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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 PMCID: PMC12102027 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] [Download PDF] [Figures] [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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Yun D, Yang JH, Sim JA, Kim M, Park JW, Jeong SY, Shin A, Kweon SS, Song N. Identification of MMP14 and MKLN1 as colorectal cancer susceptibility genes and drug-repositioning candidates from a genome-wide association study. J Transl Med 2025; 23:543. [PMID: 40369569 PMCID: PMC12079816 DOI: 10.1186/s12967-025-06491-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Accepted: 04/13/2025] [Indexed: 05/16/2025] Open
Abstract
BACKGROUND Genome-wide association studies (GWAS) and subsequent functional interpretation have been used to identify susceptible genes and potential drug-repositioning candidates. This study aimed to identify genes associated with colorectal cancer (CRC) and potential drug-repositioning candidates. METHODS Patients with CRC at Seoul National University Hospital (SNUH, discovery study) and Chonnam National University Hospital (CNUH, replication study) were included as case groups. The Korean Genome and Epidemiology Study (KoGES) participants were included as a control group. Single-nucleotide polymorphisms (SNPs) were extracted from blood-derived DNA (N = 409,063). A SNP-based logistic regression model was applied. Furthermore, post-GWAS analysis was conducted. Drug-repositioning candidates were identified using a pre-trained deep neural network and the druggability assessment tool. RESULTS In the discovery study, we conducted a 1:3 age- and sex-matched case-control study that included 500 CRC cases (mean age 63.0 ± 7.15 years) and 1,500 healthy controls (mean age 62.9 ± 7.07 years), each group comprising 50% males and 50% females. The replication study enrolled 4,860 patients with CRC and 46,384 healthy controls. The two-stage GWAS revealed statistically significant associations among MKLN1 (rs75170436, 7q32.3, beta (log odds ratio) = - 0.90, Pmeta = 5.90 × 10-13), MMP14 (rs3751489, 14q11.2, beta (log odds ratio) = - 1.91, Pmeta = 2.31 × 10-12). Post-GWAS functional analysis revealed strong associations on two genes highlighting deleterious effects and increased gene expression. Drug-repositioning analysis identified GW0742 (PPARβ/δ agonist) with the highest binding score and druggability score for MMP14 with a reference allele (12.06, 0.85). CONCLUSIONS Using GWAS, MKLN1 and MMP14 were found to be associated with CRC development and we identified GW0742 (PPARβ/δ agonist) as a potential drug-repositioning candidate for CRC based on MKLN1 and MMP14. These findings improve the understanding of CRC development and provide insights into novel therapeutic targets and candidates for CRC treatment.
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Affiliation(s)
- Dabin Yun
- College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk, Korea
| | - Jung-Ho Yang
- Department of Preventive Medicine, Chonnam National University Medical School, Hwasun-Gun, Jeollanam-Do, Korea
| | - Jin-Ah Sim
- Department of AI Convergence, Hallym University, Chuncheon, Gangwon, Korea
| | - Minjung Kim
- Department of Surgery, College of Medicine and Hospital, Seoul National University, Seoul, Korea
| | - Ji Won Park
- Department of Surgery, College of Medicine and Hospital, Seoul National University, Seoul, Korea
- Cancer Research Institute, Seoul National University, Seoul, Korea
| | - Seung Yong Jeong
- Department of Surgery, College of Medicine and Hospital, Seoul National University, Seoul, Korea
- Cancer Research Institute, Seoul National University, Seoul, Korea
| | - Aesun Shin
- Department of Preventive Medicine, College of Medicine, Seoul National University, Seoul, Korea
| | - Sun-Seog Kweon
- Department of Preventive Medicine, Chonnam National University Medical School, Hwasun-Gun, Jeollanam-Do, Korea.
| | - Nan Song
- College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk, Korea.
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Barhoum M, Brassart‐Pasco S, Dupont‐Deshorgue A, Thierry A, Kanagaratnam L, Brassart B, Ramaholimihaso F, Botsen D, Carlier C, Brugel M, Perrier M, Ramont L, Bouché O. Circulating Exosomal Proteins as New Diagnostic Biomarkers for Colorectal Cancer (EXOSCOL01): A Pilot Case-Controlled Study Focusing on MMP14 Potential. J Clin Lab Anal 2025; 39:e70016. [PMID: 40244893 PMCID: PMC12078757 DOI: 10.1002/jcla.70016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 02/18/2025] [Accepted: 02/28/2025] [Indexed: 04/19/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. The French CRC screening campaign is based on fecal immunochemical tests (FIT), confirmed by colonoscopy, an invasive procedure with a poor participation rate. This study aimed to compare the expression of circulating exosomal proteins (MMP14, β1-Integrin subunit, β3-Integrin subunit, and α1(I) Collagen chain) in patients with CRC or adenomas. METHODS A total of 71 patients were recruited, including 24 controls (normal colonoscopy), 11 patients with adenoma, and 36 with CRC. Plasmatic exosomal protein expression was measured by western blot analysis and reported to either protein or exosome content. RESULTS The three groups were comparable regarding clinical characteristics. A significant difference was observed for MMP14 relative expression (p = 0.0007), MMP14 expression reported to exosomal protein content (p = 0.0003), and MMP14 expression reported to exosome content (p = 0.0005). These three parameters were significantly higher in patients with adenoma vs. control patients (p = 0.0013, p = 0.0004, and p = 0.0003, respectively). Only MMP14 relative intensity was significantly higher in the CRC group vs. the control group (p = 0.0018). CONCLUSIONS Exosomal MMP14 is a promising early diagnostic biomarker for CRC and adenoma. These preliminary results warrant confirmation in larger studies using quantitative measurements such as ELISA or flow cytometry.
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Affiliation(s)
- Mickaël Barhoum
- Department of Gastroenterology and Digestive OncologyUniversité de Reims Champagne‐ArdenneReimsFrance
| | - Sylvie Brassart‐Pasco
- Université de Reims Champagne‐Ardenne, CNRSMEDyC Research Unit, UMR CNRS/URCA 7369ReimsFrance
| | | | - Aurore Thierry
- CHU Reims, Unité d'Aide MéthodologiqueUniversité de Reims Champagne‐Ardenne, VieFra UR 3797ReimsFrance
| | - Lukshe Kanagaratnam
- CHU Reims, Unité d'Aide MéthodologiqueUniversité de Reims Champagne‐Ardenne, VieFra UR 3797ReimsFrance
| | - Bertrand Brassart
- Université de Reims Champagne‐Ardenne, CNRSMEDyC Research Unit, UMR CNRS/URCA 7369ReimsFrance
| | - Fidy Ramaholimihaso
- Department of Gastroenterology and Digestive OncologyUniversité de Reims Champagne‐ArdenneReimsFrance
| | - Damien Botsen
- Department of Medical OncologyGodinot Cancer InstituteReimsFrance
| | - Claire Carlier
- Department of Medical OncologyGodinot Cancer InstituteReimsFrance
| | - Mathias Brugel
- Gastroenterology and Digestive Oncology DepartmentCentre Hospitalier Côte BasqueBayonneFrance
| | - Marine Perrier
- Department of Gastroenterology and Digestive OncologyUniversité de Reims Champagne‐ArdenneReimsFrance
| | - Laurent Ramont
- Université de Reims Champagne‐Ardenne, CNRSMEDyC Research Unit, UMR CNRS/URCA 7369ReimsFrance
- Biochemistry, Pharmacology and Toxicology DepartmentCHU ReimsReimsFrance
| | - Olivier Bouché
- Department of Gastroenterology and Digestive OncologyUniversité de Reims Champagne‐ArdenneReimsFrance
- Université de Reims Champagne‐Ardenne, CNRSMEDyC Research Unit, UMR CNRS/URCA 7369ReimsFrance
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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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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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6
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Wu J, Li X, Liu Y, Chen G, Li R, Jiang H, Yin W, Tong X, Cao R, Wang X, Liu X, Zhou F. MMP14 from BM-MSCs facilitates progression and Ara-C resistance in acute myeloid leukemia via the JAK/STAT pathway. Exp Hematol Oncol 2025; 14:43. [PMID: 40121502 PMCID: PMC11929205 DOI: 10.1186/s40164-025-00635-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 03/07/2025] [Indexed: 03/25/2025] Open
Abstract
Growing evidence underscores the pivotal impact of crosstalk between leukemic stem cells (LSCs) and mesenchymal stromal cells (MSCs) within their niche on leukemia initiation, progression, and therapy response. Although MMP14 plays an important role in inflammation and cancer, the regulation and role of MSC-derived MMP14 in acute myeloid leukemia (AML) are largely unknown. Here, we found that AML patient-derived MSCs (AML-MSCs) were more supportive of AML cell growth compared to healthy donor-derived MSCs (HD-MSCs). Moreover, AML-MSCs and HD-MSCs showed significant differences in gene expression and protein expression profiles. Knockdown of MMP14 in MSCs inhibited the CFU-F ability of MSC cells and increased the proportion of cells in the G0 phase, thereby inhibiting proliferation. Co-culture with MSCs inhibited the proliferation and cell cycle progression of leukemia cells, while increasing the apoptosis rate, thus impairing the leukemogenic potential of AML cells both in vitro and in vivo. Mechanistic studies revealed that MMP14-mediated alterations in the AML stromal microenvironment are driven by PGE2 secretion and activation of the JAK-STAT pathway, promoting leukemia progression. Notably, inhibition of MMP14 can attenuate the chemotherapy resistance of AML cells induced by MSCs to cytarabine (Ara-C). Together, our study, for the first time, demonstrates the critical role of MSC-derived MMP14 in promoting AML progression and chemoresistance. Targeting MMP14 signaling pathways may offer novel therapeutic options for AML.
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Affiliation(s)
- Jinxian Wu
- Department of Hematology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430072, P. R. China
| | - Xinqi Li
- Department of Hematology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430072, P. R. China
| | - Yin Liu
- Department of Hematology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430072, P. R. China
| | - Guopeng Chen
- Department of Hematology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430072, P. R. China
| | - Ruihang Li
- Department of Hematology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430072, P. R. China
| | - Hongqiang Jiang
- Department of Hematology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430072, P. R. China
| | - Wanyue Yin
- Department of Hematology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430072, P. R. China
| | - Xiqin Tong
- Department of Hematology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430072, P. R. China
| | - Rui Cao
- Department of Hematology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430072, P. R. China
| | - Xianwang Wang
- Department of Biochemistry and Molecular Biology, Center for Molecular Medicine, Health Science Center, Yangtze University, Jingzhou, 434023, Hubei, China
- Shannan Maternal and Child Health Hospital, Shannan, Xizang, 856100, China
| | - Xiaoyan Liu
- Department of Hematology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430072, P. R. China.
| | - Fuling Zhou
- Department of Hematology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430072, P. R. China.
- Research Center for Lifespan Health, Wuhan University, Wuhan, 430072, Hubei, China.
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Lo HJ, Tsai CH, Huang TW. Apoptosis-associated genetic mechanisms in the transition from rheumatoid arthritis to osteoporosis: A bioinformatics and functional analysis approach. APL Bioeng 2024; 8:046107. [PMID: 39507523 PMCID: PMC11540442 DOI: 10.1063/5.0233961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 09/30/2024] [Indexed: 11/08/2024] Open
Abstract
This study explores the mechanisms of glucocorticoid-induced osteoporosis (OP) and Rheumatoid arthritis (RA), focusing on apoptosis and its role in the progression from RA to OP. Using microarray data from the GEO database, differential gene expression analysis was conducted with the limma package, identifying significant genes in RA and OP. Weighted Gene Co-expression Network Analysis (WGCNA) further examined gene relationships with the disease status, identifying co-expression patterns. Key genes were pinpointed by intersecting differentially expressed genes from RA and OP datasets with WGCNA module genes. Functional enrichment analysis using the "clusterProfiler" package focused on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. Machine learning methods, including Lasso and Random Forest, refined the selection of key genes related to apoptosis. Immune infiltration analysis using CIBERSORT assessed immune cell differences between disease and normal samples. The study highlighted two crucial genes: ATXN2L and MMP14. These genes were identified through various analyses and found to be significantly associated with the progression of RA and OP. Gene Set Enrichment Analysis of ATXN2L and MMP14 revealed their involvement in specific biological processes and pathways. Correlation analysis between these key genes and immune cell infiltration showed significant associations. The ROC analysis evaluated the diagnostic performance of ATXN2L and MMP14, with miRNA regulatory networks related to these genes also predicted. In summary, this research provides valuable insights into the molecular mechanisms of RA and OP, emphasizing the importance of apoptosis and immune processes.
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Affiliation(s)
- Hao-Ju Lo
- Department of Orthopedic Surgery, Da-Chien General Hospital, Miaoli, Taiwan
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Du F, Li J, Zhong X, Zhang Z, Zhao Y. Endothelial-to-mesenchymal transition in the tumor microenvironment: Roles of transforming growth factor-β and matrix metalloproteins. Heliyon 2024; 10:e40118. [PMID: 39568849 PMCID: PMC11577214 DOI: 10.1016/j.heliyon.2024.e40118] [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: 08/28/2023] [Revised: 10/26/2024] [Accepted: 11/03/2024] [Indexed: 11/22/2024] Open
Abstract
Cancer is a leading cause of global morbidity and mortality. Tumor cells grow in a complex microenvironment, comprising immune cells, stromal cells, and vascular cells, collaborating to support tumor growth and facilitate metastasis. Transforming growth factor-beta (TGF-β) is a multipotent factor that can not only affect fibrosis promotion but also assume distinct roles in the early and late stages of the tumor. Matrix metalloproteinases (MMPs) primarily function to degrade the extracellular matrix, a pivotal cellular player in tumor progression. Moreover, endothelial-to-mesenchymal transition (EndMT), similar to epithelial-to-mesenchymal transition, is associated with cancer progression by promoting angiogenesis, disrupting the endothelial barrier, and leading to cancer-associated fibroblasts. Recent studies have underscored the pivotal roles of TGF-β and MMPs in EndMT. This review delves into the contributions of TGF-β and MMPs, as well as their regulatory mechanisms, within the tumor microenvironment. This collective understanding offers fresh insights into the potential for combined targeted therapies in the fight against cancer.
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Affiliation(s)
- Fei Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
- Department of Pharmacy, Meishan TianFu New Area People's Hospital, Meishan, Sichuan, China
| | - Jing Li
- Department of Oncology and Hematology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Xiaolin Zhong
- Department of Gastroenterology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Zhuo Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou, Sichuan, China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, China
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9
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Zhang ZW, Zhang KX, Liao X, Quan Y, Zhang HY. Evolutionary screening of precision oncology biomarkers and its applications in prognostic model construction. iScience 2024; 27:109859. [PMID: 38799582 PMCID: PMC11126775 DOI: 10.1016/j.isci.2024.109859] [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: 10/10/2023] [Revised: 03/15/2024] [Accepted: 04/27/2024] [Indexed: 05/29/2024] Open
Abstract
Biomarker screening is critical for precision oncology. However, one of the main challenges in precision oncology is that the screened biomarkers often fail to achieve the expected clinical effects and are rarely approved by regulatory authorities. Considering the close association between cancer pathogenesis and the evolutionary events of organisms, we first explored the evolutionary feature underlying clinically approved biomarkers, and two evolutionary features of approved biomarkers (Ohnologs and specific evolutionary stages of genes) were identified. Subsequently, we utilized evolutionary features for screening potential prognostic biomarkers in four common cancers: head and neck squamous cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, and lung squamous cell carcinoma. Finally, we constructed an evolution-strengthened prognostic model (ESPM) for cancers. These models can predict cancer patients' survival time across different cancer cohorts effectively and perform better than conventional models. In summary, our study highlights the application potentials of evolutionary information in precision oncology biomarker screening.
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Affiliation(s)
- Zhi-Wen Zhang
- Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, P.R. China
| | - Ke-Xin Zhang
- Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, P.R. China
| | - Xuan Liao
- Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, P.R. China
| | - Yuan Quan
- Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, P.R. China
| | - Hong-Yu Zhang
- Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan 430070, P.R. China
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10
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Xing M, Yao B, Xu J, Lu P, Li Q, Wu D, Chen B, Wei J, Su L, Zhao Q. NatD epigenetically activates FOXA2 expression to promote breast cancer progression by facilitating MMP14 expression. iScience 2024; 27:108840. [PMID: 38303717 PMCID: PMC10830889 DOI: 10.1016/j.isci.2024.108840] [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: 08/25/2023] [Revised: 12/09/2023] [Accepted: 01/03/2024] [Indexed: 02/03/2024] Open
Abstract
N-α-acetyltransferase D (NatD) mediates N-α-terminal acetylation of histone H4 (Nt-Ac-H4), but its role in breast cancer metastasis remains unknown. Here, we show that depletion of NatD directly represses the expression of FOXA2, and is accompanied by a significant reduction in Nt-Ac-H4 enrichment at the FOXA2 promoter. We show that NatD is commonly upregulated in primary breast cancer tissues, where its expression level correlates with FOXA2 expression, enhanced invasiveness, and poor clinical outcomes. Furthermore, we show that FOXA2 promotes the migration and invasion of breast cancer cells by activating MMP14 expression. MMP14 is also upregulated in breast cancer tissues, where its expression level correlates with FOXA2 expression and poor clinical prognosis. Our study shows that the NatD-FOXA2-MMP14 axis functions as a key signaling pathway to promote the migratory and invasive capabilities of breast cancer cells, suggesting that NatD is a critical epigenetic modulator of cell invasion during breast cancer progression.
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Affiliation(s)
- Mengying Xing
- The State Key Laboratory of Pharmaceutical Biotechnology, Department of Hematology and General Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, China-Australia Institute of Translational Medicine, School of Life Sciences, Nanjing University, Nanjing 210046, China
| | - Bing Yao
- National Experimental Teaching Center of Basic Medical Science, Nanjing Medical University, Nanjing, China
| | - Jiaxuan Xu
- The State Key Laboratory of Pharmaceutical Biotechnology, Department of Hematology and General Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, China-Australia Institute of Translational Medicine, School of Life Sciences, Nanjing University, Nanjing 210046, China
| | - Peifen Lu
- The State Key Laboratory of Pharmaceutical Biotechnology, Department of Hematology and General Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, China-Australia Institute of Translational Medicine, School of Life Sciences, Nanjing University, Nanjing 210046, China
| | - Qixiang Li
- The State Key Laboratory of Pharmaceutical Biotechnology, Department of Hematology and General Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, China-Australia Institute of Translational Medicine, School of Life Sciences, Nanjing University, Nanjing 210046, China
| | - Dongliang Wu
- The State Key Laboratory of Pharmaceutical Biotechnology, Department of Hematology and General Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, China-Australia Institute of Translational Medicine, School of Life Sciences, Nanjing University, Nanjing 210046, China
| | - Bing Chen
- The State Key Laboratory of Pharmaceutical Biotechnology, Department of Hematology and General Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, China-Australia Institute of Translational Medicine, School of Life Sciences, Nanjing University, Nanjing 210046, China
| | - Jiwu Wei
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
| | - Lei Su
- The State Key Laboratory of Pharmaceutical Biotechnology, Department of Hematology and General Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, China-Australia Institute of Translational Medicine, School of Life Sciences, Nanjing University, Nanjing 210046, China
| | - Quan Zhao
- The State Key Laboratory of Pharmaceutical Biotechnology, Department of Hematology and General Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, China-Australia Institute of Translational Medicine, School of Life Sciences, Nanjing University, Nanjing 210046, China
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11
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Koh J, Jeong D, Park SY, Han D, Kim DS, Kim HY, Kim H, Yang S, Kim S, Ryu HS. Identification of VWA5A as a novel biomarker for inhibiting metastasis in breast cancer by machine-learning based protein prioritization. Sci Rep 2024; 14:2459. [PMID: 38291227 PMCID: PMC10828438 DOI: 10.1038/s41598-024-53015-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 01/25/2024] [Indexed: 02/01/2024] Open
Abstract
Distant metastasis is the leading cause of death in breast cancer (BC). The timing of distant metastasis differs according to subtypes of BCs and there is a need for identification of biomarkers for the prediction of early and late metastasis. To identify biomarker candidates whose abundance level can discriminate metastasis types, we performed a high-throughput proteomics assay using tissue samples from BCs with no metastasis, late metastasis, and early metastasis, processed data with machine learning-based feature selection, and found that low VWA5A could be responsible for shorter duration of metastasis-free interval. Low expression of VWA5A gene in METABRIC cohort was associated with poor survival in BCs, especially in hormone receptor (HR)-positive BCs. In-vitro experiments confirmed tumor suppressive effect of VWA5A on BCs in HR+ and triple-negative BC cell lines. We found that expression of VWA5A can be assessed by immunohistochemistry (IHC) on archival tissue samples. Decreasing nuclear expression of VWA5A was significantly associated with advanced T stage and lymphatic invasion in consecutive BCs of all subtypes. We discovered lower expression of VWA5A as the potential biomarker for metastasis-prone BCs, and our results support the clinical utility of VWA5A IHC, as an adjunctive tools for prognostication of BCs.
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Affiliation(s)
- Jiwon Koh
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehakro, Seoul, 03080, South Korea
- Cancer Research Institute, Seoul National University, Seoul, South Korea
| | - Dabin Jeong
- Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, South Korea
| | - Soo Young Park
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Dohyun Han
- Proteomics Core Facility, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea
- Transdisciplinary Department of Medicine & Advanced Technology, Seoul National University Hospital, Seoul, South Korea
| | - Da Sol Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Ha Yeon Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Hyeyoon Kim
- Proteomics Core Facility, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea
| | - Sohyeon Yang
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehakro, Seoul, 03080, South Korea
| | - Sun Kim
- Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, South Korea.
- Department of Computer Science and Engineering, Institute of Engineering Research, Seoul National University, Gwanak-ro 1, Seoul, 08826, South Korea.
| | - Han Suk Ryu
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehakro, Seoul, 03080, South Korea.
- Cancer Research Institute, Seoul National University, Seoul, South Korea.
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.
- Pharmonoid Co., Ltd., Seoul, South Korea.
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12
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Fang Y, Zhang Q, Chen Z, Guo C, Wu J. Clinical significance and immune characteristics analysis of miR-221-3p and its key target genes related to epithelial-mesenchymal transition in breast cancer. Aging (Albany NY) 2024; 16:322-347. [PMID: 38189813 PMCID: PMC10817385 DOI: 10.18632/aging.205370] [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: 07/20/2023] [Accepted: 11/20/2023] [Indexed: 01/09/2024]
Abstract
BACKGROUND MicroRNA-221-3p (miR-221-3p) facilitates the advancement of breast cancer (BC) through the induction of epithelial-mesenchymal transition (EMT). Our research aimed to utilize bioinformatics to discover possible EMT-related target genes (ETGs) of miR-221-3p and examine their roles in breast cancer. METHODS We employed bioinformatics techniques to identify ten key ETGs of miR-221-3p. Subsequently, we conducted an extensive analysis of both miR-221-3p and the ten ETGs, including clinical significance and immune characteristics. RESULTS The expression of miR-221-3p was notably higher in Basal-like BC compared to other subtypes and adjacent normal tissue. Our pathway analysis suggested that miR-221-3p might regulate EMT through the MAPK signaling pathway by targeting its ETGs. Among the ETGs, seven core genes (EGFR, IGF1, KDR, FGF2, KIT, FGFR1, and FGF1) exhibited downregulation in BC. Conversely, ERBB2, SDC1, and MMP14 showed upregulation in BC and displayed potential diagnostic value. The analysis of prognostication indicated that increased levels of SDC1 and MMP14 were correlated with an unfavorable prognosis, whereas elevated expression of KIT was associated with a more favorable prognosis. The infiltration of various immune cells and the expression of immune checkpoint genes (ICGs) exhibited positive correlations with most ETGs and miR-221-3p. SDC1 exhibited a greater tumor mutational burden (TMB) score, while ERBB2, KDR, FGF2, KIT, FGFR1, and FGF1 showed lower TMB scores. Furthermore, decreased ERBB2 and KDR expression levels were correlated with elevated microsatellite instability (MSI) scores. Elevated expression of ETGs was linked to decreased mRNA stemness indices (mRNAsi), whereas miR-221-3p displayed the opposite pattern. Most ETGs and miR-221-3p expression exhibited a negative correlation with IC50 values for drugs. Among the ETGs, amplification was the most significant genetic alteration, except for IGF1. CONCLUSION In conclusion, miR-221-3p acts as a unique indicator for Basal-like BC. The examination revealed ten essential ETGs of miR-221-3p, some of which show potential as diagnostic and prognostic markers. The in-depth examination of these ten ETGs and miR-221-3p indicates their participation in the development of BC, emphasizing their promise as innovative targets for therapy in BC patients.
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Affiliation(s)
- Yutong Fang
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong, China
- Department of Central Laboratory, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Qunchen Zhang
- Department of Breast, Jiangmen Central Hospital, Jiangmen 529000, Guangdong, China
| | - Zexiao Chen
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong, China
- Department of Central Laboratory, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Cuiping Guo
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong, China
- Department of Central Laboratory, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Jundong Wu
- The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong, China
- Department of Central Laboratory, Cancer Hospital of Shantou University Medical College, Shantou 515041, Guangdong, China
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Li W, Liu L, Duanqing M, Xiong X, Gan D, Yang J, Wang M, Zhou M, Yan J. CLDN1 silencing suppresses the proliferation and migration of airway smooth muscle cells by modulating MMP14. Autoimmunity 2023; 56:2281223. [PMID: 37964516 DOI: 10.1080/08916934.2023.2281223] [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: 03/15/2023] [Accepted: 11/05/2023] [Indexed: 11/16/2023]
Abstract
Airway remodeling is an important pathologic factor in the progression of asthma. Abnormal proliferation and migration of airway smooth muscle cells (ASMCs) are important pathologic mechanisms in severe asthma. In the current study, claudin-1 (CLDN1) was identified as an asthma-related gene and was upregulated in ASMCs stimulated with platelet-derived growth factor BB (PDGF-BB). Cell counting kit-8 and EdU assays were used to evaluate cell proliferation, and transwell assay was carried out to analyze cell migration and invasion. The levels of inflammatory factors were detected using enzyme-linked immunosorbent assay. The results showed that CLDN1 knockdown inhibited the proliferation, migration, invasion, and inflammation of ASMCs treated with PDGF-BB, whereas overexpression of CLDN1 exhibited the opposite effects. Protein-protein interaction assay and co-immunoprecipitation revealed that CLDN1 directly interacted with matrix metalloproteinase 14 (MMP14). CLDN1 positively regulated MMP14 expression in asthma, and MMP14 overexpression reversed cell proliferation, migration, invasion, and inflammation induced by silenced CLDN1. Taken together, CLDN1 promotes PDGF-BB-induced cell proliferation, migration, invasion, and inflammatory responses of ASMCs by upregulating MMP14 expression, suggesting a potential role for CLDN1 in airway remodeling in asthma.
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Affiliation(s)
- Wei Li
- Pediatrics Department, The People's Hospital of Jiulongpo District, Chongqing, China
| | - Linyan Liu
- Pediatrics Department, The People's Hospital of Jiulongpo District, Chongqing, China
| | - Ming'ai Duanqing
- Pediatrics Department, The People's Hospital of Jiulongpo District, Chongqing, China
| | - Xiaoqing Xiong
- Pediatrics Department, The People's Hospital of Jiulongpo District, Chongqing, China
| | - Dejian Gan
- Pediatrics Department, The People's Hospital of Jiulongpo District, Chongqing, China
| | - Jin Yang
- Pediatrics Department, The People's Hospital of Jiulongpo District, Chongqing, China
| | - Mingya Wang
- Pediatrics Department, The People's Hospital of Jiulongpo District, Chongqing, China
| | - Min Zhou
- Pediatrics Department, The People's Hospital of Jiulongpo District, Chongqing, China
| | - Jun Yan
- Pediatrics Department, The People's Hospital of Jiulongpo District, Chongqing, China
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Maoga JB, Riaz MA, Mwaura AN, Mecha E, Omwandho COA, Scheiner-Bobis G, Meinhold-Heerlein I, Konrad L. Analysis of Membrane Type-1 Matrix Metalloproteinase (MT1-MMP, MMP14) in Eutopic and Ectopic Endometrium and in Serum and Endocervical Mucus of Endometriosis. Biomedicines 2023; 11:2730. [PMID: 37893104 PMCID: PMC10604514 DOI: 10.3390/biomedicines11102730] [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: 08/22/2023] [Revised: 09/26/2023] [Accepted: 10/04/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND Membrane type-matrix metalloproteinases (MT-MMPs) are a subgroup of the matrix metalloproteinases (MMPs) family and are key molecules in the degradation of the extracellular matrix. Membrane type-1 matrix metalloproteinase (MT1-MMP, MMP14) is often deregulated in different cancer tissues and body fluids of human cancer patients; however, MT1-MMP levels in endometriosis and adenomyosis patients are currently unknown. MATERIALS AND METHODS Tissue samples from patients with and without endometriosis or adenomyosis were analyzed with immunohistochemistry for the localization of MT1-MMP. Serum and endocervical mucus samples from patients with and without endometriosis or adenomyosis were investigated with MT1-MMP ELISAs. RESULTS MT1-MMP was localized preferentially in the glands of eutopic and ectopic endometrium. MT1-MMP protein levels are significantly reduced in ovarian endometriosis (HSCORE = 31) versus eutopic endometrium (HSCORE = 91) and adenomyosis (HSCORE = 149), but significantly increased in adenomyosis (HSCORE = 149) compared to eutopic endometrium (HSCORE = 91). Similarly, analysis of the levels of MT1-MMP using enzyme-linked immune assays (ELISAs) demonstrated a significant increase in the concentrations of MT1-MMP in the serum of endometriosis patients (1.3 ± 0.8) versus controls (0.7 ± 0.2), but not in the endocervical mucus. Furthermore, MT1-MMP levels in the endocervical mucus of patients with endometriosis were notably reduced in patients using contraception (3.2 ± 0.4) versus those without contraception (3.8 ± 0.2). CONCLUSIONS Taken together, our findings showed an opposite regulation of MT1-MMP in the tissue of ovarian endometriosis and adenomyosis compared to eutopic endometrium without endometriosis but increased serum levels in patients with endometriosis.
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Affiliation(s)
- Jane B. Maoga
- Center of Gynecology and Obstetrics, Faculty of Medicine, Justus Liebig University Giessen, 35392 Giessen, Germany; (J.B.M.); (M.A.R.); (A.N.M.); (I.M.-H.)
| | - Muhammad A. Riaz
- Center of Gynecology and Obstetrics, Faculty of Medicine, Justus Liebig University Giessen, 35392 Giessen, Germany; (J.B.M.); (M.A.R.); (A.N.M.); (I.M.-H.)
| | - Agnes N. Mwaura
- Center of Gynecology and Obstetrics, Faculty of Medicine, Justus Liebig University Giessen, 35392 Giessen, Germany; (J.B.M.); (M.A.R.); (A.N.M.); (I.M.-H.)
| | - Ezekiel Mecha
- Department of Biochemistry, University of Nairobi, Nairobi P.O. Box 30197-00100, Kenya;
| | - Charles O. A. Omwandho
- Department of Health Sciences, Kirinyaga University, Kerugoya P.O. Box 143-10300, Kenya;
| | - Georgios Scheiner-Bobis
- Institute for Veterinary Physiology and Biochemistry, School of Veterinary Medicine, Justus Liebig University Giessen, 35392 Giessen, Germany;
| | - Ivo Meinhold-Heerlein
- Center of Gynecology and Obstetrics, Faculty of Medicine, Justus Liebig University Giessen, 35392 Giessen, Germany; (J.B.M.); (M.A.R.); (A.N.M.); (I.M.-H.)
| | - Lutz Konrad
- Center of Gynecology and Obstetrics, Faculty of Medicine, Justus Liebig University Giessen, 35392 Giessen, Germany; (J.B.M.); (M.A.R.); (A.N.M.); (I.M.-H.)
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15
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Yuzhalin AE, Yu D. Critical functions of extracellular matrix in brain metastasis seeding. Cell Mol Life Sci 2023; 80:297. [PMID: 37728789 PMCID: PMC10511571 DOI: 10.1007/s00018-023-04944-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 08/16/2023] [Accepted: 08/29/2023] [Indexed: 09/21/2023]
Abstract
Human brain is characterized by extremely sparse extracellular matrix (ECM). Despite its low abundance, the significance of brain ECM in both physiological and pathological conditions should not be underestimated. Brain metastasis is a serious complication of cancer, and recent findings highlighted the contribution of ECM in brain metastasis development. In this review, we provide a comprehensive outlook on how ECM proteins promote brain metastasis seeding. In particular, we discuss (1) disruption of the blood-brain barrier in brain metastasis; (2) role of ECM in modulating brain metastasis dormancy; (3) regulation of brain metastasis seeding by ECM-activated integrin signaling; (4) functions of brain-specific ECM protein reelin in brain metastasis. Lastly, we consider the possibility of targeting ECM for brain metastasis management.
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Affiliation(s)
- Arseniy E Yuzhalin
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd, Unit 108, Houston, TX, 77030, USA
| | - Dihua Yu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd, Unit 108, Houston, TX, 77030, USA.
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16
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Shakhpazyan N, Mikhaleva L, Bedzhanyan A, Gioeva Z, Sadykhov N, Mikhalev A, Atiakshin D, Buchwalow I, Tiemann M, Orekhov A. Cellular and Molecular Mechanisms of the Tumor Stroma in Colorectal Cancer: Insights into Disease Progression and Therapeutic Targets. Biomedicines 2023; 11:2361. [PMID: 37760801 PMCID: PMC10525158 DOI: 10.3390/biomedicines11092361] [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: 06/24/2023] [Revised: 07/31/2023] [Accepted: 08/21/2023] [Indexed: 09/29/2023] Open
Abstract
Colorectal cancer (CRC) is a major health burden worldwide and is the third most common type of cancer. The early detection and diagnosis of CRC is critical to improve patient outcomes. This review explores the intricate interplay between the tumor microenvironment, stromal interactions, and the progression and metastasis of colorectal cancer. The review begins by assessing the gut microbiome's influence on CRC development, emphasizing its association with gut-associated lymphoid tissue (GALT). The role of the Wnt signaling pathway in CRC tumor stroma is scrutinized, elucidating its impact on disease progression. Tumor budding, its effect on tumor stroma, and the implications for patient prognosis are investigated. The review also identifies conserved oncogenic signatures (COS) within CRC stroma and explores their potential as therapeutic targets. Lastly, the seed and soil hypothesis is employed to contextualize metastasis, accentuating the significance of both tumor cells and the surrounding stroma in metastatic propensity. This review highlights the intricate interdependence between CRC cells and their microenvironment, providing valuable insights into prospective therapeutic approaches targeting tumor-stroma interactions.
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Affiliation(s)
- Nikolay Shakhpazyan
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, 119435 Moscow, Russia; (N.S.); (L.M.); (Z.G.); (N.S.); (A.O.)
| | - Liudmila Mikhaleva
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, 119435 Moscow, Russia; (N.S.); (L.M.); (Z.G.); (N.S.); (A.O.)
| | - Arkady Bedzhanyan
- Department of Abdominal Surgery and Oncology II (Coloproctology and Uro-Gynecology), Petrovsky National Research Center of Surgery, 119435 Moscow, Russia;
| | - Zarina Gioeva
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, 119435 Moscow, Russia; (N.S.); (L.M.); (Z.G.); (N.S.); (A.O.)
| | - Nikolay Sadykhov
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, 119435 Moscow, Russia; (N.S.); (L.M.); (Z.G.); (N.S.); (A.O.)
| | - Alexander Mikhalev
- Department of Hospital Surgery No. 2, Pirogov Russian National Research Medical University, 117997 Moscow, Russia;
| | - Dmitri Atiakshin
- Research and Educational Resource Center for Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis Innovative Technologies, Peoples’ Friendship University of Russia, 117198 Moscow, Russia;
- Research Institute of Experimental Biology and Medicine, Burdenko Voronezh State Medical University, 394036 Voronezh, Russia
| | - Igor Buchwalow
- Research and Educational Resource Center for Immunophenotyping, Digital Spatial Profiling and Ultrastructural Analysis Innovative Technologies, Peoples’ Friendship University of Russia, 117198 Moscow, Russia;
- Institute for Hematopathology, 22547 Hamburg, Germany;
| | | | - Alexander Orekhov
- Avtsyn Research Institute of Human Morphology, Petrovsky National Research Center of Surgery, 119435 Moscow, Russia; (N.S.); (L.M.); (Z.G.); (N.S.); (A.O.)
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia
- Institute for Atherosclerosis Research, 121096 Moscow, Russia
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17
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Chen Z, Yang K, Zhang J, Ren S, Chen H, Guo J, Cui Y, Wang T, Wang M. Systems crosstalk between antiviral response and cancerous pathways via extracellular vesicles in HIV-1-associated colorectal cancer. Comput Struct Biotechnol J 2023; 21:3369-3382. [PMID: 37389186 PMCID: PMC10300105 DOI: 10.1016/j.csbj.2023.06.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 05/30/2023] [Accepted: 06/10/2023] [Indexed: 07/01/2023] Open
Abstract
HIV-1 associated colorectal cancer (HA-CRC) is one of the most understudied non-AIDS-defining cancers. In this study, we analyzed the proteome of HA-CRC and the paired remote tissues (HA-RT) through data-independent acquisition mass spectrometry (MS). The quantified proteins could differentiate the HA-CRC and HA-RT groups per PCA or cluster analyses. As a background comparison, we reanalyzed the MS data of non-HIV-1 infected CRC (non-HA-CRC) published by CPTAC. According to the GSEA results, we found that HA-CRC and non-HA-CRC shared similarly over-represented KEGG pathways. Hallmark analysis suggested that terms of antiviral response were only significantly enriched in HA-CRC. The network and molecular system analysis centered the crosstalk of IFN-associated antiviral response and cancerous pathways, which was favored by significant up-regulation of ISGylated proteins as detected in the HA-CRC tissues. We further proved that defective HIV-1 reservoir cells as represented by the 8E5 cells could activate the IFN pathway in human macrophages via horizonal transfer of cell-associated HIV-1 RNA (CA-HIV RNA) carried by extracellular vesicles (EVs). In conclusion, HIV-1 reservoir cells secreted and CA-HIV RNA-containing EVs can induce IFN pathway activation in macrophages that contributes to one of the mechanistic explanations of the systems crosstalk between antiviral response and cancerous pathways in HA-CRC.
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Affiliation(s)
- Zimei Chen
- The First Affiliated Hospital, MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, China
- Department of Infectious Diseases, Institute of HIV/AIDS, The First Hospital of Changsha, Changsha, Hunan 410005, China
| | - Ke Yang
- Department of Infectious Diseases, Institute of HIV/AIDS, The First Hospital of Changsha, Changsha, Hunan 410005, China
| | - Jiayi Zhang
- The First Affiliated Hospital, MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, China
| | - Shufan Ren
- The First Affiliated Hospital, MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, China
| | - Hui Chen
- Department of Infectious Diseases, Institute of HIV/AIDS, The First Hospital of Changsha, Changsha, Hunan 410005, China
| | - Jiahui Guo
- The First Affiliated Hospital, MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, China
| | - Yizhi Cui
- The First Affiliated Hospital, MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, China
| | - Tong Wang
- The First Affiliated Hospital, MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, China
- Department of Infectious Diseases, Institute of HIV/AIDS, The First Hospital of Changsha, Changsha, Hunan 410005, China
| | - Min Wang
- Department of Infectious Diseases, Institute of HIV/AIDS, The First Hospital of Changsha, Changsha, Hunan 410005, China
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18
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Ge D, Chen J, Zhao Z, Sui B, Liang F, Wang H. Characterizing the function-related specific assembly pattern of matrix metalloproteinase-14 by dSTORM imaging. Talanta 2023; 260:124523. [PMID: 37105082 DOI: 10.1016/j.talanta.2023.124523] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 03/29/2023] [Accepted: 04/01/2023] [Indexed: 04/29/2023]
Abstract
As transmembrane proteolytic enzyme, matrix metalloproteinase-14 (MMP14) regulates cell migration and cancer metastasis, but how it works at the single molecule level is unclear. Molecular localization is closely related to its function, and revealing its spatial assemble details is thus helpful to understand bio-function. Here, we apply aptamer probe and dSTORM to characterize MMP14 distribution. With demonstrating labeling properties of the probe, we investigate the specific distributed pattern of MMP14 on various cell membranes with different migratory capacities, and find that MMP14 mostly aggregate in clustering state, which becomes more significant with enhancing its hydrolysis efficiency on high-migratory cells. Lots of MMP14 are revealed to be co-localized with its substrate PTK7, and this colocalization decreases with weakening cell migration, suggesting that MMP14 may coordinate cell migration by altering its spatial relationship with substrate proteins. This work will promote a deep understanding of the roles of MMP14 in cell migration and cancer metastasis.
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Affiliation(s)
- Dian Ge
- Improve-WUST Joint Laboratory of Advanced Technology for Point-of-Care Testing and Precision Medicine, School of Chemistry & Chemical Engineering, Wuhan University of Science and Technology, 947 Heping Street, Wuhan, Hubei, 430081, China
| | - Junling Chen
- Improve-WUST Joint Laboratory of Advanced Technology for Point-of-Care Testing and Precision Medicine, School of Chemistry & Chemical Engineering, Wuhan University of Science and Technology, 947 Heping Street, Wuhan, Hubei, 430081, China.
| | - Zhiyong Zhao
- Improve-WUST Joint Laboratory of Advanced Technology for Point-of-Care Testing and Precision Medicine, School of Chemistry & Chemical Engineering, Wuhan University of Science and Technology, 947 Heping Street, Wuhan, Hubei, 430081, China
| | - Binglin Sui
- Improve-WUST Joint Laboratory of Advanced Technology for Point-of-Care Testing and Precision Medicine, School of Chemistry & Chemical Engineering, Wuhan University of Science and Technology, 947 Heping Street, Wuhan, Hubei, 430081, China
| | - Feng Liang
- Improve-WUST Joint Laboratory of Advanced Technology for Point-of-Care Testing and Precision Medicine, School of Chemistry & Chemical Engineering, Wuhan University of Science and Technology, 947 Heping Street, Wuhan, Hubei, 430081, China.
| | - Hongda Wang
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Research Center of Biomembranomics, 5625 Renmin Street, Changchun, Jilin, 130022, China.
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19
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de Almeida Roque A, da Luz JZ, Santurio MTK, Neto FF, de Oliveira Ribeiro CA. Complex mixtures of pesticides and metabolites modulate the malignant phenotype of murine melanoma B16-F1 cells. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:47366-47380. [PMID: 36738412 DOI: 10.1007/s11356-023-25603-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 01/24/2023] [Indexed: 06/18/2023]
Abstract
Pesticides use increased worldwide with a record in Brazil. Although several works addressed the effects of pesticides on living organisms, only a few considered their mixture, and even fewer tried to unravel their role in tumoral progression. Due to the relevance of cancer, in the present study, the effects of the mixture of pesticides widely used in Brazil (Glyphosate, 2,4-dichlorophenoxyacetic acid, Mancozeb, Atrazine, Acephate, and Paraquat) and their main metabolites (Aminomethylphosphonic Acid, 2,4-diclorophenol, Ethylenethiourea, Desethylatrazine, Methamidophos, and Paraquat) were investigated on the malignancy phenotype of murine melanoma B16-F1 cells after acute (24 h) and chronic (15 days) exposures. The tested concentrations were based on the Acceptable Daily Intake (ADI) value established by Brazilian legislation. The set of results showed that these chemicals modulate important parameters of tumor progression, affecting the expression of genes related to tumor aggressiveness (Mmp14 and Cd44) and multidrug resistance (Abcb1, Abcc1, and Abcc4), as well as tissue inhibitors of metalloproteinases (Timp1, Timp2, and Timp3). These findings revealed an absence of cytotoxicity but showed modulation of migration, invasion, and colonization capacity of B16-F1 cells. Together, the results point to some negative ways that exposure to pesticides can affect the progression of melanoma and raise a concern related to the increasing trend in pesticide use in Brazil, as the country is one of the major world food suppliers.
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Affiliation(s)
- Aliciane de Almeida Roque
- Laboratory of Cell Toxicology, Department of Cellular and Molecular Biology, Federal University of Paraná, PO Box: 19031, Curitiba, PR, CEP: 81531-980, Brazil
| | - Jessica Zablocki da Luz
- Laboratory of Cell Toxicology, Department of Cellular and Molecular Biology, Federal University of Paraná, PO Box: 19031, Curitiba, PR, CEP: 81531-980, Brazil
| | - Michelle Thays Khun Santurio
- Laboratory of Cell Toxicology, Department of Cellular and Molecular Biology, Federal University of Paraná, PO Box: 19031, Curitiba, PR, CEP: 81531-980, Brazil
| | - Francisco Filipak Neto
- Laboratory of Cell Toxicology, Department of Cellular and Molecular Biology, Federal University of Paraná, PO Box: 19031, Curitiba, PR, CEP: 81531-980, Brazil
| | - Ciro Alberto de Oliveira Ribeiro
- Laboratory of Cell Toxicology, Department of Cellular and Molecular Biology, Federal University of Paraná, PO Box: 19031, Curitiba, PR, CEP: 81531-980, Brazil.
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Exosomal circ-ADRM1 promotes lung adenocarcinoma progression and induces macrophage M2 polarization through regulating MMP14 mRNA and protein. Anticancer Drugs 2023; 34:333-343. [PMID: 36454975 DOI: 10.1097/cad.0000000000001430] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
OBJECTIVE Lung adenocarcinoma (LUAD) is one of the frequent subtypes of lung cancer, featuring high rates of incidence and mortality. Matrix metalloproteinase 14 (MMP14) is known as a regulator in multiple cancers, whereas its upstream molecular mechanism remains to be investigated. This study aims to reveal the upstream molecular mechanism of MMP14 in LUSC progression. METHODS Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were conducted to examine the levels of MMP14 mRNA and protein in LUAD cells, respectively. Cell counting kit-8 (CCK-8), transwell assay and wound healing assay were implemented to unveil LUAD cell proliferation, migration and invasion after indicated transfections. Flow cytometry analysis was applied to evaluate macrophage polarization. Mechanism experiments such as western blot, co-immunoprecipitation (Co-IP), RNA pulldown assay, luciferase reporter assay and RNA-binding protein immunoprecipitation (RIP) assay were used to explore relevant molecular mechanisms. RESULTS MMP14 facilitated LUAD cell proliferation, invasion and migration. MMP14 is the target gene of miR-1287-5p. Circ-ADRM1 upregulates MMP14 expression through sponging miR-1287-5p. Circ-ADRM1 recruits USP12 to impede the ubiquitination of MMP14 protein, thereby enhancing the stability of MMP14 protein. LUAD-derived exosomes induced macrophage M2 polarization by delivering circ-ADRM1. CONCLUSIONS Circ-ADRM1 promotes LUAD cell proliferation, invasion and migration through upregulating MMP14. Additionally, circ-ADRM1 induces macrophage M2 polarization in an exosome-dependent manner.
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21
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Wang X, Liu Y, Ding Y, Feng G. CAMSAP2 promotes colorectal cancer cell migration and invasion through activation of JNK/c-Jun/MMP-1 signaling pathway. Sci Rep 2022; 12:16899. [PMID: 36207462 PMCID: PMC9546856 DOI: 10.1038/s41598-022-21345-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 09/26/2022] [Indexed: 11/10/2022] Open
Abstract
CAMSAP2 has been reported to act as an oncogene in hepatocellular carcinoma. However, the expression CAMSAP2 and its potential roles in colorectal cancer remain unclear. In this study, qRT-PCR and immunoblotting analysis were used to detect the mRNA and protein levels of CAMSAP2 in colorectal cancer tissues and cell lines. Wound-healing, transwell migration and invasion assay were performed to determine whether CAMSAP2 promotes the capabilities of migration and invasion of colorectal cancer cells. The results showed that CAMSAP2 was highly elevated in colorectal cancer tissues and cell lines. Moreover, the high CAMSAP2 expression was positively correlated with tumor invasion depth, lymph node metastasis, distant metastasis, and the poor prognosis of colorectal cancer. Additionally, ectopic expression of CAMSAP2 in colorectal cancer cells promoted the migration and invasion in vitro and enhanced the lung metastasis in nude mice. Conversely, silencing CAMSAP2 resulted in an opposite phenomenon. By gain- and loss-of function experiments, we demonstrated that MMP-1 was a substantial downstream target of CAMSAP2, and it played a crucial role in regulating the migration and invasion induced by CAMSAP2 in colorectal cancer cells. Mechanistically, CAMSAP2 promoted the activation of JNK/c-Jun signaling pathway and subsequently upregulated the transcription activity of MMP-1. Taken together, our findings demonstrated that CAMSAP2 promoted colorectal cancer cell migration, invasion and metastasis through activation of JNK/c-Jun/MMP-1 signaling pathway, indicating CAMSAP2 is a promising therapeutic target for the treatment of metastatic colorectal cancer patients.
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Affiliation(s)
- Xiaojuan Wang
- Department of Oncology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, 473 Hanzheng Street, Wuhan, 430000, Hubei, China
| | - Yumin Liu
- Department of Obstetrics and Gynecology, Wuhan Hankou Hospital, Wuhan, 430010, Hubei, China
| | - Yawen Ding
- Department of Oncology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, 473 Hanzheng Street, Wuhan, 430000, Hubei, China
| | - Gang Feng
- Department of Oncology, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, 473 Hanzheng Street, Wuhan, 430000, Hubei, China.
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22
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Li F, Song QZ, Zhang YF, Wang XR, Cao LM, Li N, Zhao LX, Zhang SX, Zhuang XF. Identifying the EMT-related signature to stratify prognosis and evaluate the tumor microenvironment in lung adenocarcinoma. Front Genet 2022; 13:1008416. [PMID: 36186418 PMCID: PMC9523218 DOI: 10.3389/fgene.2022.1008416] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 08/31/2022] [Indexed: 12/03/2022] Open
Abstract
Background: Epithelial-mesenchymal transition (EMT) is a critical process in tumor invasion and metastasis. EMT has been shown to significantly influence the invasion, metastasis, and poor prognosis in lung adenocarcinoma (LUAD). This study aimed to develop a novel EMT-related prognostic model capable of predicting overall survival (OS) in patients with LUAD. Methods: A total of 283 LUAD patients from TCGA RNA-seq dataset were assigned to a training cohort for model building, and 310 LUAD patients from GEO RNA-seq dataset were assigned to a validation cohort. EMT genes were acquired from MsigDB database and then prognosis-related EMT genes were identified by univariate Cox regression. Lasso regression was then performed to determine the genes and the corresponding variables to construct a prognosis risk model from the training cohort. Furthermore, characteristics of the tumor microenvironment (TME), mutation status and chemotherapy responses were analyzed to assess the differences between the two risk groups based on the prognostic model. In addition, RT-qPCR was employed to validate the expression patterns of the 6 genes derived from the risk model. Results: A six-gene EMT signature (PMEPA1, LOXL2, PLOD2, MMP14, SPOCK1 and DCN) was successfully constructed and validated. The signature assigned the LUAD patients into high-risk and low-risk groups. In comparison with the low-risk group, patients in the high-risk group had a significantly lower survival rate. ROC curves and calibration curves for the risk model demonstrated reliable stratification and predictive ability. The risk model was robustly correlated with multiple TME characteristics. Besides, the data showed that patients in the low-risk group had more immune activities, higher stemness scores and cytolytic activity scores and higher TMB. In addition, RT-qPCR results revealed that PMEPA1, LOXL2, PLOD2, MMP14, and SPOCK1 were notably upregulated in LUAD tissues, while DCN was downregulated. Conclusion: Our study successfully developed a novel EMT-related signature to predict prognosis of LUAD patients and guide treatment strategies. The six genes derived from the prediction signature might play a potential role in antitumor immunity and serve as promising therapeutic targets in LUAD.
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Affiliation(s)
- Feng Li
- Department of Cell Biology, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Qing-Zhen Song
- Department of Special Geriatrics, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
| | - Yi-Fan Zhang
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, China
| | - Xing-Ru Wang
- The Second Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Li-Min Cao
- The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Nan Li
- The School of Basic Medicine of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Ling-Xia Zhao
- Department of Endocrinology and Metabolism, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China
- *Correspondence: Ling-Xia Zhao, ; Sheng-Xiao Zhang, ; Xiao-Fei Zhuang,
| | - Sheng-Xiao Zhang
- Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, China
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- *Correspondence: Ling-Xia Zhao, ; Sheng-Xiao Zhang, ; Xiao-Fei Zhuang,
| | - Xiao-Fei Zhuang
- Department of Thoracic Surgery, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
- *Correspondence: Ling-Xia Zhao, ; Sheng-Xiao Zhang, ; Xiao-Fei Zhuang,
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Makutani Y, Kawakami H, Tsujikawa T, Yoshimura K, Chiba Y, Ito A, Kawamura J, Haratani K, Nakagawa K. Contribution of MMP14-expressing cancer-associated fibroblasts in the tumor immune microenvironment to progression of colorectal cancer. Front Oncol 2022; 12:956270. [PMID: 36052235 PMCID: PMC9424903 DOI: 10.3389/fonc.2022.956270] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 07/28/2022] [Indexed: 11/13/2022] Open
Abstract
Matrix metalloproteinase 14 (MMP14) expression is implicated in progression of colorectal cancer, but its role in the tumor microenvironment (TME) has been unclear. The relevance of MMP14 to colorectal cancer progression was explored by analysis of transcriptomic data for colorectal adenocarcinoma patients (n = 592) in The Cancer Genome Atlas. The role of MMP14 in the TME was investigated in a retrospective analysis of tumor samples from 86 individuals with stage III colorectal cancer by single cell–based spatial profiling of MMP14 expression as performed by 12-color multiplex immunohistochemistry (mIHC). Analysis of gene expression data revealed that high MMP14 expression was associated with tumor progression and implicated both cancer-associated fibroblasts (CAFs) and tumor-associated macrophages in such progression. Spatial profiling by mIHC revealed that a higher percentage of MMP14+ cells among intratumoral CAFs (MMP14+ CAF/CAF ratio) was associated with poorer relapse-free survival. Multivariable analysis including key clinical factors identified the MMP14+ CAF/CAF ratio as an independent poor prognostic factor. Moreover, the patient subset with both a high MMP14+ CAF/CAF ratio and a low tumor-infiltrating lymphocyte density showed the worst prognosis. Our results suggest that MMP14+ CAFs play an important role in progression of stage III colorectal cancer and may therefore be a promising therapeutic target.
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Affiliation(s)
- Yusuke Makutani
- Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Hisato Kawakami
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
- *Correspondence: Hisato Kawakami, ; Koji Haratani,
| | - Takahiro Tsujikawa
- Department of Otolaryngology–Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kanako Yoshimura
- Department of Otolaryngology–Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yasutaka Chiba
- Clinical Research Center, Kindai University Hospital, Osaka-Sayama, Japan
| | - Akihiko Ito
- Department of Pathology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Junichiro Kawamura
- Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Koji Haratani
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
- *Correspondence: Hisato Kawakami, ; Koji Haratani,
| | - Kazuhiko Nakagawa
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
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Hu J, He Y, Liao K, Yang Q, Xu Y, Cao G, Wang X. Identification of inflammatory factor-related genes associated with the prognostic and immune cell infiltration in colorectal cancer patients. Genes Dis 2022. [PMID: 37492736 PMCID: PMC10363590 DOI: 10.1016/j.gendis.2022.07.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
This study aims to identify the inflammatory factor-related genes which help to predict the prognosis of patients with colorectal cancer. GSEA (Gene Set Enrichment Analysis) was used to acquire inflammation-related genes and the corresponding expression information was collected from TCGA database to determine the DEGs (differentially-expressed genes) in CRC patients. We conducted enrichment analysis and PPI (protein-protein interaction) of these DEGs. Besides, key genes that are both differentially-expressed and prognosis-related were screened out, which were used to establish the prognostic model. We obtained 79 DEGs and 19 prognostic genes, 10 prognostic-related differential genes were eventually screened. These genes were used to construct the prognostic model. We also identified that the immune infiltration score of macrophages between different risk groups was significantly different and similar distinction was witnessed in immune function score of APC (antigen-presenting cell) co-stimulation and type I IFN (interferon) response.
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25
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Li X, Li K, Li M, Lin X, Mei Y, Huang X, Yang H. Chemoresistance Transmission via Exosome-Transferred MMP14 in Pancreatic Cancer. Front Oncol 2022; 12:844648. [PMID: 35223528 PMCID: PMC8865617 DOI: 10.3389/fonc.2022.844648] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 01/17/2022] [Indexed: 12/19/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. Gemcitabine is the most commonly used chemotherapy for the treatment of PDAC, but the development of drug resistance still remains challenging. Recently, exosomes have emerged as important mediators for intercellular communication. Exosomes affect recipient cells’ behavior through the engulfed cargos, however the specific cargos responsible for gemcitabine resistance in PDAC are poorly understood. Here, we reported that exosomes could transfer gemcitabine resistance via a metalloproteinase 14 (MMP14)-dependent mechanism. MMP14 was identified as a major differentially secreted protein from the gemcitabine-resistant PDAC cells by comparative secretome. It was packaged into the exosomes and transmitted from the chemoresistant cells to the sensitive ones. The exosome-transferred MMP14 could enhance drug resistance and promotes the sphere-formation and migration abilities of the recipient sensitive PDAC cells. Mechanically, exosome-transferred MMP14 promotes the stability of CD44, the cancer stem cell marker in the recipient cells. Our results indicate that MMP14 is a key player for exosome-mediated transfer of gemcitabine resistance, thus targeting MMP14 in exosomes may represent a novel strategy to limit gemcitabine resistance in PDAC.
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Affiliation(s)
- Xinyuan Li
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Kai Li
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Mengmeng Li
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Xiaoyu Lin
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Yu Mei
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Xuemei Huang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Huanjie Yang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
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26
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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: 14] [Impact Index Per Article: 4.7] [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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Ionica E, Gaina G, Tica M, Chifiriuc MC, Gradisteanu-Pircalabioru G. Contribution of Epithelial and Gut Microbiome Inflammatory Biomarkers to the Improvement of Colorectal Cancer Patients' Stratification. Front Oncol 2022; 11:811486. [PMID: 35198435 PMCID: PMC8859258 DOI: 10.3389/fonc.2021.811486] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 12/20/2021] [Indexed: 12/24/2022] Open
Abstract
In order to ensure that primary endpoints of clinical studies are attained, the patients' stratification is an important aspect. Selection criteria include age, gender, and also specific biomarkers, such as inflammation scores. These criteria are not sufficient to achieve a straightforward selection, however, in case of multifactorial diseases, with unknown or partially identified mechanisms, occasionally including host factors, and the microbiome. In these cases, the efficacy of interventions is difficult to predict, and as a result, the selection of subjects is often random. Colorectal cancer (CRC) is a highly heterogeneous disease, with variable clinical features, outcomes, and response to therapy; the CRC onset and progress involves multiple sequential steps with accumulation of genetic alterations, namely, mutations, gene amplification, and epigenetic changes. The gut microbes, either eubiotic or dysbiotic, could influence the CRC evolution through a complex and versatile crosstalk with the intestinal and immune cells, permanently changing the tumor microenvironment. There have been significant advances in the development of personalized approaches for CRC screening, treatment, and potential prevention. Advances in molecular techniques bring new criteria for patients' stratification-mutational analysis at the time of diagnosis to guide treatment, for example. Gut microbiome has emerged as the main trigger of gut mucosal homeostasis. This may impact cancer susceptibility through maintenance of the epithelial/mucus barrier and production of protective metabolites, such as short-chain fatty acids (SCFAs) via interactions with the hosts' diet and metabolism. Microbiome dysbiosis leads to the enrichment of cancer-promoting bacterial populations, loss of protective populations or maintaining an inflammatory chronic state, all of which contribute to the development and progression of CRC. Meanwhile, variations in patient responses to anti-cancer immuno- and chemotherapies were also linked to inter-individual differences in intestine microbiomes. The authors aim to highlight the contribution of epithelial and gut microbiome inflammatory biomarkers in the improvement of CRC patients' stratification towards a personalized approach of early diagnosis and treatment.
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Affiliation(s)
- Elena Ionica
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Gisela Gaina
- Laboratory of Cell Biology, Neuroscience and Experimental Miology, Victor Babes National Institute of Pathology, Bucharest, Romania
| | - Mihaela Tica
- Bucharest Emergency University Hospital, Bucharest, Romania
| | - Mariana-Carmen Chifiriuc
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania
- Biological Science Division, Romanian Academy of Sciences, Bucharest, Romania
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Pezeshkian Z, Nobili S, Peyravian N, Shojaee B, Nazari H, Soleimani H, Asadzadeh-Aghdaei H, Ashrafian Bonab M, Nazemalhosseini-Mojarad E, Mini E. Insights into the Role of Matrix Metalloproteinases in Precancerous Conditions and in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13246226. [PMID: 34944846 PMCID: PMC8699154 DOI: 10.3390/cancers13246226] [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: 11/14/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 01/06/2023] Open
Abstract
Simple Summary Colorectal cancer (CRC) is one of the most common cancer worldwide. CRC is derived from polyps and many factors, such as Matrix Metalloproteinases (MMPs) can gain the progression of colorectal carcinogenesis. Many investigations have indicated the role of MMPs in CRC development while there is not enough knowledge about the function of MMPs in precancerous conditions. This review summarizes the current information about the role of MMPs in polyps and CRC progression. Abstract Colorectal cancer (CRC) is the third and second cancer for incidence and mortality worldwide, respectively, and is becoming prevalent in developing countries. Most CRCs derive from polyps, especially adenomatous polyps, which can gradually transform into CRC. The family of Matrix Metalloproteinases (MMPs) plays a critical role in the initiation and progression of CRC. Prominent MMPs, including MMP-1, MMP-2, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, MMP-14, and MMP-21, have been detected in CRC patients, and the expression of most of them correlates with a poor prognosis. Moreover, many studies have explored the inhibition of MMPs and targeted therapy for CRC, but there is not enough information about the role of MMPs in polyp malignancy. In this review, we discuss the role of MMPs in colorectal cancer and its pathogenesis
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Affiliation(s)
- Zahra Pezeshkian
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Stefania Nobili
- Department of Neurosciences, Imaging and Clinical Sciences, “G. D’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy;
- Center for Advanced Studies and Technology (CAST), University “G. D’Annunzio” Chieti-Pescara, 66100 Chieti, Italy
| | - Noshad Peyravian
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Bahador Shojaee
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Haniye Nazari
- Department of Microbiology, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran 19395-1495, Iran;
| | - Hiva Soleimani
- Department of General Biology, Faculty of Fundamental Science, Islamic Azad University of Shahr-E-Qods, Tehran 37515-374, Iran;
| | - Hamid Asadzadeh-Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran; (Z.P.); (N.P.); (B.S.); (H.A.-A.)
| | - Maziar Ashrafian Bonab
- School of Medicine, University of Sunderland, City Campus, Chester Road, Sunderland SR1 3SD, UK;
| | - Ehsan Nazemalhosseini-Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 19835-178, Iran
- Correspondence: (E.N.-M.); (E.M.)
| | - Enrico Mini
- Department of Health Sciences, University of Florence, 50139 Florence, Italy
- DENOTHE Excellence Center, University of Florence, 50139 Florence, Italy
- Correspondence: (E.N.-M.); (E.M.)
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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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Yu J, He Z, He X, Luo Z, Lian L, Wu B, Lan P, Chen H. Comprehensive Analysis of the Expression and Prognosis for MMPs in Human Colorectal Cancer. Front Oncol 2021; 11:771099. [PMID: 34804973 PMCID: PMC8602079 DOI: 10.3389/fonc.2021.771099] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 10/13/2021] [Indexed: 12/22/2022] Open
Abstract
Background Previous study implicated that genes of matrix metalloproteinase (MMP) family play an important role in tumor invasion, neoangiogenesis, and metastasis. However, the diverse expression patterns and prognostic values of 24 MMPs in colorectal cancer are yet to be analyzed. Methods In this study, by integrating public database and our data, we first investigated the expression levels and protein levels of MMPs in patients with colorectal cancer. Then, by using TCGA and GEO datasets, we evaluated the association of MMPs with clinicopathological parameters and prognosis of colorectal cancer. Finally, by using the cBioPortal online tool, we analyzed the alterations of MMPs and did the network and pathway analyses for MMPs and their nearby genes. Results We found that, MMP1, MMP3, MMP7, MMP9–MMP12, and MMP14 were consistently upregulated in public dataset and our samples. Whereas, MMP28 was consistently downregulated in public dataset and our samples. In the clinicopathological analyses, upregulated MMP11, MMP14, MMP16, MMP17, MMP19, and MMP23B were significantly associated with a higher tumor stage. In the survival analyses, upregulated MMP11, MMP14, MMP17, and MMP19 were significantly associated with a shorter progression-free survival (PFS) time and a shorter relapse-free (RFS) time. Discussion This study implied that MMP11, MMP14, MMP17, and MMP19 are potential targets of precision therapy for patients with colorectal cancer.
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Affiliation(s)
- Jing Yu
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, China
| | - Zhen He
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, China
| | - Xiaowen He
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, China
| | - Zhanhao Luo
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, China
| | - Lei Lian
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, China
| | - Baixing Wu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for Ribose Nucleic Acid (RNA) Medicine, Ribose Nucleic Acid (RNA) Biomedical Institute, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ping Lan
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, Guangzhou, China
| | - Haitao Chen
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China.,School of Public Health, Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
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31
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Li M, Li S, Zhou L, Yang L, Wu X, Tang B, Xie S, Fang L, Zheng S, Hong T. Immune Infiltration of MMP14 in Pan Cancer and Its Prognostic Effect on Tumors. Front Oncol 2021; 11:717606. [PMID: 34604053 PMCID: PMC8484967 DOI: 10.3389/fonc.2021.717606] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 08/25/2021] [Indexed: 12/12/2022] Open
Abstract
Background Matrix metalloproteinase 14 (MMP14) is a member of the MMP family, which interacts with tissue inhibitors of metalloproteinase (TIMPs), and is involved in normal physiological functions such as cell migration, invasion, metastasis, angiogenesis, and proliferation, as well as tumor genesis and progression. However, there has been a lack of relevant reports on the effect of MMP14 across cancers. This study aims to explore the correlation between MMP14 and pan-cancer prognosis, immune infiltration, and the effects of pan-cancer gene mismatch repair (MMR), microsatellite instability (MSI), tumor mutational burden (TMB), DNA methylation, and immune checkpoint genes. Methods In this study, we used bioinformatics to analyze data from multiple databases, including The Cancer Genome Atlas (TCGA), ONCOMINE, and Kaplan–Meier plotter. We investigated the relationship between the expression of MMP14 in tumors and tumor prognosis, the relationship between MMP14 expression and tumor cell immune infiltration, and the relationship between MMR gene MMR, MSI, TMB, DNA methylation, and immune checkpoint genes. Results MMP14 expression is highly associated with the prognosis of a variety of cancers and tumor immune invasion and has important effects on pan oncologic MMR, MSI, TMB, DNA methylation, and immune checkpoint genes. Conclusion MMP14 is highly correlated with tumor prognosis and immune invasion and affects the occurrence and progression of many tumors. All of these results fully indicate that MMP14 may be a biomarker for the prognosis, diagnosis, and treatment of many tumors and provide new ideas and direction for subsequent tumor immune research and treatment strategies.
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Affiliation(s)
- Minde Li
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Shaoyang Li
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Lin Zhou
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Le Yang
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiao Wu
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Bin Tang
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Shenhao Xie
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Linchun Fang
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Suyue Zheng
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Tao Hong
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
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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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33
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Albadawy R, Agwa SHA, Khairy E, Saad M, El Touchy N, Othman M, Matboli M. Clinical Significance of HSPD1/MMP14/ITGB1/miR-6881-5P/Lnc-SPARCL1-1:2 RNA Panel in NAFLD/NASH Diagnosis: Egyptian Pilot Study. Biomedicines 2021; 9:1248. [PMID: 34572434 PMCID: PMC8472260 DOI: 10.3390/biomedicines9091248] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/15/2021] [Accepted: 09/15/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Non-alcoholic steatohepatitis ((NASH) is the progressive form of (non-alcoholic fatty liver disease) (NAFLD), which can progress to liver cirrhosis and hepatocellular carcinoma. There is no available reliable non-invasive diagnostic tool to diagnose NASH, and still the liver biopsy is the gold standard in diagnosis. In this pilot study, we aimed to evaluate the Nod-like receptor (NLR) signaling pathway related RNA panel in the diagnosis of NASH. METHODS Bioinformatics analysis was done, with retrieval of the HSPD1/MMP14/ITGB1/miR-6881-5P/Lnc-SPARCL1-1:2 RNA panel based on the relation to the NLR-signaling pathway. Hepatitis serum markers, lipid profile, NAFLD score and fibrosis score were assessed in the patients' sera. Reverse transcriptase real time polymerase chain reaction (RT-PCR) was done to assess the relative expression of the RNA panel among patients who had NAFLD without steatosis, NAFLD with simple steatosis, NASH and healthy controls. RESULTS We observed up-regulation of Lnc-SPARCL1-1:2 lncRNA that led to upregulation of miR-6881-5P with a subsequent increase in levels of HSPD1, MMP14, and ITGB1 mRNAs. In addition, ROC curve analysis was done, with discriminative cutoff values that aided discrimination between NASH cases and control, and also between NAFLD, simple steatosis and NASH. CONCLUSION This pilot study concluded that HSPD1/MMP14/ITGB1/miR-6881-5P/Lnc-SPARCL1-1:2 panel expression has potential in the diagnosis of NASH, and also differentiation between NAFLD, simple steatosis and NASH cases.
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Affiliation(s)
- Reda Albadawy
- Department of Gastroentrology, Hepatology & Infectious Disease, Faculty of Medicine, Benha University, Benha 13518, Egypt;
| | - Sara H. A. Agwa
- Molecular Genomics Unit, Clinical Pathology Department, Medical Ain Shams Research Institute (MASRI), School of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Eman Khairy
- Medicinal Biochemistry and Molecular Biology Department, School of Medicine, Ain Shams University, Cairo 11566, Egypt;
| | - Maha Saad
- Biochemistry Department, Faculty of Medicine, Modern University for Technology and Information, Cairo 11382, Egypt;
| | - Naglaa El Touchy
- Department of Gastroentrology, Hepatology & Infectious Disease, Faculty of Medicine, Benha University, Benha 13518, Egypt;
| | - Mohamed Othman
- Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Marwa Matboli
- Medicinal Biochemistry and Molecular Biology Department, School of Medicine, Ain Shams University, Cairo 11566, Egypt;
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Li J, Wang Z, Tie C. High expression of ladinin-1 (LAD1) predicts adverse outcomes: a new candidate docetaxel resistance gene for prostatic cancer (PCa). Bioengineered 2021; 12:5749-5759. [PMID: 34516317 PMCID: PMC8806705 DOI: 10.1080/21655979.2021.1968647] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Docetaxel resistance is one of the major obstacles that undermine the treatment outcome of PCa. Exploring molecular mechanisms associated with docetaxel resistance could provide insights into the formulation of novel strategies enhancing the efficacy of PCa treatment. Ladinin-1 (LAD1) is an anchoring filament protein in basement membranes, which contributes to the association of the epithelial cells with the underlying mesenchyme. LAD1 has been implicated in the progression of different cancers. However, its role in PCa remains to be investigated. In the present study, we found that LAD1 was highly expressed in docetaxel-resistant PCa cells, while its expression was significantly suppressed in tumor samples after docetaxel treatment. Moreover, the expression level of LAD1 in PCa tissues was significantly higher than that of normal tissue, and high expression level of LAD1 was significantly associated with adverse outcomes of PCa patients. Finally, high expression of LAD1 in PCa tissue was also correlated with the expression level of genes involving in tumor cell proliferation and invasive behaviors. Collectively, our data suggest that LAD1 may serve as a potential prognostic factor in PCa patients.
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Affiliation(s)
- Jianping Li
- Department of Urology, The Second Affiliated Hospital of Xi'an Jiaotong University, China
| | - Ziming Wang
- Department of Urology, The Second Affiliated Hospital of Xi'an Jiaotong University, China
| | - Chong Tie
- Department of Urology, The Second Affiliated Hospital of Xi'an Jiaotong University, China
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35
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Hong Q, Li B, Cai X, Lv Z, Cai S, Zhong Y, Wen B. Transcriptomic Analyses of the Adenoma-Carcinoma Sequence Identify Hallmarks Associated With the Onset of Colorectal Cancer. Front Oncol 2021; 11:704531. [PMID: 34458146 PMCID: PMC8387103 DOI: 10.3389/fonc.2021.704531] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 07/15/2021] [Indexed: 12/12/2022] Open
Abstract
The concept of the adenoma-carcinoma sequence in colorectal cancer (CRC) is widely accepted. However, the relationship between the characteristics of the transcriptome and the adenoma-carcinoma sequence in CRC remains unclear. Here, the transcriptome profiles of 15 tissue samples from five CRC patients were generated by RNAseq. Six specific dynamic expression patterns of differentially expressed genes (DEGs) were generated by mFuzz. Weighted correlation network analysis showed that DEGs in cluster 4 were associated with carcinoma tissues, and those in cluster 6 were associated with non-normal tissues. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses identified metabolic dysregulation as a consistent finding throughout the transition process, whereas downregulation of the immune response occurred during normal to adenoma transition, and the upregulation of canonical pathways was associated with adenoma to carcinoma transition. Overall survival analysis of patients in cluster 6 identified TPD52L1 as a marker of poor prognosis, and cell proliferation, colony formation, wound healing, and Transwell invasion assays showed that high expression levels of TPD52L1 promoted malignant behaviors. In total, 70 proteins were identified as potential partners of hD53 by mass spectrometry. CRC formation was associated with three cancer hallmarks: dysregulation of metabolism, inactivation of the immune response, and activation of canonical cancer pathways. The TPD52L1 gene was identified as a potential marker to track tumor formation in CRC and as an indicator of poor patient prognosis.
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Affiliation(s)
- Qin Hong
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Bing Li
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiumei Cai
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Zhengtao Lv
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shilun Cai
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yunshi Zhong
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Bo Wen
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.,Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
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36
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Kim MS, Ha SE, Wu M, Zogg H, Ronkon CF, Lee MY, Ro S. Extracellular Matrix Biomarkers in Colorectal Cancer. Int J Mol Sci 2021; 22:9185. [PMID: 34502094 PMCID: PMC8430714 DOI: 10.3390/ijms22179185] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/12/2021] [Accepted: 08/18/2021] [Indexed: 12/12/2022] Open
Abstract
The cellular microenvironment composition and changes therein play an extremely important role in cancer development. Changes in the extracellular matrix (ECM), which constitutes a majority of the tumor stroma, significantly contribute to the development of the tumor microenvironment. These alterations within the ECM and formation of the tumor microenvironment ultimately lead to tumor development, invasion, and metastasis. The ECM is composed of various molecules such as collagen, elastin, laminin, fibronectin, and the MMPs that cleave these protein fibers and play a central role in tissue remodeling. When healthy cells undergo an insult like DNA damage and become cancerous, if the ECM does not support these neoplastic cells, further development, invasion, and metastasis fail to occur. Therefore, ECM-related cancer research is indispensable, and ECM components can be useful biomarkers as well as therapeutic targets. Colorectal cancer specifically, is also affected by the ECM and many studies have been conducted to unravel the complex association between the two. Here we summarize the importance of several ECM components in colorectal cancer as well as their potential roles as biomarkers.
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Affiliation(s)
- Min-Seob Kim
- Department of Physiology, Digestive Disease Research Institute and Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan 54538, Korea; (M.-S.K.); (M.W.)
| | - Se-Eun Ha
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV 89557, USA; (S.-E.H.); (H.Z.); (C.F.R.)
| | - Moxin Wu
- Department of Physiology, Digestive Disease Research Institute and Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan 54538, Korea; (M.-S.K.); (M.W.)
- Department of Medical Laboratory, Affiliated Hospital of Jiujiang University, Jiujiang 332000, China
| | - Hannah Zogg
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV 89557, USA; (S.-E.H.); (H.Z.); (C.F.R.)
| | - Charles F. Ronkon
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV 89557, USA; (S.-E.H.); (H.Z.); (C.F.R.)
| | - Moon-Young Lee
- Department of Physiology, Digestive Disease Research Institute and Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, Iksan 54538, Korea; (M.-S.K.); (M.W.)
| | - Seungil Ro
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV 89557, USA; (S.-E.H.); (H.Z.); (C.F.R.)
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Abstract
Objective Glioblastoma (GB) is a refractory malignancy with a high rate of recurrence and treatment resistance. Hypoxia-related genes are promising prognostic indicators for GB, so we herein developed a reliable hypoxia-related gene risk scoring model to predict the prognosis of patients with GB. Method Gene expression profiles and corresponding clinicopathological features of patients with GB were obtained from the Cancer Genome Atlas (TCGA; n = 160) and Gene Expression Omnibus (GEO) GSE7696 (n = 80) databases. Univariate and multivariate Cox regression analyses of differentially expressed hypoxia-related genes were performed using R 3.5.1 software. Result Fourteen prognosis-related genes were identified and used to construct a risk signature. Patients with high-risk scores had significantly lower overall survival (OS) than those with low-risk scores. The median risk score was used as a critical value and for OS prediction in an independent external verification GSE7696 cohort. Risk score was not significantly affected by clinical-related factors. We also developed a prediction nomogram based on the TCGA training set to predict survival rates, and included six independent prognostic parameters in the TCGA prediction model. Conclusion We determined a reliable hypoxia-related gene risk scoring model for predicting the prognosis of patients with GB.
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Affiliation(s)
- Chao-Qun Lin
- School of Medicine, Southeast University, Nanjing, Jiangsu, China
| | - Lu-Kui Chen
- School of Medicine, Southeast University, Nanjing, Jiangsu, China.,Department of Neurosurgery, Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China
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38
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Alabi A, Xia XD, Gu HM, Wang F, Deng SJ, Yang N, Adijiang A, Douglas DN, Kneteman NM, Xue Y, Chen L, Qin S, Wang G, Zhang DW. Membrane type 1 matrix metalloproteinase promotes LDL receptor shedding and accelerates the development of atherosclerosis. Nat Commun 2021; 12:1889. [PMID: 33767172 PMCID: PMC7994674 DOI: 10.1038/s41467-021-22167-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 03/02/2021] [Indexed: 01/07/2023] Open
Abstract
Plasma low-density lipoprotein (LDL) is primarily cleared by LDL receptor (LDLR). LDLR can be proteolytically cleaved to release its soluble ectodomain (sLDLR) into extracellular milieu. However, the proteinase responsible for LDLR cleavage is unknown. Here we report that membrane type 1-matrix metalloproteinase (MT1-MMP) co-immunoprecipitates and co-localizes with LDLR and promotes LDLR cleavage. Plasma sLDLR and cholesterol levels are reduced while hepatic LDLR is increased in mice lacking hepatic MT1-MMP. Opposite effects are observed when MT1-MMP is overexpressed. MT1-MMP overexpression significantly increases atherosclerotic lesions, while MT1-MMP knockdown significantly reduces cholesteryl ester accumulation in the aortas of apolipoprotein E (apoE) knockout mice. Furthermore, sLDLR is associated with apoB and apoE-containing lipoproteins in mouse and human plasma. Plasma levels of sLDLR are significantly increased in subjects with high plasma LDL cholesterol levels. Thus, we demonstrate that MT1-MMP promotes ectodomain shedding of hepatic LDLR, thereby regulating plasma cholesterol levels and the development of atherosclerosis.
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Affiliation(s)
- Adekunle Alabi
- The Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Xiao-Dan Xia
- The Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.,Department of Orthopedics, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Hong-Mei Gu
- The Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Faqi Wang
- The Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Shi-Jun Deng
- The Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Nana Yang
- Experimental Center for Medical Research, Weifang Medical University, Weifang, China
| | - Ayinuer Adijiang
- The Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Donna N Douglas
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Norman M Kneteman
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Yazhuo Xue
- Institute of Atherosclerosis in Shandong First Medical University (Shandong Academy of Medical Sciences), Taian, China
| | - Li Chen
- Institute of Atherosclerosis in Shandong First Medical University (Shandong Academy of Medical Sciences), Taian, China
| | - Shucun Qin
- Institute of Atherosclerosis in Shandong First Medical University (Shandong Academy of Medical Sciences), Taian, China
| | - Guiqing Wang
- Department of Orthopedics, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Da-Wei Zhang
- The Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
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J V, Mishra D, Meher D, Dash S, Besra K, Pattnaik N, Singh SP, Dixit M. Genetic association of MMP14 promoter variants and their functional significance in gallbladder cancer pathogenesis. J Hum Genet 2021; 66:947-956. [PMID: 33727629 DOI: 10.1038/s10038-021-00917-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 02/26/2021] [Accepted: 03/01/2021] [Indexed: 12/30/2022]
Abstract
Gallbladder cancer (GBC) is relatively rare but shows high frequency in certain geographical regions and ethnic groups, which include Northern and Eastern states of India. Previous studies in India have indicated the possible role of genetic predisposition in GBC pathogenesis. Although matrix metalloproteinase-14 (MMP14) is known modulator of tumour microenvironment and tumorigenesis and TCGA data also suggests its upregulation yet, its role in genetic predisposition for GBC is completely unknown. We explored MMP14 promoter genetic variants as risk factors and their implication in expression modulation and the pathogenesis of GBC. We genotyped all single nucleotide polymorphisms of MMP14 promoter by Sanger's sequencing in approximately 300 GBC and 300 control study subjects of Indian ethnicity and, in 26 GBC tissue samples. Protein expression of MMP14 in GBC tissue samples was checked by immunohistochemistry. In vitro luciferase reporter assay was carried out to elucidate role of promoter genetic variants on expression levels in two different cell lines. MMP14 promoter variants, rs1003349 (p value = 0.0008) and rs1004030 (p value = 0.0001) were significantly associated with GBC. Luciferase reporter assay showed high expression for risk alleles of both the SNPs. Genotype-phenotype correlation for rs1003349 and rs1004030, in patient sample, confirmed that risk allele carriers had higher expression levels of MMP14; moreover, the correlation pattern matched with genetic association models. Overall, this study unravels the association of MMP14 promoter SNPs with GBC which contribute to pathogenesis by increasing its expression.
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Affiliation(s)
- Vinay J
- National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India.,Homi Bhabha National Institute, Mumbai, India
| | - Debakanta Mishra
- Department of Gastroenterology, Sriram Chandra Bhanja Medical College & Hospital, Cuttack, Odisha, India
| | - Dinesh Meher
- Department of Gastroenterology, Sriram Chandra Bhanja Medical College & Hospital, Cuttack, Odisha, India
| | - Sashibhusan Dash
- Department of Pathology, Acharya Harihar Post Graduate Institute of Cancer, Cuttack, Odisha, India
| | - Kusumbati Besra
- Department of Pathology, Acharya Harihar Post Graduate Institute of Cancer, Cuttack, Odisha, India
| | | | - Shivaram Prasad Singh
- Department of Gastroenterology, Sriram Chandra Bhanja Medical College & Hospital, Cuttack, Odisha, India
| | - Manjusha Dixit
- National Institute of Science Education and Research, School of Biological Sciences, Bhubaneswar, Odisha, India. .,Homi Bhabha National Institute, Mumbai, India.
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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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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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miR-4319 inhibited retinoblastoma cells proliferation, migration, invasion and EMT progress via suppressing CD147 mediated MMPs expression. J Mol Histol 2021; 52:269-277. [PMID: 33474692 DOI: 10.1007/s10735-020-09946-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 12/07/2020] [Indexed: 01/15/2023]
Abstract
Tumor migration is the critical step that lead to the migration in retinoblastoma (RB), in which microRNAs (miRNAs) play important roles. This study aimed to investigate the role of microRNA-4319 (miR-4319) in the development of retinoblastoma by identifying its targets, as well as its underlying regulatory mechanisms. Our data shown that miR-4319 was downregulated in RB tissues and RB cell lines. Enhanced miR-4319 suppressed cell proliferation, migration, invasion and EMT progress, promoted cell apoptosis in SO-RB50 and RB-Y79 cells. Of note, extracellular matrix metalloproteinase inducer (EMMPRI/CD147) was identified as a direct target gene for miR-4319. MMPs were regulated by CD147 and participated in the miR-4319 regulatory network in SO-RB50 cells. In addition, overexpression of CD147 abrogated the inhibitory effect of miR-4319 on RB cells. In summary, miR-4319 overexpression suppressed cell proliferation, migration and invasion may through suppressing the CD147 mediated MMPs expression, suggesting that miR-4319 may serve as a potential diagnostic biomarker and treatment target for RB.
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Hermawan A, Putri H. Integrative Bioinformatics Analysis Reveals Potential Target Genes and TNFα Signaling Inhibition by Brazilin in Metastatic Breast Cancer Cells. Asian Pac J Cancer Prev 2020; 21:2751-2762. [PMID: 32986377 PMCID: PMC7779440 DOI: 10.31557/apjcp.2020.21.9.2751] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Indexed: 01/06/2023] Open
Abstract
OBJECTIVE Metastasis is the most significant cause of morbidity and mortality in breast cancer patients. Previously, a combination of brazilin and doxorubicin has been shown to inhibit metastasis in HER2-positive breast cancer cells. This present study used an integrative bioinformatics approach to identify new targets and the molecular mechanism of brazilin in inhibiting metastasis in breast cancer. METHODS Cytotoxicity and mRNA arrays data were retreived from the DTP website, whereas genes that regulate metastatic breast cancer cells were retreived from PubMed with keywords "breast cancer metastasis". Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and Drug association analysis were carried out by using WEB-based GEne SeT AnaLysis Toolkit (WebGestalt). Construction of protein-protein interaction (PPI) network analysis was performed by STRING-DB v11.0 and Cytoscape, respectively. The genetic alterations of the potential therapeutic target genes of brazilin (PB) were analyzed using cBioPortal. RESULTS Analysis of cytotoxicity with the public database of COMPARE showed that brazilin exerts almost the same cytotoxicity in the NCI-60 cells panel showing by similar GI50 value, in which the lowest GI50 value was observed in MDA-MB 231, a metastatic breast cancer cells. KEGG enrichment indicated several pathways regulated by brazilin such as TNF signaling pathway, cellular senescence, and pathways in cancer. We found ten drugs that are associated with PB, including protein kinase inhibitors, TNFα inhibitors, enzyme inhibitors, and anti-inflammatory agents. CONCLUSION In conclusion, this study identified eight PB, including MMP14, PTGS2, ADAM17, PTEN, CCL2, PIK3CB, MAP3K8, and CXCL3. In addition, brazilin possibly inhibits metastatic breast cancer through inhibition of TNFα signaling. The study results study need to be validated with in vitro and in vivo studies to strengthen scientific evidence of the use of brazilin in breast cancer metastasis inhibition.
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Affiliation(s)
- Adam Hermawan
- Laboratory of Macromolecular Engineering, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, 55281 Yogyakarta, Indonesia
| | - Herwandhani Putri
- Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, 55281 Yogyakarta, Indonesia
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Roles of Proteoglycans and Glycosaminoglycans in Cancer Development and Progression. Int J Mol Sci 2020; 21:ijms21175983. [PMID: 32825245 PMCID: PMC7504257 DOI: 10.3390/ijms21175983] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 08/18/2020] [Accepted: 08/18/2020] [Indexed: 12/11/2022] Open
Abstract
The extracellular matrix (ECM) spatiotemporally controls cell fate; however, dysregulation of ECM remodeling can lead to tumorigenesis and cancer development by providing favorable conditions for tumor cells. Proteoglycans (PGs) and glycosaminoglycans (GAGs) are the major macromolecules composing ECM. They influence both cell behavior and matrix properties through direct and indirect interactions with various cytokines, growth factors, cell surface receptors, adhesion molecules, enzymes, and glycoproteins within the ECM. The classical features of PGs/GAGs play well-known roles in cancer angiogenesis, proliferation, invasion, and metastasis. Several lines of evidence suggest that PGs/GAGs critically affect broader aspects in cancer initiation and the progression process, including regulation of cell metabolism, serving as a sensor of ECM's mechanical properties, affecting immune supervision, and participating in therapeutic resistance to various forms of treatment. These functions may be implemented through the characteristics of PGs/GAGs as molecular bridges linking ECM and cells in cell-specific and context-specific manners within the tumor microenvironment (TME). In this review, we intend to present a comprehensive illustration of the ways in which PGs/GAGs participate in and regulate several aspects of tumorigenesis; we put forward a perspective regarding their effects as biomarkers or targets for diagnoses and therapeutic interventions.
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Li S, Huang J, Qin M, Zhang J, Liao C. High expression of CDCA7 predicts tumor progression and poor prognosis in human colorectal cancer. Mol Med Rep 2020; 22:57-66. [PMID: 32319649 PMCID: PMC7248471 DOI: 10.3892/mmr.2020.11089] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Accepted: 02/07/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most fatal types of cancer worldwide. This study aimed to determine the predictive and prognostic values of cell division cycle associated protein 7 (CDCA7) in CRC. Firstly, the relationship between CDCA7 and CRC was assessed through bioinformatics analysis. Subsequently, CDCA7 expression levels were detected in various CRC cell lines, as well as 15 fresh human CRC tissues and their paired adjacent normal colorectal tissues using reverse transcription‑quantitative PCR and western blotting. Additionally, immunohistochemical staining was used to determine the levels of CDCA7 in 104 CRC tissues and their paired adjacent normal colorectal tissues. The present study revealed that CDCA7 expression was upregulated in CRC tissues and cell lines. The positive expression rates of CDCA7 in normal and CRC tissues were 26.92 and 75.96%, respectively. The intensities of CDCA7 immunostaining were significantly associated with CRC invasion depth, lymph node metastasis, tumor‑node‑metastasis stage and distant metastasis. However, no significant differences in sex, age, tumor size and CRC differentiation were found between high and low CDCA7 expression groups. Furthermore, patients with low CDCA7 expression exhibited a greater overall survival rate of CRC compared to those with high CDCA7 expression. The findings of this study indicated that CDCA7 may serve a significant role in CRC prognosis and progression, and may be considered a novel biomarker for the prediction of patient survival after colectomy.
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Affiliation(s)
- Siman Li
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Jiean Huang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, P.R. China
| | - Mengbin Qin
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, P.R. China
| | - Jinxiu Zhang
- Department of Gastroenterology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, P.R. China
| | - Cun Liao
- Department of Colorectal-Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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Andrieu C, Montigny A, Bibonne A, Despin-Guitard E, Alfandari D, Théveneau E. MMP14 is required for delamination of chick neural crest cells independently of its catalytic activity. Development 2020; 147:dev.183954. [PMID: 32280063 DOI: 10.1242/dev.183954] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 02/24/2020] [Indexed: 12/13/2022]
Abstract
Matrix metalloproteinases have a broad spectrum of substrates ranging from extracellular matrix components and adhesion molecules to chemokines and growth factors. Despite being mostly secreted, MMPs have been detected in the cytosol, the mitochondria or the nucleus. Although most of the attention is focused on their role in matrix remodeling, the diversity of their substrates and their complex trafficking open the possibility for non-canonical functions. Yet in vivo examples and experimental demonstration of the physiological relevance of such activities are rare. Here, we have used chick neural crest (NC) cells, a highly migratory stem cell population likened to invasive cancer cells, as a model for physiological epithelial-mesenchymal transition (EMT). We demonstrate that MMP14 is required for NC delamination. Interestingly, this role is independent of its cytoplasmic tail and of its catalytic activity. Our in vivo data indicate that, in addition to being a late pro-invasive factor, MMP14 is also likely to be an early player, owing to its role in EMT.
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Affiliation(s)
- Cyril Andrieu
- Centre de Biologie du Développement, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, 31062, France
| | - Audrey Montigny
- Centre de Biologie du Développement, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, 31062, France
| | - Anne Bibonne
- Centre de Biologie du Développement, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, 31062, France
| | - Evangeline Despin-Guitard
- Centre de Biologie du Développement, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, 31062, France
| | - Dominique Alfandari
- Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003, USA
| | - Eric Théveneau
- Centre de Biologie du Développement, Centre de Biologie Intégrative, Université de Toulouse, CNRS, UPS, Toulouse, 31062, France
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Lu J, Xu Y, Wang YH, Huang XY, Wu Y, Xie JW, Wang JB, Lin JX, Li P, Zheng CH, Huang AM, Huang CM. TBX2 Expression predicts Tumor Recurrence and Adjuvant Chemotherapy Benefits in Gastric Cancer Patients following R0 Resection: a proposed approach for risk stratification. J Cancer 2020; 11:3172-3179. [PMID: 32231721 PMCID: PMC7097955 DOI: 10.7150/jca.34929] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Accepted: 09/22/2019] [Indexed: 11/29/2022] Open
Abstract
Aims: TBX2 is related to tumor progression and drug resistance. However, the roles of TBX2 in gastric cancer (GC) remain unclear. Our study aims at investigating the clinical roles of TBX2 in GC. Methods: The protein expression levels of TBX2 in fresh GC tissue (n=20) were investigated with Western blotting analyses. The correlation between TBX2 expression and its prognostic significance was evaluated by immunohistochemical analyses of 401 patients. The survival benefit of postoperative adjuvant chemotherapy (PAC) for patients was evaluated. Results: The expression of TBX2 was increased in GC tissue compared with adjacent paracancerous tissue (p=0.020). Immunohistochemistry demonstrated that TBX2 expression was significantly associated with lymphovascular invasion (p=0.024) and lymph node metastasis (p=0.044). A high level of TBX2 expression was an independent indicator of unfavorable recurrence-free and overall survival (p=0.002 and p=0.033, respectively). The prognostic model incorporating TBX2 expression exhibited greater predictive accuracy than the primary model. More importantly, the benefit of PAC noted in stage II/III GC patients with low TBX2 expression was superior to high TBX2 expression. Conclusion: TBX2 may be not only a useful prognostic marker for GC but also a predictive biomarker of response to PAC in stage II/III GC patients. The current findings warrant further verification.
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Affiliation(s)
- Jun Lu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Yu Xu
- Department of Pathology, the School of Basic Medical Sciences, Fujian Medical University
- Institute of Oncology of Fujian Medical University, Fuzhou, China
| | - Yao-hui Wang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Xiao-yan Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Yuan Wu
- Department of Pathology, the School of Basic Medical Sciences, Fujian Medical University
- Institute of Oncology of Fujian Medical University, Fuzhou, China
| | - Jian-wei Xie
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Jia-bin Wang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Jian-xian Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Ping Li
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Chao-hui Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Ai-min Huang
- Department of Pathology, the School of Basic Medical Sciences, Fujian Medical University
- Institute of Oncology of Fujian Medical University, Fuzhou, China
| | - Chang-ming Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
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High MMP14 expression is predictive of poor prognosis in resectable hepatocellular carcinoma. Pathology 2020; 52:359-365. [PMID: 32122646 DOI: 10.1016/j.pathol.2020.01.436] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 01/08/2020] [Accepted: 01/20/2020] [Indexed: 12/18/2022]
Abstract
Matrix metalloproteinase 14 (MMP14) has been found to play multiple biological roles in cancers, including hepatocellular carcinoma (HCC). Up to now, its expression, clinicopathological and prognostic implications in HCC have not been comprehensively investigated. In the present study, MMP14 expression was detected, using tissue microarray-based immunohistochemical staining, in paired HCC and adjacent liver (AL) samples from 260 patients who underwent radical hepatectomy. The associations of MMP14 staining H-scores with clinicopathological parameters, overall and disease-free survival were then evaluated. Finally, its expression and prognostic value were confirmed in some online publicly available databases. It was shown that MMP14 expression was significantly higher in HCC than in AL tissues (p=0.035). Furthermore, MMP14 expression correlated positively with tumour size, Edmondson-Steiner grade and α-fetoprotein level (p<0.05). For survival, MMP14 expression was negatively associated with both overall and disease-free survival in univariate analyses (p<0.05), while it remained statistically significant for disease-free survival by multivariate Cox regression test. In the Ualcan and Kaplan-Meier Plotter databases, MMP14 was also revealed to be overexpressed and prognostic. Taken together, our study indicated that high MMP14 expression was predictive for unfavourable biological behaviours and long-term prognosis in resectable HCC.
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Duan F, Peng Z, Yin J, Yang Z, Shang J. Expression of MMP-14 and prognosis in digestive system carcinoma: a meta-analysis and databases validation. J Cancer 2020; 11:1141-1150. [PMID: 31956360 PMCID: PMC6959085 DOI: 10.7150/jca.36469] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 11/20/2019] [Indexed: 12/24/2022] Open
Abstract
Background: The Matrix metalloproteinase-14 (MMP-14) expression has been shown to be overexpressed in different cancers. However, there is no comprehensive quantitative evaluation of the MMP-14 prognostic value in digestive system carcinoma (DSC). The aim of this study is to explore the correlation between the MMP-14 expression and DSC prognosis. Methods: We conducted a meta-analysis to estimate the association strength between MMP-14 expression and prognosis. GEPIA and Kaplan Meier plotters were used to assess overall survival (OS), disease-free survival (DFS)/progression-free survival (PFS) in DSC patients and the differential expression of MMP-14 in DSC tissues and adjacent tissues. Results: A total of 20 studies including 2,519 patients with OS and 438 patients with DFS/PFS data were analyzed in evidence synthesis. Overall, the combined hazard ratio (HR) with 95% confidence interval (95% CI) was 1.98 (95%Cl: 1.77-2.22, P<0.001) for OS and 3.61 (95%Cl: 2.39-5.43, P<0.001) for DFS/PFS. For subgroup analyses, significant correlations were revealed between increased MMP-14 expression and poor OS in patients with gastric cancer (HR=2.21, 95%CI: 1.76-2.77, P<0.001), esophageal carcinoma (HR=2.01, 95%CI: 1.58-2.57, P<0.001), oral cancer (HR = 1.69, 95% CI: 1.30-2.20, P < 0.001) (HR=2.14, 95%CI 1.35-2.19, P<0.001) and hepatocarcinoma. In database verification analyses, the MMP-14 expression levels in normal tissues were significantly higher than that in DSC tissues, and significant associations were observed between high MMP-14 expression levels and poor prognosis. Conclusions: The high expression levels of MMP-14 might predict poor prognosis in DSC. Larger prospective clinical cohort studies are required to validate the prognostic role.
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Affiliation(s)
- Fujiao Duan
- Medical Research Office, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China.,College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China
| | - Zhen Peng
- Department of Infectious Disease, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China
| | - Jingjing Yin
- College of Public Health, Zhengzhou University, Zhengzhou, Henan Province, China
| | - Zhongyu Yang
- College of Art and Science, The Ohio State University, Columbus, Ohio, US
| | - Jia Shang
- Department of Infectious Disease, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China
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50
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Wang X, Yu Q, Ghareeb WM, Zhang Y, Lu X, Huang Y, Huang S, Sun Y, Lin J, Liu J, Chi P. Downregulated SPINK4 is associated with poor survival in colorectal cancer. BMC Cancer 2019; 19:1258. [PMID: 31888570 PMCID: PMC6938003 DOI: 10.1186/s12885-019-6484-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 12/18/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND SPINK4 is known as a gastrointestinal peptide in the gastrointestinal tract and is abundantly expressed in human goblet cells. The clinical significance of SPINK4 in colorectal cancer (CRC) is largely unknown. METHODS We retrieved the expression data of 1168 CRC patients from 3 Gene Expression Omnibus (GEO) datasets (GSE24551, GSE39582, GSE32323) and The Cancer Genome Atlas (TCGA) to compare the expression level of SPINK4 between CRC tissues and normal colorectal tissues and to evaluate its value in predicting the survival of CRC patients. At the protein level, these results were further confirmed by data mining in the Human Protein Atlas and by immunohistochemical staining of samples from 81 CRC cases in our own center. RESULTS SPINK4 expression was downregulated in CRC compared with that in normal tissues, and decreased SPINK4 expression at both the mRNA and protein levels was associated with poor prognosis in CRC patients from all 3 GEO datasets, the TCGA database and our cohort. Additionally, lower SPINK4 expression was significantly related to higher TNM stage. Moreover, in multivariate regression, SPINK4 was confirmed as an independent indicator of poor survival in CRC patients in all databases and in our own cohort. CONCLUSIONS We concluded that reduced expression of SPINK4 relates to poor survival in CRC, functioning as a novel indicator.
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Affiliation(s)
- Xiaojie Wang
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, 29 Xin-Quan Road, Fuzhou, Fujian, 350001, People's Republic of China
| | - Qian Yu
- Department of Pathology, Union Hospital, Fujian Medical University, Fuzhou, People's Republic of China
| | - Waleed M Ghareeb
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, 29 Xin-Quan Road, Fuzhou, Fujian, 350001, People's Republic of China
- Department of General and Gastrointestinal Surgery, Suez Canal University, Suez, Egypt
| | - Yiyi Zhang
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, 29 Xin-Quan Road, Fuzhou, Fujian, 350001, People's Republic of China
| | - Xingrong Lu
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, 29 Xin-Quan Road, Fuzhou, Fujian, 350001, People's Republic of China
| | - Ying Huang
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, 29 Xin-Quan Road, Fuzhou, Fujian, 350001, People's Republic of China
| | - Shenghui Huang
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, 29 Xin-Quan Road, Fuzhou, Fujian, 350001, People's Republic of China
| | - Yanwu Sun
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, 29 Xin-Quan Road, Fuzhou, Fujian, 350001, People's Republic of China
| | - Jiayi Lin
- Clinical Laboratory, Union Hospital, Fujian Medical University, Fuzhou, People's Republic of China
| | - Jin Liu
- Clinical Laboratory, Union Hospital, Fujian Medical University, Fuzhou, People's Republic of China
| | - Pan Chi
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, 29 Xin-Quan Road, Fuzhou, Fujian, 350001, People's Republic of China.
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