bone repair of fragility fracture.
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Affiliation(s)
- Kai Zheng
- Department of Spine Surgery, Zhucheng People's Hospital, Weifang, 262200, Shandong, China
| | - Ying Wang
- Department of Hand and Foot Surgery, Zhucheng People's Hospital, No. 59 Nanhuan Road, Weifang, 262200, Shandong, China.
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Wang M, Xie F, Lin J, Zhao Y, Zhang Q, Liao Z, Wei P. Diagnostic and Prognostic Value of Circulating CircRNAs in Cancer. Front Med (Lausanne) 2021; 8:649383. [PMID: 33816529 PMCID: PMC8012499 DOI: 10.3389/fmed.2021.649383] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 02/15/2021] [Indexed: 12/24/2022] Open
Abstract
Cancer has been regarded as one of the leading causes of mortality worldwide. Diagnostic and prognostic biomarkers with high sensitivity and specificity for cancer play a crucial role in preventing or treating cancer. Circular RNAs (circRNAs), which hold great potential for the management of cancer patients due to their abundance, stable property, and high specificity in serum, plasma, and other body fluids, can be used as non-invasive and blood-based biomarkers in cancer diagnosis and prognosis. There are four types of circRNAs including exonic circRNAs (ecircRNA), intronic circRNAs, exon-intron circRNAs (EIciRNA), and intergenic circRNAs. CircRNAs can act as miRNA sponges, affect protein translation, interplay with RNA binding proteins, regulate protein recruitment, and modulate protein scaffolding and assembly. Therefore, the multifunctionalities of circRNAs make them ideal for detecting and predicting cancer. Indeed, circRNAs manifest high sensitivity and specificity in more than ten types of cancer. This review aims to consolidate the types and functions of circRNAs, as well as discuss the diagnostic and prognostic value of circulating circRNAs in cancer.
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Affiliation(s)
- Mina Wang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.,Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing, China
| | - Feiyu Xie
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.,Oncology Department, Wangjing Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiaran Lin
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.,Department of Nephrology and Endocrinology, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China
| | - Yihan Zhao
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Qian Zhang
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Zehuan Liao
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.,Department of Microbiology, Tumor, and Cell Biology (MTC), Karolinska Institutet, Biomedicum, Solnavägen, Sweden
| | - Peng Wei
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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Yao LC, Jiang XH, Yan SS, Wang W, Wu L, Zhai LL, Xiang F, Ji T, Ye L, Tang ZG. Four potential microRNAs affect the progression of pancreatic ductal adenocarcinoma by targeting MET via the PI3K/AKT signaling pathway. Oncol Lett 2021; 21:326. [PMID: 33692858 PMCID: PMC7933770 DOI: 10.3892/ol.2021.12588] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 12/23/2020] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common tumor subtype of pancreatic cancer, which exhibits poor patient prognosis due to the lack of effective biomarkers in the diagnosis and treatment. The present study aimed to identify the potential biomarkers of PDAC carcinogenesis and progression using three microarray datasets, GSE15471, GSE16515 and GSE28735, which were downloaded from the Gene Expression Omnibus database. The datasets were analyzed to screen out differentially expressed genes (DEGs) in PDAC tissues and adjacent normal tissues. A total of 143 DEGs were identified, including 132 upregulated genes and 11 downregulated genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional and signaling pathway enrichment analyses were performed on the DEGs, and the Search Tool for the Retrieval of Interacting Genes/Proteins database was used to construct a protein-protein interaction network. The main functions of DEGs include extracellular matrix degradation, and regulation of matrix metalloproteinase activity and the PI3K-Akt signaling pathway. The five hub genes were subsequently screened using Cytoscape software, and survival analysis demonstrated that abnormal expression levels of the hub genes was associated with poor disease-free survival and overall survival. Biological experiments were performed to confirm whether mesenchymal-to-epithelial transition (MET) factors promote the proliferation, migration and invasion of PDAC cells via the PI3K/AKT signaling pathway. In addition, six MET-targeted microRNAs (miRNAs) were identified, four of which had conserved binding sites with MET. Based on the signaling pathway enrichment analysis of these miRNAs, it is suggested that they can affect the progression of PDAC by targeting MET via the PI3K/AKT signaling pathway. In conclusion, the hub genes and miRNAs that were identified in the present study contribute to the molecular mechanisms of PDAC carcinogenesis and progression. They also provide candidate biomarkers for early diagnosis and treatment of patients with PDAC.
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Affiliation(s)
- Li-Chao Yao
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Xiu-Hua Jiang
- Department of Geriatrics, General Hospital of Central Theater Command, Wuhan, Hubei 430071, P.R. China
| | - Si-Si Yan
- Reproductive Medical Center, Renmin Hospital of Wuhan University and Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Wei Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Lun Wu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Lu-Lu Zhai
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Feng Xiang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Tao Ji
- Department of Cardiothoracic Surgery, General Hospital of Central Theater Command, Wuhan, Hubei 430071, P.R. China
| | - Lin Ye
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Zhi-Gang Tang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430060, P.R. China
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Cai Z, Zhai T, Muhanhali D, Ling Y. TNRC6C Functions as a Tumor Suppressor and Is Frequently Downregulated in Papillary Thyroid Cancer. Int J Endocrinol 2021; 2021:6686998. [PMID: 33564303 PMCID: PMC7867448 DOI: 10.1155/2021/6686998] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 12/29/2020] [Accepted: 01/22/2021] [Indexed: 12/21/2022] Open
Abstract
Our previous study found that trinucleotide repeat containing adaptor 6C (TNRC6C) may act as a tumor suppressor in papillary thyroid cancer (PTC). In this study, we aimed to confirm the effect of TNRC6C on PTC and investigate the underlying molecular mechanism. The difference of mRNA level of TNRC6C between PTC tissue and noncancerous thyroid tissue and the association of expression level of TNRC6C with clinicopathological features of PTC were analyzed using TCGA data. Immunohistochemical assay was performed to detect the protein expression of TNRC6C in PTC and its adjacent noncancerous tissue. Cell proliferation, migration, invasion, and apoptosis were analyzed after knockdown or overexpression of TNRC6C in BCPAP cells. RNA-sequencing was performed to find the target genes of TNRC6C, and potential targets were validated in BCPAP and TPC1 cells. Our results showed that TNRC6C was downregulated in PTC, and lower expression level of TNRC6C was associated with worse clinicopathological features. Overexpression of TNRC6C significantly inhibited proliferation, migration, and invasion of BCPAP cells and promoted its apoptosis, while knockdown of TNRC6C acted the opposite role. By analyzing RNA-sequencing data and TCGA data, 12 genes (SCD, CRLF1, APCDD1L, CTHRC1, PTPRU, ALDH1A3, VCAN, TNC, ECE1, COL1A1, CAMK2N2, and MMP14) were considered as potential target genes of TNRC6C, and most of them were associated with clinicopathological features of PTC in TCGA. All of them except CAMK2N2 were significantly downregulated after overexpressing TNRC6C. Our study demonstrated that TNRC6C functions as a tumor suppressor in PTC and may serve as a useful therapeutic target and prognostic marker for PTC patients.
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Affiliation(s)
- Zhenqin Cai
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, No.180 Fenglin Road, Shanghai 200032, China
| | - Tianyu Zhai
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, No.180 Fenglin Road, Shanghai 200032, China
| | - Dilidaer Muhanhali
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, No.180 Fenglin Road, Shanghai 200032, China
| | - Yan Ling
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, No.180 Fenglin Road, Shanghai 200032, China
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Robles-Fort A, García-Robles I, Fernando W, Hoskin DW, Rausell C, Real MD. Dual Antimicrobial and Antiproliferative Activity of TcPaSK Peptide Derived from a Tribolium castaneum Insect Defensin. Microorganisms 2021; 9:222. [PMID: 33499187 PMCID: PMC7912591 DOI: 10.3390/microorganisms9020222] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/14/2021] [Accepted: 01/19/2021] [Indexed: 02/08/2023] Open
Abstract
Antimicrobial peptides (AMPs) found in the innate immune system of a wide range of organisms might prove useful to fight infections, due to the reported slower development of resistance to AMPs. Increasing the cationicity and keeping moderate hydrophobicity of the AMPs have been described to improve antimicrobial activity. We previously found a peptide derived from the Tribolium castaneum insect defensin 3, exhibiting antrimicrobial activity against several human pathogens. Here, we analyzed the effect against Staphyloccocus aureus of an extended peptide (TcPaSK) containing two additional amino acids, lysine and asparagine, flanking the former peptide fragment in the original insect defensin 3 protein. TcPaSK peptide displayed higher antimicrobial activity against S. aureus, and additionally showed antiproliferative activity against the MDA-MB-231 triple negative breast cancer cell line. A SWATH proteomic analysis revealed the downregulation of proteins involved in cell growth and tumor progression upon TcPaSK cell treatment. The dual role of TcPaSK peptide as antimicrobial and antiproliferative agent makes it a versatile molecule that warrants exploration for its use in novel therapeutic developments as an alternative approach to overcome bacterial antibiotic resistance and to increase the efficacy of conventional cancer treatments.
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Affiliation(s)
- Aida Robles-Fort
- Department of Genetics, University of Valencia, Burjassot, 46100 Valencia, Spain; (A.R.-F.); (I.G.-R.); (C.R.)
| | - Inmaculada García-Robles
- Department of Genetics, University of Valencia, Burjassot, 46100 Valencia, Spain; (A.R.-F.); (I.G.-R.); (C.R.)
| | - Wasundara Fernando
- Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada; (W.F.); (D.W.H.)
| | - David W. Hoskin
- Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada; (W.F.); (D.W.H.)
- Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Department of Surgery, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada
| | - Carolina Rausell
- Department of Genetics, University of Valencia, Burjassot, 46100 Valencia, Spain; (A.R.-F.); (I.G.-R.); (C.R.)
| | - María Dolores Real
- Department of Genetics, University of Valencia, Burjassot, 46100 Valencia, Spain; (A.R.-F.); (I.G.-R.); (C.R.)
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Tan Y, Wang M, Yang K, Chi T, Liao Z, Wei P. PPAR-α Modulators as Current and Potential Cancer Treatments. Front Oncol 2021; 11:599995. [PMID: 33833983 PMCID: PMC8021859 DOI: 10.3389/fonc.2021.599995] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 02/22/2021] [Indexed: 12/24/2022] Open
Abstract
Cancer is one of the leading causes of mortality worldwide. PPAR modulators may hold great potential for the management of cancer patients. Indeed, PPARs are critical sensors and regulators of lipid, and they are able to promote eNOS activation, regulate immunity and inflammation response, and affect proliferation and differentiation of cancer cells. Cancer, a name given to a group of diseases, is characterized by multiple distinctive biological behaviors, including angiogenesis, abnormal cell proliferation, aerobic glycolysis, inflammation, etc. In the last decade, emerging evidence has shown that PPAR-α, a nuclear hormone receptor, can modulate carcinogenesis via exerting effects on one or several characteristic pathological behaviors of cancer. Therefore, the multi-functional PPAR modulators have substantial promise in various types of cancer therapies. This review aims to consolidate the functions of PPAR-α, as well as discuss the current and potential applications of PPAR-α agonists and antagonists in tackling cancer.
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Affiliation(s)
- Yan Tan
- School of Traditional Chinese Medicine and School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Mina Wang
- School of Traditional Chinese Medicine and School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
- Beijing Key Laboratory of Acupuncture Neuromodulation, Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Ke Yang
- School of Traditional Chinese Medicine and School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Tiange Chi
- The First Clinical Medical School, Beijing University of Chinese Medicine, Beijing, China
| | - Zehuan Liao
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
- Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Biomedicum, Stockholm, Sweden
- Zehuan Liao
| | - Peng Wei
- School of Traditional Chinese Medicine and School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Peng Wei
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50
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Niland S, Eble JA. Hold on or Cut? Integrin- and MMP-Mediated Cell-Matrix Interactions in the Tumor Microenvironment. Int J Mol Sci 2020; 22:ijms22010238. [PMID: 33379400 PMCID: PMC7794804 DOI: 10.3390/ijms22010238] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/21/2020] [Accepted: 12/23/2020] [Indexed: 02/07/2023] Open
Abstract
The tumor microenvironment (TME) has become the focus of interest in cancer research and treatment. It includes the extracellular matrix (ECM) and ECM-modifying enzymes that are secreted by cancer and neighboring cells. The ECM serves both to anchor the tumor cells embedded in it and as a means of communication between the various cellular and non-cellular components of the TME. The cells of the TME modify their surrounding cancer-characteristic ECM. This in turn provides feedback to them via cellular receptors, thereby regulating, together with cytokines and exosomes, differentiation processes as well as tumor progression and spread. Matrix remodeling is accomplished by altering the repertoire of ECM components and by biophysical changes in stiffness and tension caused by ECM-crosslinking and ECM-degrading enzymes, in particular matrix metalloproteinases (MMPs). These can degrade ECM barriers or, by partial proteolysis, release soluble ECM fragments called matrikines, which influence cells inside and outside the TME. This review examines the changes in the ECM of the TME and the interaction between cells and the ECM, with a particular focus on MMPs.
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