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Mi Y, Jiang P, Luan J, Feng L, Zhang D, Gao X. Peptide‑based therapeutic strategies for glioma: Current state and prospects. Peptides 2025; 185:171354. [PMID: 39922284 DOI: 10.1016/j.peptides.2025.171354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 01/21/2025] [Accepted: 02/03/2025] [Indexed: 02/10/2025]
Abstract
Glioma is a prevalent form of primary malignant central nervous system tumor, characterized by its cellular invasiveness, rapid growth, and the presence of the blood-brain barrier (BBB)/blood-brain tumor barrier (BBTB). Current therapeutic approaches, such as chemotherapy and radiotherapy, have shown limited efficacy in achieving significant antitumor effects. Therefore, there is an urgent demand for new treatments. Therapeutic peptides represent an innovative class of pharmaceutical agents with lower immunogenicity and toxicity. They are easily modifiable via chemical means and possess deep tissue penetration capabilities which reduce side effects and drug resistance. These unique pharmacokinetic characteristics make peptides a rapidly growing class of new therapeutics that have demonstrated significant progress in glioma treatment. This review outlines the efforts and accomplishments in peptide-based therapeutic strategies for glioma. These therapeutic peptides can be classified into four types based on their anti-tumor function: tumor-homing peptides, inhibitor/antagonist peptides targeting cell surface receptors, interference peptides, and peptide vaccines. Furthermore, we briefly summarize the results from clinical trials of therapeutic peptides in glioma, which shows that peptide-based therapeutic strategies exhibit great potential as multifunctional players in glioma therapy.
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Affiliation(s)
- Yajing Mi
- Institute of Basic Medical Sciences, School of Basic Medical Science, Xi'an Medical University, Xi'an, China; Shaanxi Key Laboratory of Brain Disorders, School of Basic Medical Science, Xi'an Medical University, Xi'an, China
| | - Pengtao Jiang
- Institute of Basic Medical Sciences, School of Basic Medical Science, Xi'an Medical University, Xi'an, China
| | - Jing Luan
- Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi, China
| | - Lin Feng
- Institute of Basic Medical Sciences, School of Basic Medical Science, Xi'an Medical University, Xi'an, China
| | - Dian Zhang
- Institute of Basic Medical Sciences, School of Basic Medical Science, Xi'an Medical University, Xi'an, China
| | - Xingchun Gao
- Institute of Basic Medical Sciences, School of Basic Medical Science, Xi'an Medical University, Xi'an, China; Shaanxi Key Laboratory of Brain Disorders, School of Basic Medical Science, Xi'an Medical University, Xi'an, China.
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Vaziri-Moghadam A, Foroughmand-Araabi MH. Integrating machine learning and bioinformatics approaches for identifying novel diagnostic gene biomarkers in colorectal cancer. Sci Rep 2024; 14:24786. [PMID: 39433800 PMCID: PMC11494190 DOI: 10.1038/s41598-024-75438-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 10/04/2024] [Indexed: 10/23/2024] Open
Abstract
This study aimed to identify diagnostic gene biomarkers for colorectal cancer (CRC) by analyzing differentially expressed genes (DEGs) in tumor and adjacent normal samples across five colon cancer gene-expression profiles (GSE10950, GSE25070, GSE41328, GSE74602, GSE142279) from the Gene Expression Omnibus (GEO) database. Intersecting identified DEGs with the module with the highest correlation to gene expression patterns of tumor samples in the gene co-expression network analysis revealed 283 overlapped genes. Centrality measures were calculated for these genes in the reconstructed STRING protein-protein interaction network. Applying LASSO logistic regression, eleven genes were ultimately recognized as candidate diagnostic genes. Among these genes, the area under the receiver operating characteristic curve (AUROC) values for nine genes (CDC25B, CDK4, IQGAP3, MMP1, MMP7, SLC7A5, TEAD4, TRIB3, and UHRF1) surpassed the threshold of 0.92 in both the training and validation sets. We evaluated the diagnostic performance of these genes with four machine learning algorithms: random forest (RF), support vector machines (SVM), artificial neural network (ANN), and gradient boosting machine (GBM). In the testing dataset (GSE21815 and GSE106582), the AUROC scores were greater than 0.95 for all of the machine learning algorithms, indicating the high diagnostic performance of the nine genes. Besides, these nine genes are also significantly correlated to twelve immune cells, namely Mast cells activated, Macrophages M0, M1, and M2, Neutrophils, T cells CD4 memory activated, T cells follicular helper, T cells CD8, T cells CD4 memory resting, B cells memory, Plasma cells, and Mast cells resting (P < 0.05). These results strongly suggest that all of the nine genes have the potential to serve as reliable diagnostic biomarkers for CRC.
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Zhou Y, Tao L, Qiu J, Xu J, Yang X, Zhang Y, Tian X, Guan X, Cen X, Zhao Y. Tumor biomarkers for diagnosis, prognosis and targeted therapy. Signal Transduct Target Ther 2024; 9:132. [PMID: 38763973 PMCID: PMC11102923 DOI: 10.1038/s41392-024-01823-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 03/07/2024] [Accepted: 04/02/2024] [Indexed: 05/21/2024] Open
Abstract
Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.
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Affiliation(s)
- Yue Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lei Tao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiahao Qiu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Xu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinyu Yang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Yu Zhang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
- School of Medicine, Tibet University, Lhasa, 850000, China
| | - Xinyu Tian
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinqi Guan
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaobo Cen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yinglan Zhao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Ando W, Sogabe M, Ishikawa S, Uematsu T, Furuya H, Yokomori H, Kohgo Y, Otori K, Nakano T, Endo S, Tsubochi H, Okazaki I. Matrix metalloproteinase‑1 and microRNA‑486‑5p in urinary exosomes can be used to detect early lung cancer: A preliminary report. Oncol Lett 2024; 27:127. [PMID: 38333640 PMCID: PMC10851336 DOI: 10.3892/ol.2024.14261] [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: 03/01/2023] [Accepted: 12/21/2023] [Indexed: 02/10/2024] Open
Abstract
The present study describes a novel molecular-genetic method suitable for lung cancer (LC) screening in the work-place and at community health centers. Using urinary-isolated exosomes from 35 patients with LC and 40 healthy volunteers, the expression ratio of MMP-1/CD63, and the relative expression levels of both microRNA (miRNA)-21 and miRNA-486-5p were measured. MMP-1/CD63 expression ratio was significantly higher in patients with LC than in the healthy controls {1.342 [95% confidence interval (CI): 0.890-1.974] vs. 0.600 (0.490-0.900); P<0.0001}. The relative expression of miRNA-486-5p in male healthy controls was significantly different from that in female healthy controls, whereas there was no significant difference in miRNA-21. Receiver operating characteristic curve (ROC) analysis of MMP-1/CD63 showed 92.5% sensitivity and 54.3% specificity, whereas miRNA-486-5p showed 85% sensitivity and 70.8% specificity for men, and 70.0% sensitivity and 72.7% specificity for women. The logistic regression model used to evaluate the association of LC with the combination of MMP-1/CD63 and miRNA-486-5p revealed that the area under the ROC curve was 0.954 (95% CI: 0.908-1.000), and the model had 89% sensitivity and 88% specificity after adjusting for age, sex and smoking status. These data suggested that the combined analysis of MMP-1/CD63 and miRNA-486-5p in urinary exosomes may be used to detect patients with early-stage LC in the work-place and at community health centers, although confirmational studies are warranted.
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Affiliation(s)
- Wataru Ando
- Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, Kitasato University School of Pharmacy, Tokyo 108-8641, Japan
| | - Masaya Sogabe
- Department of General Thoracic Surgery, Jichi Medical University Saitama Medical Center, Saitama 330-0834, Japan
- Center for Respiratory Diseases, International University of Health and Welfare Hospital, Nasu-Shiobara, Tochigi 329-2763, Japan
- Department of Chest Surgery, International University of Health and Welfare Hospital, Nasu-Shiobara, Tochigi 329-2763, Japan
| | - Shigemi Ishikawa
- Center for Respiratory Diseases, International University of Health and Welfare Hospital, Nasu-Shiobara, Tochigi 329-2763, Japan
- Department of Chest Surgery, International University of Health and Welfare Hospital, Nasu-Shiobara, Tochigi 329-2763, Japan
| | - Takayuki Uematsu
- Biomedical Laboratory, Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Saitama 364-8501, Japan
| | - Hiroyuki Furuya
- Basic Clinical Science and Public Health, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan
| | - Hiroaki Yokomori
- Department of Internal Medicine, Kitasato University Medical Center, Kitamoto, Saitama 364-8501, Japan
| | - Yutaka Kohgo
- Department of Internal Medicine, International University of Health and Welfare Hospital, Nasu-Shiobara, Tochigi 329-2763, Japan
- Department of Preventive Medicine, International University of Health and Welfare Hospital, Nasu-Shiobara, Tochigi 329-2763, Japan
| | - Katsuya Otori
- Research and Education Center for Clinical Pharmacy, Division of Clinical Pharmacy, Laboratory of Pharmacy Practice and Science 1, Kitasato University School of Pharmacy, Sagamihara, Kanagawa 252-0375, Japan
| | - Tomoyuki Nakano
- Center for Respiratory Diseases, International University of Health and Welfare Hospital, Nasu-Shiobara, Tochigi 329-2763, Japan
- Department of Chest Surgery, International University of Health and Welfare Hospital, Nasu-Shiobara, Tochigi 329-2763, Japan
| | - Shunsuke Endo
- Department of General Thoracic Surgery, Jichi Medical University Saitama Medical Center, Saitama 330-0834, Japan
| | - Hiroyoshi Tsubochi
- Department of General Thoracic Surgery, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan
| | - Isao Okazaki
- Department of Health and Welfare, Higashi Nippon International University, Iwaki, Fukushima 970-8023, Japan
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Sampaio Moura N, Schledwitz A, Alizadeh M, Patil SA, Raufman JP. Matrix metalloproteinases as biomarkers and therapeutic targets in colitis-associated cancer. Front Oncol 2024; 13:1325095. [PMID: 38288108 PMCID: PMC10824561 DOI: 10.3389/fonc.2023.1325095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 12/26/2023] [Indexed: 01/31/2024] Open
Abstract
Colorectal cancer (CRC) remains a major cause of morbidity and mortality. Therapeutic approaches for advanced CRC are limited and rarely provide long-term benefit. Enzymes comprising the 24-member matrix metalloproteinase (MMP) family of zinc- and calcium-dependent endopeptidases are key players in extracellular matrix degradation, a requirement for colon tumor expansion, invasion, and metastasis; hence, MMPs are an important research focus. Compared to sporadic CRC, less is known regarding the molecular mechanisms and the role of MMPs in the development and progression of colitis-associated cancer (CAC) - CRC on a background of chronic inflammatory bowel disease (IBD) - primarily ulcerative colitis and Crohn's disease. Hence, the potential of MMPs as biomarkers and therapeutic targets for CAC is uncertain. Our goal was to review data regarding the role of MMPs in the development and progression of CAC. We sought to identify promising prognostic and therapeutic opportunities and novel lines of investigation. A key observation is that since MMPs may be more active in early phases of CAC, using MMPs as biomarkers of advancing neoplasia and as potential therapeutic targets for adjuvant therapy in those with advanced stage primary CAC rather than overt metastases may yield more favorable outcomes.
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Affiliation(s)
- Natalia Sampaio Moura
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Alyssa Schledwitz
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Madeline Alizadeh
- The Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Seema A. Patil
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Jean-Pierre Raufman
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, United States
- Medical Service, Veterans Affairs Maryland Healthcare System, Baltimore, MD, United States
- Marlene and Stewart Greenebaum Cancer Center, University of Maryland Medical Center, Baltimore, MD, United States
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, United States
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Tedja R, Alvero AB, Fox A, Cardenas C, Pitruzzello M, Chehade H, Bawa T, Adzibolosu N, Gogoi R, Mor G. Generation of Stable Epithelial-Mesenchymal Hybrid Cancer Cells with Tumorigenic Potential. Cancers (Basel) 2023; 15:cancers15030684. [PMID: 36765641 PMCID: PMC9913490 DOI: 10.3390/cancers15030684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 01/11/2023] [Accepted: 01/16/2023] [Indexed: 01/25/2023] Open
Abstract
PURPOSE Cancer progression, invasiveness, and metastatic potential have been associated with the activation of the cellular development program known as epithelial-to-mesenchymal transition (EMT). This process is known to yield not only mesenchymal cells, but instead an array of cells with different degrees of epithelial and mesenchymal phenotypes with high plasticity, usually referred to as E/M hybrid cells. The characteristics of E/M hybrid cells, their importance in tumor progression, and the key regulators in the tumor microenvironment that support this phenotype are still poorly understood. METHODS In this study, we established an in vitro model of EMT and characterized the different stages of differentiation, allowing us to identify the main genomic signature associated with the E/M hybrid state. RESULTS We report that once the cells enter the E/M hybrid state, they acquire stable anoikis resistance, invasive capacity, and tumorigenic potential. We identified the hepatocyte growth factor (HGF)/c-MET pathway as a major driver that pushes cells in the E/M hybrid state. CONCLUSIONS Herein, we provide a detailed characterization of the signaling pathway(s) promoting and the genes associated with the E/M hybrid state.
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Affiliation(s)
- Roslyn Tedja
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA
- Correspondence: (R.T.); (G.M.)
| | - Ayesha B. Alvero
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA
| | - Alexandra Fox
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA
| | - Carlos Cardenas
- Department of Obstetrics and Gynecology, Family HealthCare Network, Porterville, CA 93257, USA
| | - Mary Pitruzzello
- Department of Dermatology, Yale Medical School, New Haven, CT 06510, USA
| | - Hussein Chehade
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA
| | - Tejeshwhar Bawa
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA
| | - Nicholas Adzibolosu
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA
- Department of Physiology, Wayne State University, Detroit, MI 48201, USA
| | - Radhika Gogoi
- C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA
- Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
| | - Gil Mor
- Department of Obstetrics and Gynecology, Family HealthCare Network, Porterville, CA 93257, USA
- Correspondence: (R.T.); (G.M.)
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Okamura K, Sato M, Suzuki T, Nohara K. Inorganic arsenic exposure-induced premature senescence and senescence-associated secretory phenotype (SASP) in human hepatic stellate cells. Toxicol Appl Pharmacol 2022; 454:116231. [PMID: 36089002 DOI: 10.1016/j.taap.2022.116231] [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: 07/06/2022] [Revised: 08/31/2022] [Accepted: 09/04/2022] [Indexed: 01/10/2023]
Abstract
Exposure to inorganic arsenic has been known to induce cancers in various organs, however, the underlying mechanisms remain unclear. Premature senescence refers to the irreversible growth arrest induced by stress stimuli. The senescence-associated secretory phenotype (SASP), particularly in fibroblasts, has been shown to promote cancer development. In this study, we examined whether arsenite exposure causes premature senescence and induction of SASP in liver fibroblasts using the human hepatic stellate cell line, LX-2. Exposure of LX-2 cells to 5 or 7.5 μM of sodium arsenite for 144 h induced the features of senescence in the cells, including morphological changes, growth inhibition, increased senescence-associated β-galactosidase activity, increased P21 gene expression, and decreased LAMINB1 gene expression. The mRNA expressions of SASP factors, such as MMP1, MMP3, IL-8, IL-1β, and CXCL1, were also highly upregulated. The wound healing assay revealed that the conditioned medium from LX-2 cells with arsenite-induced senescence increased the migration activity of cells of the human hepatoma cell line, Huh-7. Gene expression data of liver cancer samples from the Human Protein Atlas showed that high expression levels of the SASP factors that were upregulated in the cells with arsenite-induced senescence were strongly associated with a poor prognosis. In addition, the cellular levels of γ-H2AX, a DNA double-strand break marker, were increased by arsenite exposure, suggesting that DNA damage could contribute to premature senescence induction. These results show that arsenite exposure induces premature senescence in hepatic stellate cells and suggest that the SASP factors from the senescent cells promote hepatic carcinogenesis.
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Affiliation(s)
- Kazuyuki Okamura
- Health and Environmental Risk Division, National Institute for Environmental Studies, Tsukuba 305-8506, Japan.
| | - Miyuki Sato
- Health and Environmental Risk Division, National Institute for Environmental Studies, Tsukuba 305-8506, Japan
| | - Takehiro Suzuki
- Health and Environmental Risk Division, National Institute for Environmental Studies, Tsukuba 305-8506, Japan
| | - Keiko Nohara
- Health and Environmental Risk Division, National Institute for Environmental Studies, Tsukuba 305-8506, Japan
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Wei X, Zhang B, Pan B. MMP1 Is a Prognostic-Related Biomarker and Correlated with Immune Infiltration in Breast Cancer. Health (London) 2022. [DOI: 10.4236/health.2022.142017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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Ito K, Kitajima Y, Kai K, Matsufuji S, Yamada K, Egawa N, Kitagawa H, Okuyama K, Tanaka T, Noshiro H. Matrix metalloproteinase‑1 expression is regulated by HIF‑1‑dependent and epigenetic mechanisms and serves a tumor‑suppressive role in gastric cancer progression. Int J Oncol 2021; 59:102. [PMID: 34738626 PMCID: PMC8577796 DOI: 10.3892/ijo.2021.5282] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 10/11/2021] [Indexed: 02/05/2023] Open
Abstract
The matrix metalloproteinase (MMP) family is associated with degradation of the extracellular matrix and is known to promote cancer invasion. The present study aimed to investigate the biological role of MMP‑1 in gastric cancer cells and analyze the association between MMP‑1 expression and the clinical outcomes of gastric cancer patients. In the present study, hypoxia accelerated invasion, accompanied by elevated MMP‑1 expression in the gastric cancer cell line 58As9. Additionally, hypoxia‑inducible factor‑1α (HIF‑1α) knockdown in 58As9 cells reduced MMP‑1 expression under hypoxic conditions. Treatment with 5‑aza‑2‑deoxycytidine and trichostatin A restored MMP‑1 expression in the MMP‑1‑deficient cell lines MKN45 and MKN74. These results indicated that MMP‑1 expression was controlled by both HIF‑1α‑dependent and epigenetic mechanisms in gastric cancer cell lines. In addition, MMP‑1 knockdown impaired the hypoxia‑induced invasiveness of 58As9 cells, implicating MMP‑1 in the elevated invasion. By contrast, knockdown enhanced the proliferative ability of 58As9 cells, whereby expression of cell cycle‑related genes was subsequently altered. In nude mouse models, the knockdown accelerated the growth of xenograft tumor and the development of peritoneal dissemination. In an immunohistochemical study using 161 surgically resected cancer tissues, the Ki67 score was significantly higher in the group with low MMP‑1 expression (P<0.001). Disease‑free survival (DFS) and disease‑specific survival (DSS) were both significantly reduced in patients with low MMP‑1 expression (log‑rank test; DFS: P=0.005; DSS: P=0.022). Multivariate analysis demonstrated that MMP‑1 expression was an independent prognostic factor for DFS and DSS [DFS: HR=2.11 (1.22‑3.92) P=0.005, DSS: HR=2.90 (1.23‑8.50) P=0.012]. In conclusion, the present study indicated that MMP‑1 may serve as a tumor‑suppressive factor that inhibits gastric cancer progression, although it promoted invasion in vitro.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Animals
- Apoptosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Cell Proliferation
- Epigenesis, Genetic
- Female
- Gene Expression Regulation, Neoplastic
- Genes, Tumor Suppressor
- Humans
- Hypoxia/physiopathology
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Male
- Matrix Metalloproteinase 1/genetics
- Matrix Metalloproteinase 1/metabolism
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Middle Aged
- Neoplasm Invasiveness
- Prognosis
- Stomach Neoplasms/genetics
- Stomach Neoplasms/pathology
- Survival Rate
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Kotaro Ito
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Yoshihiko Kitajima
- Department of Surgery, National Hospital Organization Higashisaga Hospital, Miyaki, Saga 849-0101, Japan
| | - Keita Kai
- Department of Pathology, Saga University Hospital, Saga 849-8501, Japan
| | - Shohei Matsufuji
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Kohei Yamada
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Noriyuki Egawa
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Hiroshi Kitagawa
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Keiichiro Okuyama
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Tomokazu Tanaka
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
| | - Hirokazu Noshiro
- Department of Surgery, Saga University Faculty of Medicine, Saga 849-8501, Japan
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10
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Si X, Ji G, Ma S, Xu Y, Zhao J, Zhang Y, Huang Z, Tang Z, Song W, Chen X. In-Situ-Sprayed Dual-Functional Immunotherapeutic Gel for Colorectal Cancer Postsurgical Treatment. Adv Healthc Mater 2021; 10:e2100862. [PMID: 34347370 DOI: 10.1002/adhm.202100862] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 07/14/2021] [Indexed: 12/13/2022]
Abstract
Surgery remains the most preferred treatment options for colorectal cancer (CRC). Paradoxically, local recurrence and distant metastasis are usually accelerated postsurgery as a consequence of local and systemic immunosuppression caused by surgery. Therefore, modulating tumor postoperative immune microenvironment and activating systemic antitumor immunity are necessary supplementaries for CRC therapy. Here, an in-situ-sprayed immunotherapeutic gel loaded with anti-OX40 antibody (iSGels@aOX40) is reported for CRC postsurgical treatment. The iSGel is formed instantly after spraying with strong adhesion ability via crosslinking between tannic acid (TA) and poly(l-glutamic acid)-g-methoxy poly(ethylene glycol)/phenyl boronic acid (PLG-g-mPEG/PBA). TA not only serves as one component of the iSGel but also relieves the postsurgical immunosuppressive microenvironment by inhibiting the activity of cyclo-oxygenase-2 (COX-2). The aOX40 serves as an immune agonistic antibody and is released from the iSGel in a constant manner lasting for over 20 days. In a subcutaneous murine CRC model, the iSGels@aOX40 results in complete inhibition on tumor recurrence. In addition, the cured mice show resistance to tumor re-challenge, suggesting that immune memory effects are established after the iSGels@aOX40 treatment. In an orthotopic CRC peritoneal metastatic model, the iSGels@aOX40 also remarkably inhibits the growth of the abdominal metastatic tumors, suggesting great potential for clinical CRC therapy.
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Affiliation(s)
- Xinghui Si
- Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun 130022 China
- Jilin Biomedical Polymers Engineering Laboratory Changchun 130022 China
| | - Guofeng Ji
- Department Gastrointestinal Surgery China–Japan Union Hospital of Jilin University Changchun 130021 China
| | - Sheng Ma
- Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun 130022 China
- Jilin Biomedical Polymers Engineering Laboratory Changchun 130022 China
| | - Yudi Xu
- Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun 130022 China
- University of Chinese Academy of Sciences Beijing 100039 China
| | - Jiayu Zhao
- Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun 130022 China
- University of Science and Technology of China Hefei 230026 China
| | - Yu Zhang
- Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun 130022 China
- Jilin Biomedical Polymers Engineering Laboratory Changchun 130022 China
| | - Zichao Huang
- Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun 130022 China
- University of Science and Technology of China Hefei 230026 China
| | - Zhaohui Tang
- Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun 130022 China
- Jilin Biomedical Polymers Engineering Laboratory Changchun 130022 China
| | - Wantong Song
- Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun 130022 China
- Jilin Biomedical Polymers Engineering Laboratory Changchun 130022 China
| | - Xuesi Chen
- Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun 130022 China
- Jilin Biomedical Polymers Engineering Laboratory Changchun 130022 China
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11
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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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12
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Yu C, You M, Zhang P, Zhang S, Yin Y, Zhang X. A five-gene signature is a prognostic biomarker in pan-cancer and related with immunologically associated extracellular matrix. Cancer Med 2021; 10:4629-4643. [PMID: 34121340 PMCID: PMC8267129 DOI: 10.1002/cam4.3986] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/20/2021] [Accepted: 04/23/2021] [Indexed: 12/20/2022] Open
Abstract
The tumor microenvironment (TME) is related to extracellular matrix (ECM) dynamics and has a broad fundamental and mechanistic role in tumorigenesis and cancer progression. We hypothesized that ECM regulators might play an essential role in pan-cancer attribution by causing a generic effect through its regulation of the dynamics of ECM alteration. By analyzing data from TCGA using GSEA and univariate Cox regression analysis, we found that ECM regulator genes were significantly enriched and contributed to mortality in various cancer types. Notably, UMAP analysis revealed that ECM regulator genes dominated the differences between tumor and adjacent normal tissues based on 59 or 31 pan-survival-related ECM gene sets. Subsequently, a five-gene signature consisting of the predominant ECM regulators ADAM12, MMP1, SERPINE1, PLOD3, and P4HA3 was identified. We found that this five-gene signature was pro-mortality in 18 types of cancer in TCGA, and validated eleven other cancer types in TCGA and seven types in the TARGET and CoMMpass databases using overall survival analysis. KEGG pathway enrichment and Pearson correlation analysis indicated that these five component genes that were correlated with specific ECM proteins involved in tumorigenesis from the ECM receptor interaction gene set. Additionally, the fitted results of a linear model were applied to strengthen the discovery, demonstrating that the five genes were correlated with immune infiltration score and especially associated with typically immunologically "cold" tumors. We thus conclude that the ADAM12, MMP1, SERPINE1, PLOD3, and P4HA3 signature showed a close association with a pan-cancer effect on prognosis and is related to ECM proteins in the TME which corresponding with immunologically "cold" cancer types.
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Affiliation(s)
- Chunlai Yu
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)GuangzhouChina
| | - Mingliang You
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang ProvinceHangzhou Cancer InstituteAffiliated Hangzhou Cancer HospitalZhejiang University School of MedicineHangzhouChina
| | - Peizhen Zhang
- Department of Obstetrics and GynecologyThird Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Sheng Zhang
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)GuangzhouChina
| | - Yuzhu Yin
- Department of Obstetrics and GynecologyThird Affiliated HospitalSun Yat‐Sen UniversityGuangzhouChina
| | - Xiao Zhang
- Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory)GuangzhouChina
- CAS Key Laboratory of Regenerative BiologyJoint School of Life SciencesGuangzhou Institutes of Biomedicine and HealthChinese Academy of Sciencesand Guangzhou Medical UniversityGuangzhouGuangdongChina
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13
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Olig2 regulates p53-mediated apoptosis, migration and invasion of melanoma cells. Sci Rep 2021; 11:7778. [PMID: 33833342 PMCID: PMC8032681 DOI: 10.1038/s41598-021-87438-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 03/19/2021] [Indexed: 11/08/2022] Open
Abstract
Melanoma is a disease with a high recurrence rate and poor prognosis; therefore, the need for targeted therapeutics is steadily increasing. Oligodendrocyte transcription factor2 (Olig2) is a basic helix-loop-helix transcription factor that is expressed in the central nervous system during embryonic development. Olig2 is overexpressed in various malignant cell lines such as lung carcinoma, glioma and melanoma. Olig2 is known as a key transcription factor that promotes tumor growth in malignant glioma. However, the role of Olig2 in melanoma is not well characterized. We analyzed the role of Olig2 in apoptosis, migration, and invasion of melanoma cells. We confirmed that Olig2 was overexpressed in melanoma cells and tissues. Reduction of Olig2 increased apoptosis in melanoma cells by increasing p53 level and caspase-3/-7 enzyme activity. In addition, downregulation of Olig2 suppressed migration and invasion of melanoma cells by inhibiting EMT. Reduction of Olig2 inhibited expression of MMP-1 and the enzyme activity of MMP-2/-9 induced by TGF-β. Moreover, Olig2 was involved in the downstream stages of MEK/ERK and PI3K/AKT, which are major signaling pathways in metastatic progression of melanoma. In conclusion, this study demonstrated the crucial roles of Olig2 in apoptosis, migration, and invasion of melanoma and may help to further our understanding of the relationship between Olig2 and melanoma progression.
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14
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Ali O, Tolaymat M, Hu S, Xie G, Raufman JP. Overcoming Obstacles to Targeting Muscarinic Receptor Signaling in Colorectal Cancer. Int J Mol Sci 2021; 22:ijms22020716. [PMID: 33450835 PMCID: PMC7828259 DOI: 10.3390/ijms22020716] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/08/2021] [Accepted: 01/10/2021] [Indexed: 01/05/2023] Open
Abstract
Despite great advances in our understanding of the pathobiology of colorectal cancer and the genetic and environmental factors that mitigate its onset and progression, a paucity of effective treatments persists. The five-year survival for advanced, stage IV disease remains substantially less than 20%. This review examines a relatively untapped reservoir of potential therapies to target muscarinic receptor expression, activation, and signaling in colorectal cancer. Most colorectal cancers overexpress M3 muscarinic receptors (M3R), and both in vitro and in vivo studies have shown that activating these receptors stimulates cellular programs that result in colon cancer growth, survival, and spread. In vivo studies using mouse models of intestinal neoplasia have shown that using either genetic or pharmacological approaches to block M3R expression and activation, respectively, attenuates the development and progression of colon cancer. Moreover, both in vitro and in vivo studies have shown that blocking the activity of matrix metalloproteinases (MMPs) that are induced selectively by M3R activation, i.e., MMP1 and MMP7, also impedes colon cancer growth and progression. Nonetheless, the widespread expression of muscarinic receptors and MMPs and their importance for many cellular functions raises important concerns about off-target effects and the safety of employing similar strategies in humans. As we highlight in this review, highly selective approaches can overcome these obstacles and permit clinicians to exploit the reliance of colon cancer cells on muscarinic receptors and their downstream signal transduction pathways for therapeutic purposes.
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Affiliation(s)
- Osman Ali
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MA 21201, USA; (O.A.); (M.T.); (S.H.); (G.X.)
| | - Mazen Tolaymat
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MA 21201, USA; (O.A.); (M.T.); (S.H.); (G.X.)
| | - Shien Hu
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MA 21201, USA; (O.A.); (M.T.); (S.H.); (G.X.)
- Veterans Affairs Maryland Healthcare System, Baltimore, MA 21201, USA
| | - Guofeng Xie
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MA 21201, USA; (O.A.); (M.T.); (S.H.); (G.X.)
- Veterans Affairs Maryland Healthcare System, Baltimore, MA 21201, USA
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MA 21201, USA
| | - Jean-Pierre Raufman
- Department of Medicine, Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore, MA 21201, USA; (O.A.); (M.T.); (S.H.); (G.X.)
- Veterans Affairs Maryland Healthcare System, Baltimore, MA 21201, USA
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MA 21201, USA
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MA 21201, USA
- Correspondence: ; Tel.: +1-410-328-8728
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15
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Hozhabri H, Lashkari A, Razavi SM, Mohammadian A. Integration of gene expression data identifies key genes and pathways in colorectal cancer. Med Oncol 2021; 38:7. [PMID: 33411100 DOI: 10.1007/s12032-020-01448-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 11/21/2020] [Indexed: 12/16/2022]
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumor and prevalent cause of cancer-related death worldwide. In this study, we analyzed the gene expression profiles of patients with CRC with the aim of better understanding the molecular mechanism and key genes in CRC. Four gene expression profiles including, GSE9348, GSE41328, GSE41657, and GSE113513 were downloaded from GEO database. The data were processed using R programming language, in which 319 common differentially expressed genes including 94 up-regulated and 225 down-regulated were identified. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were conducted to find the most significant enriched pathways in CRC. Based on the GO and KEGG pathway analysis, the most important dysregulated pathways were regulation of cell proliferation, biocarbonate transport, Wnt, and IL-17 signaling pathways, and nitrogen metabolism. The protein-protein interaction (PPI) network of the DEGs was constructed using Cytoscape software and hub genes including MYC, CXCL1, CD44, MMP1, and CXCL12 were identified as the most critical hub genes. The present study enhances our understanding of the molecular mechanisms of the CRC, which might potentially be applied in the treatment strategies of CRC as molecular targets and diagnostic biomarkers.
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Affiliation(s)
- Hossein Hozhabri
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
| | - Ali Lashkari
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Seyed-Morteza Razavi
- Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran.,Salari Institute of Cognitive and Behavioral Disorders (SICBD), Karaj, Alborz, Iran.,Systems Biology Research Lab, Bioinformatics Group, Systems Biology of Next Generation Company (SBNGC), Qom, Iran
| | - Ali Mohammadian
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
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16
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Berberine inhibited metastasis through miR-145/MMP16 axis in vitro. J Ovarian Res 2021; 14:4. [PMID: 33407764 PMCID: PMC7789793 DOI: 10.1186/s13048-020-00752-2] [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: 02/02/2020] [Accepted: 12/07/2020] [Indexed: 12/11/2022] Open
Abstract
Ovarian cancer is the first leading cause of death in gynecological cancers. The continuous survival and metastasis of cancer cells are the main causes of death and poor prognosis in patients with ovarian cancer. Berberine is an effective component extracted from the rhizomes of coptis chinensis and phellodendron chinensis. In our study, we aim to explore the molecular mechanism underlying the regulation of proliferation, migration and invasion by berberine in ovarian cancer cells. CCK8 assay was used for detection of proliferative capacity of SKOV3 and 3AO cells. Wound healing assay was used to estimate cell migration and transwell assay was used to assess cell invasion. The mRNA expression of miR-145 and MMP16 were examined by quantitative real-time polymerase chain reaction (qRT-PCR). The protein level of MMP16 was detected by western blot analysis. In addition, luciferase reporter assays were used to demonstrate MMP16 was a target of miR-145. The results demonstrated berberine inhibited proliferation, migration and invasion, promoted miR-145 expression, and decreased MMP16 expression in SKOV3 and 3AO cells. MMP16 was a target of miR-145. Moreover, downregulation of MMP16 contributed to the inhibition of proliferation, migration and invasion by berberine. Together, our results revealed that berberine inhibited proliferation, migration and invasion through miR-145/MMP16 in SKOV3 and 3AO cells, highlighting the potentiality of berberine to be used as a therapeutic agent for ovarian cancer.
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17
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Abstract
Through novel methodologies, including both basic and clinical research, progress has been made in the therapy of solid cancer. Recent innovations in anticancer therapies, including immune checkpoint inhibitor biologics, therapeutic vaccines, small drugs, and CAR-T cell injections, mark a new epoch in cancer research, already known for faster (epi-)genomics, transcriptomics, and proteomics. As the long-sought after personalization of cancer therapies comes to fruition, the need to evaluate all current therapeutic possibilities and select the best for each patient is of paramount importance. This is a novel task for medical care that deserves prominence in therapeutic considerations in the future. This is because cancer is a complex genetic disease. In its deadly form, metastatic cancer, it includes altered genes (and their regulators) that encode ten hallmarks of cancer-independent growth, dodging apoptosis, immortalization, multidrug resistance, neovascularization, invasiveness, genome instability, inflammation, deregulation of metabolism, and avoidance of destruction by the immune system. These factors have been known targets for many anticancer drugs and treatments, and their modulation is a therapeutic goal, with the hope of rendering solid cancer a chronic rather than deadly disease. In this article, the current therapeutic arsenal against cancers is reviewed with a focus on immunotherapies.
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Affiliation(s)
- Zlatko Dembic
- Molecular Genetics Laboratory, Department of Oral Biology, Faculty of Dentistry, University of Oslo, 0316 Oslo, Norway
- Molecular Genetics Laboratory, Department of Oral Biology, Faculty of Dentistry, University of Oslo, 0316 Oslo, Norway
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18
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The Role of Tachykinins in the Initiation and Progression of Gastrointestinal Cancers: A Review. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2020. [DOI: 10.5812/ijcm.100717] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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19
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Min MW, Kim CE, Chauhan S, Park HJ, Park CS, Yoo TH, Kang TJ. Identification of peptide inhibitors of matrix metalloproteinase 1 using an in-house assay system for the enzyme. Enzyme Microb Technol 2019; 127:65-69. [DOI: 10.1016/j.enzmictec.2019.04.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 04/08/2019] [Accepted: 04/19/2019] [Indexed: 11/30/2022]
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20
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Bogdanov AA, Solovyev ID, Savitsky AP. Sensors for Proteolytic Activity Visualization and Their Application in Animal Models of Human Diseases. BIOCHEMISTRY (MOSCOW) 2019; 84:S1-S18. [PMID: 31213192 DOI: 10.1134/s0006297919140013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Various sensors designed for optical and photo(opto)acoustic imaging in living systems are becoming essential components of basic and applied biomedical research. Some of them including those developed for determining enzyme activity in vivo are becoming commercially available. These sensors can be used for various fluorescent signal detection methods: from whole body tomography to endoscopy with miniature cameras. Sensor molecules including enzyme-cleavable macromolecules carrying multiple quenched near-infrared fluorophores are able to deliver their payload in vivo and have long circulation time in bloodstream enabling detection of enzyme activity for extended periods of time at low doses of these sensors. In the future, more effective "activated" probes are expected to become available with optimized sensitivity to enzymatic activity, spectral characteristics suitable for intraoperative imaging of surgical field, biocompatibility and lack of immunogenicity and toxicity. New in vivo optical imaging methods such as the fluorescence lifetime and photo(opto)acoustic imaging will contribute to early diagnosis of human diseases. The use of sensors for in vivo optical imaging will include more extensive preclinical applications of experimental therapies. At the same time, the ongoing development and improvement of optical signal detectors as well as the availability of biologically inert and highly specific fluorescent probes will further contribute to the introduction of fluorescence imaging into the clinic.
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Affiliation(s)
- A A Bogdanov
- University of Massachusetts Medical School, Department of Radiology, Laboratory of Molecular Imaging Probes, Worcester, MA 01655, USA. .,A. N. Bach Institute of Biochemistry, Federal Research Center "Fundamentals of Biotechnology", Russian Academy of Sciences, Laboratory of Molecular Imaging, Moscow, 119071, Russia.,Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Moscow, 119991, Russia
| | - I D Solovyev
- A. N. Bach Institute of Biochemistry, Federal Research Center "Fundamentals of Biotechnology", Russian Academy of Sciences, Laboratory of Molecular Imaging, Moscow, 119071, Russia.,A. N. Bach Institute of Biochemistry, Fundamentals of Biotechnology Federal Research Center, Russian Academy of Sciences, Laboratory of Physical Biochemistry, Moscow, 119071, Russia
| | - A P Savitsky
- A. N. Bach Institute of Biochemistry, Federal Research Center "Fundamentals of Biotechnology", Russian Academy of Sciences, Laboratory of Molecular Imaging, Moscow, 119071, Russia.,A. N. Bach Institute of Biochemistry, Fundamentals of Biotechnology Federal Research Center, Russian Academy of Sciences, Laboratory of Physical Biochemistry, Moscow, 119071, Russia
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21
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Gao J, Wang H, Zhuang J, Thayumanavan S. Tunable enzyme responses in amphiphilic nanoassemblies through alterations in the unimer-aggregate equilibrium. Chem Sci 2019; 10:3018-3024. [PMID: 30996882 PMCID: PMC6427939 DOI: 10.1039/c8sc04744h] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 01/11/2019] [Indexed: 12/31/2022] Open
Abstract
Developing design rules that offer tailorability in materials' response to enzymes is of great importance, as such materials are of interest in a variety of biomedical applications including sensing, diagnostics and drug delivery. Using an amphiphilic oligomeric platform, we show that the degree of polymerization and hydrophilic-lipophilic balance variations can be utilized to alter the unimer-aggregate equilibrium, which in turn offers robust tunability of the host-guest properties of the amphiphilic nanoassemblies. We found that oligomeric assemblies with higher degree of polymerization are less sensitive to enzymatic degradation and release the guest molecules at a slower rate. Similarly, increasing the hydrophilicity makes these assemblies more sensitive to enzymes. These trends can be understood by correlating these changes to predictable modifications in the dynamics of the unimer-aggregate equilibrium, which affects the substrate availability for enzymes. These findings provide insights into rationally tuning the response of enzyme-sensitive supramolecular assemblies.
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Affiliation(s)
- Jingjing Gao
- Department of Chemistry , University of Massachusetts Amherst , Amherst , MA 01003 , USA .
| | - Hui Wang
- Department of Chemistry , University of Massachusetts Amherst , Amherst , MA 01003 , USA .
- U.S. Army Edgewood Chemical Biological Center , 8198 Blackhawk Road, Aberdeen Proving Ground , MD 21010 , USA
| | - Jiaming Zhuang
- Department of Chemistry , University of Massachusetts Amherst , Amherst , MA 01003 , USA .
| | - S Thayumanavan
- Department of Chemistry , University of Massachusetts Amherst , Amherst , MA 01003 , USA .
- Molecular and Cellular Biology Program , University of Massachusetts Amherst , Amherst , MA 01003 , USA
- Center for Bioactive Delivery , Institute for Applied Life Sciences , University of Massachusetts Amherst , Amherst , MA 01003 , USA
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22
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The expression of brown fat‐associated proteins in colorectal cancer and the relationship of uncoupling protein 1 with prognosis. Int J Cancer 2019; 145:1138-1147. [DOI: 10.1002/ijc.32198] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 01/17/2019] [Accepted: 01/28/2019] [Indexed: 12/12/2022]
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23
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Ju F, Li N, Wang W, Yuan H. Effects of varying radiation dosages on MMP1 expression, and MMP1 knockdown on the viability and migration of SW620 cells. Mol Med Rep 2019; 19:2503-2508. [PMID: 30720073 PMCID: PMC6423606 DOI: 10.3892/mmr.2019.9899] [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: 01/02/2018] [Accepted: 10/10/2018] [Indexed: 11/10/2022] Open
Abstract
Colorectal cancer (CRC), also known as bowel cancer, is one of the leading causes of cancer-associated mortality worldwide at present. The aim of the present study was to detect the effects of matrix metalloproteinase 1 (MMP1) on the viability and migration of a CRC cell line in the presence or absence of variation X-ray radiation doses. The CRC cell line, SW620, was cultured and treated with different X-ray doses (0, 0.1, 0.5, 1, 3 and 6 Gy). MMP1 expression was downregulated via the application of a specific small interfering (si)-RNA. The viability and migration of SW620 cells prior to and following transfection were detected with MTT and Transwell chamber assays, respectively. The application of siRNA transfection to silence MMP1 in SW620 cells resulted in reduced cell viability and migration (P<0.05). Compared with the control, the cell viability and migration of cells were significantly reduced when exposed to 0.5, 1, 3, and 6 Gy X-ray radiation (P<0.05). In SW620 cells treated with different X-ray doses, the mRNA expression levels of MMP1 were significantly reduced (P<0.05). Cells treated with 0.5 Gy X-ray exposure exhibited the lowest mRNA expression levels of MMP1 when compared with other doses of X-ray radiation. The expression of MMP1 was associated with the promotion of the viability and migration of SW620 cells. X-ray radiation with 6 Gy dosages significantly reduced cell viability when compared with the control. Thus, MMP1-targeted therapy combined with radiotherapy could be used for treating CRC.
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Affiliation(s)
- Fang Ju
- Department of Oncology, Qingdao Central Hospital, Qingdao, Shandong 266042, P.R. China
| | - Na Li
- Department of Respiratory Medicine, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China
| | - Wenming Wang
- Department of Oncology, Qingdao Central Hospital, Qingdao, Shandong 266042, P.R. China
| | - Haicheng Yuan
- Department of Neurology, Qingdao Central Hospital, Qingdao, Shandong 266042, P.R. China
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24
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Eiro N, Carrión JF, Cid S, Andicoechea A, García-Muñiz JL, González LO, Vizoso FJ. Toll-Like Receptor 4 and Matrix Metalloproteases 11 and 13 as Predictors of Tumor Recurrence and Survival in Stage II Colorectal Cancer. Pathol Oncol Res 2019; 25:1589-1597. [PMID: 30710321 DOI: 10.1007/s12253-019-00611-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 01/24/2019] [Indexed: 12/20/2022]
Abstract
Current clinical-pathologic stratification factors do not allow clear identification of high-risk stage II colorectal cancer (CRC) patients. Therefore, the identification of additional prognostic markers is desirable. Toll-like receptor (TLR)-4 is activated during tumorigenesis and matrix metalloproteases (MMPs) are involved in invasion and metastasis. We aimed to evaluate the expression and clinical relevance of TLR4, MMP11 and MMP13 for patients with stage II CRC. Immunohistochemistry was used to study the expression of TLR4, MMP11 and MMP13 in 96 patients with stage II CRC. We measured the global expression and the expression by different cell types (tumor cells, cancer-associated fibroblasts (CAFs) and mononuclear inflammatory cells (MICs)). The potential relationship between expressions of factors and different prognostic variables were evaluated. Our results show significant relationships between either TLR4 expression by tumor cells and MMP11 expression by CAFs and high risk of tumor recurrence. In addition, the concurrence of age ≥ 75 years and the non-expression of MMP11 by CAFs identify a subgroup of patients with a good prognosis. Our results show that TLR4 expression by tumor cells and MMP11 expression by CAFs may to improve the identification of patients with stage II CRC with a high-risk of relapse.
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Affiliation(s)
- Noemi Eiro
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain
| | - Juan Francisco Carrión
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain
| | - Sandra Cid
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain
| | - Alejandro Andicoechea
- Servicio de Cirugía General, Fundación Hospital de Jove, 33290, Gijón, Asturias, Spain
| | - José Luis García-Muñiz
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain
| | - Luis O González
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain
- Servicio de Anatomía Patológica, Fundación Hospital de Jove, 33290, Gijón, Asturias, Spain
| | - Francisco J Vizoso
- Unidad de Investigación, Fundación Hospital de Jove, Avda. Eduardo Castro 161, 33290, Gijón, Asturias, Spain.
- Servicio de Cirugía General, Fundación Hospital de Jove, 33290, Gijón, Asturias, Spain.
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Jiang XF, Ding L, Tian Y, Han N, Li ZQ. Interaction of STAT3 and RelB modulates MMP-1 in colon cancer. Chem Biol Interact 2018; 293:94-99. [PMID: 30040915 DOI: 10.1016/j.cbi.2018.07.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 07/06/2018] [Accepted: 07/20/2018] [Indexed: 01/05/2023]
Abstract
BACKGROUND MMP-1 (Matrix metalloproteinase-1) promotes carcinogenesis and distant metastasis in different cancers. Regulation of MMP-1 could occur at multiple levels: epigenetically, post-transcriptionally, or post-translationally. An increasing body of evidence supports that the cytoplasmic transcription factor STAT3 (signal transducer and activator of transcription 3) is activated constitutively in a variety of cancers wherein it significantly affects the growth of tumors and also facilitates metastasis. In addition, STAT3 has been found to regulate nuclear activity pro-inflammatory transcriptional factor, NF-κB signaling, especially, the alternative one (RelB/p100) by directly interacting with them METHOD AND RESULTS: In this proof of concept study, we tested the hypothesis that STAT3 interacts with RelB to promote tumor invasion by positively regulating MMP-1 in colon cancer. We found that RelB and STAT3 were constitutively localized in the nucleus of colon cancer in surgically-resected specimens with use of Western blot analysis, which was further confirmed by immunofluorescence (IF) staining in colon carcinoma cell line HT29. We further observed that STAT3/RelB knockdown resulted in reduced MMP-1. Our results from chromatin immunoprecipitation studies further established that association between RelB and MMP-1 promoter decreased when STAT3 was depleted, and conversely, STAT3 association with MMP-1 decreased with the knockdown of RelB. CONCLUSION These results suggest that STAT3 and ReB constitute a minimal activator complex for positive regulation of MMP-1 in colon cancer.
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Affiliation(s)
- Xue-Feng Jiang
- Department of Gastroenterology, China-Japan Union Hospital of Jilin University, China
| | - Lei Ding
- Department of Radiology, China-Japan Union Hospital of Jilin University, China.
| | - Yuan Tian
- Medical Examination Center, China-Japan Union Hospital of Jilin University, China
| | - Ning Han
- Department of Radiology, China-Japan Union Hospital of Jilin University, China
| | - Zhi-Qi Li
- Department of Radiology, No.208 PLA Hospital, Changchun, China
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Mohammadi A, Mansoori B, Baradaran PC, Baradaran SC, Baradaran B. Anacyclus Pyrethrum Extract Exerts Anticancer Activities on the Human Colorectal Cancer Cell Line (HCT) by Targeting Apoptosis, Metastasis and Cell Cycle Arrest. J Gastrointest Cancer 2018; 48:333-340. [PMID: 27796737 DOI: 10.1007/s12029-016-9884-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Colorectal cancer is the second leading cause of cancer mortality in the USA. There are a number of medicinal plants triggering apoptosis response in cancer cells, thus have a therapeutic potential. On the other hand, due to traditional uses and availability of Anacyclus pyrethrum extract, we decided to evaluate the efficacy of this medicinal herb on human colorectal cancer cell line (HCT). MATERIALS AND METHODS In the present study, the cytotoxic effects of Anacyclus pyrethrum extract were assessed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, and trypan blue viability dye. Then, flow cytometry assay was exploited to measure cell death and apoptosis stage. The scratch test was exploited to assess the effect of Anacyclus pyrethrum on the migration of cancer cells. The expression levels of Caspase 3, Bcl-2, MMP1, and Vimentin genes were quantified by real-time PCR. Finally, cell cycle was analyzed by flow cytometry. RESULTS MTT assay showed that Anacyclus pyrethrum extract significantly inhibited the cell growth. According to the flow cytometry assay result, the herbal extract was able to induce apoptosis in colorectal cancer cells. Our findings also demonstrated that the plant extract substantially increases the caspase 3 mRNA expression, while decreases Bcl-2, MMP1, and Vimentin. Cell cycle arrest occurred in G1 stage, due to the results of flow cytometry. CONCLUSION These results indicate that Anacyclus pyrethrum extract can successfully induce apoptosis in HCT cells. Therefore, it could be used as a novel therapeutic candidate for colorectal cancer treatment.
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Affiliation(s)
- Ali Mohammadi
- Immunology Research Center, Tabriz University of Medical Sciences, daneshghah Ave, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, daneshghah Ave, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, daneshghah Ave, Tabriz, Iran.
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Characterisation of the oxysterol metabolising enzyme pathway in mismatch repair proficient and deficient colorectal cancer. Oncotarget 2018; 7:46509-46527. [PMID: 27341022 PMCID: PMC5216813 DOI: 10.18632/oncotarget.10224] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 05/26/2016] [Indexed: 12/13/2022] Open
Abstract
Oxysterols are oxidised derivatives of cholesterol, formed by the enzymatic activity of several cytochrome P450 enzymes and tumour-derived oxysterols have been implicated in tumour growth and survival. The aim of this study was to profile the expression of oxysterol metabolising enzymes in primary colorectal cancer and assess the association between expression and prognosis. Immunohistochemistry was performed on a colorectal cancer tissue microarray containing 650 primary colorectal cancers using monoclonal antibodies to CYP2R1, CYP7B1, CYP8B1, CYP27A1, CYP39A1, CYP46A1 and CYP51A1, which we have developed. Unsupervised hierarchical cluster analysis was used to examine the overall relationship of oxysterol metabolising enzyme expression with outcome and based on this identify an oxysterol metabolising enzyme signature associated with prognosis. Cluster analysis of the whole patient cohort identified a good prognosis group (mean survival=146 months 95% CI 127-165 months) that had a significantly better survival (δ2=12.984, p<0.001, HR=1.983, 95% CI 1.341-2.799) than the poor prognosis group (mean survival=107 months, 95% CI 98-123 months). For the mismatch repair proficient cohort, the good prognosis group had a significantly better survival (δ2=8.985, p=0.003, HR=1.845, 95% CI 1.227-2.774) than the poor prognosis group. Multi-variate analysis showed that cluster group was independently prognostically significant in both the whole patient cohort (p=0.02, HR=1.554, 95% CI 1.072-2.252) and the mismatch repair proficient group (p=0.04, HR=1.530, 95% CI 1.014-2.310). Individual oxysterol metabolising enzymes are overexpressed in colorectal cancer and an oxysterol metabolising enzyme expression profile associated with prognosis has been identified in the whole patient cohort and in mismatch repair proficient colorectal cancers.
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Cho BH, Jung YH, Kim DJ, Woo BH, Jung JE, Lee JH, Choi YW, Park HR. Acetylshikonin suppresses invasion of Porphyromonas gingivalis‑infected YD10B oral cancer cells by modulating the interleukin-8/matrix metalloproteinase axis. Mol Med Rep 2018; 17:2327-2334. [PMID: 29207110 PMCID: PMC5783479 DOI: 10.3892/mmr.2017.8151] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 11/14/2017] [Indexed: 12/19/2022] Open
Abstract
The development of pharmaceutical agents possessing anti‑invasive and anti‑metastatic abilities, as well as apoptotic activity, is important in decreasing the incidence and recurrence of oral cancer. Cancer cells are known to acquire invasiveness not only through epigenetic changes, but also from inflammatory stimuli within the tumor microenvironment. Accordingly, the identification of agents that can suppress the inflammation‑promoted invasiveness of cancer cells may be important in treating cancer and improving the prognosis of patients with cancer. Acetylshikonin, a flavonoid with anti‑inflammatory activity, inhibits proliferation and induces apoptosis of oral cancer cells. In the present study, the anti‑invasive effect of acetylshikonin on YD10B oral cancer cells infected with Porphyromonas gingivalis, a major pathogen of chronic periodontitis, and the mechanisms involved were investigated. Firstly, we examined whether P. gingivalis infection increased the invasiveness of YD10B cells. Results suggested that YD10B oral cancer cells become more aggressive when they are infected with P. gingivalis. Secondly, acetylshikonin significantly inhibited the invasion of P. gingivalis‑infected YD10B cells by suppressing IL‑8 release and IL‑8‑dependent MMP release. These data suggest that acetylshikonin may be a useful preventive and therapeutic candidate for oral cancer that is chronically infected with periodontal pathogens.
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Affiliation(s)
- Bong-Hae Cho
- Department of Oral and Maxillofacial Radiology, School of Dentistry, Pusan National University, Miryang, Gyeongsangnam-do 50463, Republic of Korea
- Dental Research Institute, Pusan National University Dental Hospital, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Yun-Hoa Jung
- Department of Oral and Maxillofacial Radiology, School of Dentistry, Pusan National University, Miryang, Gyeongsangnam-do 50463, Republic of Korea
- Dental Research Institute, Pusan National University Dental Hospital, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Da Jeong Kim
- Department of Oral Pathology and BK21 PLUS Project, School of Dentistry, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Bok Hee Woo
- Department of Oral Pathology and BK21 PLUS Project, School of Dentistry, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Ji Eun Jung
- Department of Oral Pathology and BK21 PLUS Project, School of Dentistry, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
- Institute of Translational Dental Sciences, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Ji Hye Lee
- Department of Oral Pathology and BK21 PLUS Project, School of Dentistry, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
- Institute of Translational Dental Sciences, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
| | - Young Whan Choi
- Department of Horticultural Bioscience, Pusan National University, Miryang, Gyeongsangnam-do 50463, Republic of Korea
| | - Hae Ryoun Park
- Department of Oral Pathology and BK21 PLUS Project, School of Dentistry, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
- Institute of Translational Dental Sciences, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
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Zhang S, Xiao J, Chai Y, Hong Z, Liu Z, Yuan R, Luo Z, Zhou X, Lucero-Prisno DE, Huang K. Speckle-Type POZ Protein Down-Regulates Matrix Metalloproteinase 2 Expression via Sp1/PI3K/Akt Signaling Pathway in Colorectal Cancer. Dig Dis Sci 2018; 63:395-402. [PMID: 29260353 DOI: 10.1007/s10620-017-4884-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 12/12/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Elevated expression of matrix metalloproteinases (MMPs) is correlated with invasion and metastasis of colorectal cancer (CRC). Recently, a previous study has suggested that speckle-type POZ protein (SPOP) could inhibit cancer cell proliferation and migration through down-regulation of MMP2 and MMP7, with a mechanism remaining unknown. AIM In this study, we, by using both CRC cells and normal colorectal cells, aimed to investigate the causal relationship between SPOP and MMP2, as well as the potential signaling pathways. METHODS The causal relationship between SPOP and MMP2 was determined by both RT-PCR and Western blot in cells with SPOP expression or siRNA interference. The signaling pathway involved in MMP2 down-regulation by SPOP was subsequently identified by determination on the expression and phosphorylation of key signaling pathway proteins. Transcription factor involving in this MMP2 regulation was identified by determination on expression, phosphorylation, and nuclear translocation of key transcription factors. RESULTS SPOP overexpression could significantly decrease MMP2 expression, while the knockdown of SPOP, in contrast, resulted in enhanced MMP2 level. Measurement of expression and phosphorylation of key signaling pathway proteins revealed that SPOP could inhibit PI3K and p-Akt level. Further tests on transcription factors showed that SPOP could inhibit SP1 phosphorylation and nuclear translocation. CONCLUSIONS SPOP could down-regulate MMP2 expression in CRC, and this regulation is mediated by inhibiting SP1 phosphorylation and nuclear translocation through PI3K/Akt signaling pathway. Our findings in this study provide understanding of MMP2 regulation in CRC and may also shed lights on the development of anti-CRC treatments.
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Affiliation(s)
- Shouhua Zhang
- Department of General Surgery, Jiangxi Provincial Children's Hospital, Nanchang, 330006, China
| | - Juhua Xiao
- Department of Ultrasound, Jiangxi Maternal and Child Health Hospital, Nanchang, 330006, China
| | - Yong Chai
- Department of General Surgery, Jiangxi Provincial Children's Hospital, Nanchang, 330006, China
| | - Zhengdong Hong
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Zhiqiang Liu
- Department of General Surgery, Jiangxi Provincial Children's Hospital, Nanchang, 330006, China
| | - Rongfa Yuan
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Zhipeng Luo
- Department of Gastrointestinal Surgery, Jiangxi Provincial Cancer Hospital, No. 519, Beijing East Road, Nanchang, 330029, Jiangxi, China
| | - Xin Zhou
- Department of Ultrasound, Jiangxi Maternal and Child Health Hospital, Nanchang, 330006, China
| | | | - Kai Huang
- Department of Gastrointestinal Surgery, Jiangxi Provincial Cancer Hospital, No. 519, Beijing East Road, Nanchang, 330029, Jiangxi, China.
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Nunes BL, Jucá MJ, Gomes EG, Menezes HL, Costa HO, Matos D, Saad SS. Metalloproteinase-1, Metalloproteinase-7, and p53 Immunoexpression and their Correlation with Clinicopathological Prognostic Factors in Colorectal Adenocarcinoma. Int J Biol Markers 2018; 24:156-64. [DOI: 10.1177/172460080902400305] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Aim The aim of this study was to analyze the immunoexpression of metalloproteinase-1, metalloproteinase-7, and p53 in colorectal adenocarcinoma, and to correlate this with clinicopathological prognostic factors. Material and methods Formalin-fixed paraffin-embedded tumor tissue from 82 patients was analyzed by means of immunohistochemistry, using the streptavidin-biotin method and the tissue microarray technique. Protein tissue expression was correlated with the variables of the degree of cell differentiation, stage, relapse-free survival, recurrence, survival, and specific mortality. Results All of the tumors were positive for metalloproteinase-1, while 50 (61%) were positive for metalloproteinase-7, and 32 (39%) were negative for the latter. For p53, 70 (85.4%) of the tumors were positive and 12 (14.6%) were negative. Correlation of the marker expressions separately and in conjunction did not produce any statistically significant data. Conclusion The immunoexpression of metalloproteinase-1, metalloproteinase-7, and p53 did not correlate with recurrence, mortality, relapse-free survival, survival, degree of cell differentiation, or staging of colorectal cancer.
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Affiliation(s)
| | - Mário J. Jucá
- Department of Coloproctology, School of Medicine, Federal University of AlagoasUFAL, Alagoas
| | - Edmundo G.A. Gomes
- Department of Coloproctology, School of Medicine, Federal University of AlagoasUFAL, Alagoas
| | | | - Henrique O. Costa
- Department of Pathology, State University of Health Sciences of Alagoas (UNCISAL), Alagoas
| | - Delcio Matos
- Department of Surgical Gastroenterology, Paulista School of Medicine, Federal University of São Paulo (UNIFESPEPM), São Paulo - Brazil
| | - Sarhan S. Saad
- Department of Surgical Gastroenterology, Paulista School of Medicine, Federal University of São Paulo (UNIFESPEPM), São Paulo - Brazil
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de Lima JM, de Souza LG, da Silva IDCG, Forones NM. E-Cadherin and Metalloproteinase-1 and -7 Polymorphisms in Colorectal Cancer. Int J Biol Markers 2018; 24:99-106. [DOI: 10.1177/172460080902400206] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Purpose E-cadherin (CDH1) and metalloproteinase (MMP) polymorphisms could play a crucial role in cancer invasion. Our aim was to investigate the influence of the -160C/A CDH1, -1607ins/delG MMP-1 and -181A/G MMP-7 polymorphisms on the frequency and progression of colorectal cancer (CRC). Experimental design A total of 130 patients with CRC and 130 noncancer controls were studied. The -160C/A CDH1, -1607ins/delG MMP-1 and -181A/G MMP-7 genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Results Patients with the 1G allele and a family history of CRC showed a six times higher risk of developing CRC (OR: 6.45, 95%CI: 2.02–20.6, p=0.001). The A/A CDH1 genotype was associated with a higher risk of metastatic disease (OR: 3.43, 95%CI: 1.27–9.27, p=0.023). A higher marginal risk of metastatic disease was observed for MMP-1 genotypes 1G/1G and 1G/2G (OR: 2.97, 95%CI: 0.93–9.47, p=0.098). Conclusions The -160C/A CDH1, -1607ins/delG MMP-1 and -181A/G MMP-7 single nucleotide polymorphisms did not modify the risk of CRC development. Patients with the 1G/1G or 1G/2G genotype and a family history of CRC presented a higher risk of CRC. The AA CDH1 and 1G/1G and 1G/2G MMP-1 genotypes might be associated with advanced metastatic disease, but are not markers of lymphatic metastasis.
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Affiliation(s)
- Jacqueline Miranda de Lima
- Oncology Group, Gastroenterology Division, Federal University of Sao Paulo (UNIFESP/EPM), Sao Paulo - Brazil
| | - Lessileia Gomes de Souza
- Oncology Group, Gastroenterology Division, Federal University of Sao Paulo (UNIFESP/EPM), Sao Paulo - Brazil
| | | | - Nora Manoukian Forones
- Oncology Group, Gastroenterology Division, Federal University of Sao Paulo (UNIFESP/EPM), Sao Paulo - Brazil
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Abstract
The majority of cancer-related deaths result from metastasis, the process by which cancer cells escape the primary tumor site and enter into the blood circulation in order to disseminate to secondary locations throughout the body. Tumor cells found within the circulation are referred to as circulating tumor cells (CTCs), and their detection and enumeration correlate with poor prognosis. The epithelial-to-mesenchymal transition (EMT) is a dynamic process that imparts epithelial cells with mesenchymal-like properties, thus facilitating tumor cell dissemination and contributing to metastasis. However, EMT also results in the downregulation of various epithelial proteins typically utilized by CTC technologies for enrichment and detection of these rare cells, resulting in reduced detection of some CTCs, potentially those with a more metastatic phenotype. In addition to the current clinical role of CTCs as a prognostic biomarker, they also have potential as a predictive biomarker via CTC characterization. However, CTC characterization is complicated by the unknown biological significance of CTCs possessing an EMT-like phenotype, and the ability to capture and understand this CTC subpopulation is an essential step in the utilization of CTCs for patient management. This chapter will review the process of EMT and its contribution to metastasis; discusses current and future clinical applications of CTCs; and describes both traditional and novel methods for CTC enrichment, detection, and characterization with a specific focus on CTCs with an EMT phenotype.
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Mackawy AM, Megahed O. Significance of matrix metalloproteinase-1 and -3 gene polymorphisms and their expression in normal and neoplastic endometrium. Meta Gene 2017. [DOI: 10.1016/j.mgene.2017.08.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Synergistic effect of collagenase-1 (MMP1), stromelysin-1 (MMP3) and gelatinase-B (MMP9) gene polymorphisms in breast cancer. PLoS One 2017; 12:e0184448. [PMID: 28961241 PMCID: PMC5621673 DOI: 10.1371/journal.pone.0184448] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 08/24/2017] [Indexed: 12/11/2022] Open
Abstract
Background Extracellular matrix degradation by matrix metalloproteinases (MMPs) is an important mechanism involved in tumor invasion and metastasis. Genetic variations of MMPs have shown association with multiple cancers. The present study is focused to elucidate the association of MMP-1, 3 and 9 genetic variants with respect to epidemiological and clinicopathological variables by haplotype, LD, MDR, survival in silico analyses among South Indian women. Material and methods MMP3–1171 5A/6A and MMP9–1562 C/T SNPs were genotyped by Allele specific polymerase chain reaction and MMP1-1607 1G/2G polymorphism by restriction fragment length polymorphism assays respectively, in 300 BC patients and age-matched 300 healthy controls. Statistical analysis was performed using the SNPStats and SPSS software. Linkage disequilibrium and gene-gene interactions were performed using Haploview and MDR software respectively. Further, transcription factor binding sites in the promoter regions of SNPs under study were carried out using AliBaba2.1 software. Results We have observed an increased frequency of 2G-allele of MMP1, 6A-allele of MMP3 and T-allele of MMP9 (p<0.05) respectively in BC subjects. The 2G-6A haplotype (minor alleles of MMP-1 and MMP-3 respectively) has shown an increased susceptibility to BC. Further, MMP polymorphisms were associated with the clinical characteristics of BC patients such as steroid hormone receptor status, lymph node involvement and metastasis. SNP combinations were in perfect LD in controls. MDR analysis revealed a positive interaction between the SNPs. 5-years survival rate and cox-regression analysis showed a significant association with clinicopathological variables. Conclusion Our results suggest that MMP1–1607 1G/2G, MMP3–1171 5A/6A and MMP9–1562 C/T gene polymorphisms have synergistic effect on breast cancer. The interactions of MMPs clinical risk factors such as lymph node involvement has shown a strong correlation and might influence the 5-years survival rate, suggesting their potential role in the breast carcinogenesis.
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Hondo FY, Kishi H, Safatle-Ribeiro AV, Pessorrusso FCS, Ribeiro U, Maluf-Filho F. CHARACTERIZATION OF THE MUCIN PHENOTYPE CAN PREDICT GASTRIC CANCER RECURRENCE AFTER ENDOSCOPIC MUCOSAL RESECTION. ARQUIVOS DE GASTROENTEROLOGIA 2017; 54:308-314. [PMID: 28954038 DOI: 10.1590/s0004-2803.201700000-38] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 05/22/2017] [Indexed: 01/27/2023]
Abstract
BACKGROUND Endoscopic mucosal resection is still considered an accepted treatment for early gastric cancer for selected cases. Histopathologic criteria for curative endoscopic resection are intramucosal well-differentiated adenocarcinoma, lateral and deep margins free of tumor, no histological ulceration, and no venous or lymphatic embolism. A 5% local recurrence rate has been described even when all the above-mentioned criteria are met. On the other hand, antigen expression by tumoral cells has been related to the biological behavior of several tumors. OBJECTIVE To evaluate whether early gastric cancer mucin immunoexpression, p53 and Ki-67, can predict recurrence after endoscopic mucosal resection, even when standard histopathologic criteria for curative measures have been attempted. METHODS Twenty-two patients with early gastric cancer were considered to have been completely resected by endoscopic mucosal resection. Local recurrence occurred in 5/22 (22.7%). Immunohistochemical study was possible in 18 (81.8%) resected specimens. Patients were divided in two groups: those with and those without local recurrence. They were compared across demographic, endoscopic, histologic data, and immunohistochemical factors for MUC2, MUC5a, CD10, p53, and Ki-67. RESULTS Mucin immunoexpression allowed a reclassification of gastric adenocarcinoma in intestinal (10), gastric (2), mixed (4), and null phenotypes (2). Mixed phenotype (positive for both MUC2 and MUC5a) was found in 80% of cases in the local recurrence group, while the intestinal type (positive MUC2 and negative MUC5a) was found in 76.9% of cases without local recurrence (P=0.004). Other observed features did not correlate with neoplastic recurrence. CONCLUSION The mixed phenotype of early gastric adenocarcinoma is associated with a higher probability of local recurrence after endoscopic mucosal resection.
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Affiliation(s)
- Fabio Yuji Hondo
- Gastrocirurgia, Faculdade de Medicina, Universidade de São Paulo, SP, Brazil
| | - Humberto Kishi
- Patologia, Faculdade de Medicina, Universidade de São Paulo, SP, Brazil
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Wang J, Ye C, Lu D, Chen Y, Jia Y, Ying X, Xiong H, Zhao W, Zhou J, Wang L. Matrix metalloproteinase-1 expression in breast carcinoma: a marker for unfavorable prognosis. Oncotarget 2017; 8:91379-91390. [PMID: 29207651 PMCID: PMC5710931 DOI: 10.18632/oncotarget.20557] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 08/04/2017] [Indexed: 12/31/2022] Open
Abstract
Matrix metalloproteinase-1 (MMP1) is a member of the matrix metalloproteinases family, and its aberrant expression is implicated in tumor invasion and metastasis. However, the relationship between MMP1 abnormal expression and clinical outcome in breast cancer patients remains to be elucidated. To address this issue, we conducted immunohistochemistry in breast cancer and adjacent normal tissues, and mined the transcriptional and survival data of MMP1 in breast cancer patients through Oncomine, Kaplan-Meier Plotter, bc-GenExMiner, COSMIC and cBioPortal databases. First, we found that both protein and mRNA levels of MMP1 expression were significantly higher in breast cancer tissues. Second, high MMP1 mRNA expression correlated with worse overall survival among grade II (HR = 1.75; p = 0.011), nodal-negative (HR = 2.00; p = 0.00028), ER-positive (HR = 1.61; p = 0.00027) and HER2-negative (HR = 3.17; p = 0.029) patients with breast cancer by using Kaplan-Meier plotter database. Third, the overexpression of MMP1 was associated with unfavorable survival results including overall survival (HR = 1.6; p = 1.6e-05), relapse free survival (HR = 1.78; p < 1e-16) and distant metastasis free survival (HR = 1.65; p = 5.3e-05) in patients with breast cancer. Taken together, the expression status of MMP1 is a significant prognostic indicator and a potential drug target for breast cancer.
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Affiliation(s)
- Ji Wang
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, 310016, China
| | - Chenyang Ye
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China
| | - Demin Lu
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China.,Department of Medical Oncology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China
| | - Yongxia Chen
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, 310016, China
| | - Yunlu Jia
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, 310016, China
| | - Xiaogang Ying
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, 310016, China
| | - Hanchu Xiong
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, 310016, China
| | - Wenhe Zhao
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, 310016, China
| | - Jichun Zhou
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, 310016, China
| | - Linbo Wang
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China.,Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, 310016, China
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37
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Li H, Zhong A, Li S, Meng X, Wang X, Xu F, Lai M. The integrated pathway of TGFβ/Snail with TNFα/NFκB may facilitate the tumor-stroma interaction in the EMT process and colorectal cancer prognosis. Sci Rep 2017; 7:4915. [PMID: 28687755 PMCID: PMC5501852 DOI: 10.1038/s41598-017-05280-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 05/26/2017] [Indexed: 12/14/2022] Open
Abstract
Substantial evidence has shown that epithelial-mesenchymal transition (EMT) plays critical roles in colorectal cancer (CRC) development and prognosis. To uncover the pivotal regulators that function in the cooperative interactions between cancer cells and their microenvironment and consequently affect the EMT process, we carried out a systematic analysis and evaluated prognosis in CRC specimens. Tumor buds and their surrounding stroma were captured using laser microdissection. We used gene expression profiling, bioinformatics analysis and regulatory network construction for molecular selection. The clinical significance of potential biomarkers was investigated. We identified potential EMT biomarkers, including BGN, MMP1, LGALS1, SERPINB5, and TM4SF4, all of which participated in the integrated pathway of TGFβ/Snail with TNFα/NFκB. We also found that BGN, MMP1, LGALS1, SERPINB5 and TM4SF4 were related to CRC patient prognosis. Patients with higher expression of these individual potential biomarkers had poorer prognosis. Among the identified biomarkers, BGN and TM4SF4 are reported, for the first time, to probably be involved in the EMT process and to predict CRC prognosis. Our results strongly suggest that the integrated pathway of TGFβ/Snail with TNFα/NFκB may be the principal axis that links cancer cells to their microenvironment during the EMT process and results in poor prognosis in CRC patients.
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Affiliation(s)
- Hui Li
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, 310058, China.,Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, 310058, China
| | - Anjing Zhong
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, 310058, China.,Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, 310058, China
| | - Si Li
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, 310058, China.,Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, 310058, China
| | - Xianwen Meng
- Department of Bioinformatics, State Key Laboratory of Plant Physiology and Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Xue Wang
- China Pharmaceutical University, Nanjing, 320100, China
| | - Fangying Xu
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, 310058, China.,Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, 310058, China
| | - Maode Lai
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, 310058, China. .,Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, 310058, China.
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Garg NK, Tyagi RK, Sharma G, Jain A, Singh B, Jain S, Katare OP. Functionalized Lipid-Polymer Hybrid Nanoparticles Mediated Codelivery of Methotrexate and Aceclofenac: A Synergistic Effect in Breast Cancer with Improved Pharmacokinetics Attributes. Mol Pharm 2017; 14:1883-1897. [PMID: 28402673 DOI: 10.1021/acs.molpharmaceut.6b01148] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The present study was aimed to coencapsulate methotrexate (MTX) and aceclofenac (ACL) in fucose anchored lipid-polymer hybrid nanoparticles (Fu-LPHNPs) to achieve target specific and controlled delivery for developing therapeutic interventions against breast cancer. The effective combination therapy requires coadministration of drugs to achieve synergistic effect on tumor with minimum adverse effects. Present study investigates the potential of codelivery of MTX and ACL through LPHNPs in MCF-7 and triple negative breast cancer cells (MDA-MB-231). We obtained LPHNPs in the nanosize range (<150 nm) with better particle size distribution (<0.3). The entrapment and loading efficiency of MTX and ACL was calculated as 85-90% and 10-12%, respectively. The coumarin-6 LPHNP formulations showed rapid internalization within 2 h incubation with MCF-7 and MDA-MB-231 cells. With 8-10 times, greater bioavailability of drug-loaded LPHNPs than free MTX and ACL was obtained. Also, antitumor efficacy of MTX- and ACL-loaded LPHNPs was determined on DMBA-induced experimental breast cancer mouse model. This model showed better control over tumor growth with MTX- and ACL-loaded LPHNPs than the combination of MTX and ACL or MTX alone. ACL-loaded LPHNPs showed prophylactic and anticancer activity in DMBA-induced mouse model at higher dose (10 mg/kg). ACL-LPHNPs confer synergistic anticancer effect when administered in combination with MTX. In conclusion, ACL enhances the therapeutic and anticancer efficacy of MTX, when coencapsulated into fucose-anchored LPHNPs, as confirmed by cell viability and serum angiogenesis (IL-6, TNF-α, IL-1β, COX2, and MMP1) at both transcript and proteome level.
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Affiliation(s)
- Neeraj K Garg
- University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University , Chandigarh 160014, India
| | - Rajeev K Tyagi
- Institute of Science, Nirma University , SG Highway, Ahmedabad, Gujarat 382481 India
| | - Gajanand Sharma
- University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University , Chandigarh 160014, India
| | - Ashay Jain
- University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University , Chandigarh 160014, India
| | - Bhupinder Singh
- University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University , Chandigarh 160014, India
- UGC-Centre of Excellence in Applications of Nanomaterials, Nanoparticles & Nanocomposites (Biomedical Sciences), Panjab University , Chandigarh 160 014, India
| | - Sanyog Jain
- Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) , Sector 67, SAS Nagar, Mohali, Punjab 160062, India
| | - O P Katare
- University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University , Chandigarh 160014, India
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Eiró N, González LO, Cid S, Andicoechea A, Vizoso FJ. Matrix metalloproteases expression in different histological types of colorectal polyps. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2017; 109:414-420. [PMID: 28376625 DOI: 10.17235/reed.2017.4551/2016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
INTRODUCTION Colorectal carcinoma (CC) may begin as benign polyps, which may be classified in different histological types with a different risk to develop cancer. Matrix metalloproteases (MMPs) are able to degrade all components in the extracellular matrix and are important tissue-remodeling enzymes and key elements in tumor invasion and metastasis. The aim of this study was to investigate the expression and clinical relevance of MMPs in different histological types of colorectal polyps. METHODS The expression levels of MMP-1, 2, 7, 9, 11, 13 and 14 were analyzed by real-time PCR, Western-blot and immunohistochemistry in 50 patients with different histological types of colorectal polyps, 28 of which developed CC. RESULTS The results indicate that hyperplastic polyps had the lowest levels of MMP-1 and MMP-7, tubular polyps showed higher levels of both MMP-7 and MMP-14, and tubulovillous adenoma showed higher levels of MMP-1, MMP-7 and MMP-14. CONCLUSION MMP expression was decreased in hyperplastic, tubular and tubulovillous adenoma polyps from patients who developed CC. Our findings suggest that MMP expression may be a pathological marker of colorectal polyps and for cancer susceptibility, which may improve strategies for CC prevention based on screening colonoscopy.
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Affiliation(s)
- Noemi Eiró
- Unidad de Investigación, Fundación Hospital de Jove
| | - Luis O González
- Unidad de Investigación y Servicio de Anatomía Pat, Fundación Hospital de Jove
| | - Sandra Cid
- Unidad de Investigación, Fundación Hospital de Jove
| | | | - Francisco J Vizoso
- Unidad de Investigación y Servicio de Cirugía Gene, Fundación Hospital de Jove, España
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Alnabulsi A, Swan R, Cash B, Alnabulsi A, Murray GI. The differential expression of omega-3 and omega-6 fatty acid metabolising enzymes in colorectal cancer and its prognostic significance. Br J Cancer 2017; 116:1612-1620. [PMID: 28557975 PMCID: PMC5518862 DOI: 10.1038/bjc.2017.135] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 04/13/2017] [Accepted: 04/24/2017] [Indexed: 12/28/2022] Open
Abstract
Background: Colorectal cancer is a common malignancy and one of the leading causes of cancer-related deaths. The metabolism of omega fatty acids has been implicated in tumour growth and metastasis. Methods: This study has characterised the expression of omega fatty acid metabolising enzymes CYP4A11, CYP4F11, CYP4V2 and CYP4Z1 using monoclonal antibodies we have developed. Immunohistochemistry was performed on a tissue microarray containing 650 primary colorectal cancers, 285 lymph node metastasis and 50 normal colonic mucosa. Results: The differential expression of CYP4A11 and CYP4F11 showed a strong association with survival in both the whole patient cohort (hazard ratio (HR)=1.203, 95% CI=1.092–1.324, χ2=14.968, P=0.001) and in mismatch repair-proficient tumours (HR=1.276, 95% CI=1.095–1.488, χ2=9.988, P=0.007). Multivariate analysis revealed that the differential expression of CYP4A11 and CYP4F11 was independently prognostic in both the whole patient cohort (P=0.019) and in mismatch repair proficient tumours (P=0.046). Conclusions: A significant and independent association has been identified between overall survival and the differential expression of CYP4A11 and CYP4F11 in the whole patient cohort and in mismatch repair-proficient tumours.
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Affiliation(s)
- Abdo Alnabulsi
- Department of Pathology, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25, 2ZD, UK.,Vertebrate Antibodies, Zoology Building, Tillydrone Avenue, Aberdeen AB24 2TZ, UK
| | - Rebecca Swan
- Department of Pathology, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25, 2ZD, UK
| | - Beatriz Cash
- Vertebrate Antibodies, Zoology Building, Tillydrone Avenue, Aberdeen AB24 2TZ, UK
| | - Ayham Alnabulsi
- Vertebrate Antibodies, Zoology Building, Tillydrone Avenue, Aberdeen AB24 2TZ, UK
| | - Graeme I Murray
- Department of Pathology, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25, 2ZD, UK
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Cheng K, Shang AC, Drachenberg CB, Zhan M, Raufman JP. Differential expression of M3 muscarinic receptors in progressive colon neoplasia and metastasis. Oncotarget 2017; 8:21106-21114. [PMID: 28416748 PMCID: PMC5400569 DOI: 10.18632/oncotarget.15500] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 02/07/2017] [Indexed: 12/20/2022] Open
Abstract
M3 muscarinic receptor (M3R) activation promotes colon cancer cell proliferation, migration, and invasion in vitro. Although over-expression of CHRM3, the gene encoding M3R, is reported in primary colon cancers, expression of M3R itself has not been studied in colon neoplasia. We compared M3R expression in normal colon to colon adenomas, and primary and metastatic colon cancers. Compared to adjacent normal colon, CHRM3 expression was increased up to 128-fold in 10 of 18 consecutive surgical cancer specimens (56%) and associated with metastatic spread (P < 0.05). To analyze M3R protein expression we interrogated 29 consecutive paraffin-embedded colon adenocarcinomas and adjacent normal colon using a specific anti-M3R antibody and immunoperoxidase staining. This revealed weak M3R expression in normal colonocytes, primarily on basolateral surfaces. In contrast, in 25 of 29 cancer tissues (86%) we observed both cytoplasmic and plasma membrane over-expression of M3R; compared to normal epithelium, mean M3R staining intensity was increased more than two-fold in colon cancer (P < 0.001). M3R staining was also increased in 22 colon adenomas compared to adjacent normal colon (P < 0.001). In contrast, M3R staining intensity was not increased in lymph node or liver metastases. These findings suggest M3R expression plays an important role in early progression and invasion of colon neoplasia but is less important once tumors have spread.
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Affiliation(s)
- Kunrong Cheng
- Veterans Affairs Maryland Healthcare System, Baltimore VA Medical Center, Baltimore, MD, USA.,Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Aaron C Shang
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Cinthia B Drachenberg
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Min Zhan
- Veterans Affairs Maryland Healthcare System, Baltimore VA Medical Center, Baltimore, MD, USA.,Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Jean-Pierre Raufman
- Veterans Affairs Maryland Healthcare System, Baltimore VA Medical Center, Baltimore, MD, USA.,Department of Medicine, Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD, USA.,Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
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42
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Proteolysis in Helicobacter pylori-Induced Gastric Cancer. Toxins (Basel) 2017; 9:toxins9040134. [PMID: 28398251 PMCID: PMC5408208 DOI: 10.3390/toxins9040134] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 04/03/2017] [Accepted: 04/06/2017] [Indexed: 12/15/2022] Open
Abstract
Persistent infections with the human pathogen and class-I carcinogen Helicobacter pylori (H. pylori) are closely associated with the development of acute and chronic gastritis, ulceration, gastric adenocarcinoma and lymphoma of the mucosa-associated lymphoid tissue (MALT) system. Disruption and depolarization of the epithelium is a hallmark of H. pylori-associated disorders and requires extensive modulation of epithelial cell surface structures. Hence, the complex network of controlled proteolysis which facilitates tissue homeostasis in healthy individuals is deregulated and crucially contributes to the induction and progression of gastric cancer through processing of extracellular matrix (ECM) proteins, cell surface receptors, membrane-bound cytokines, and lateral adhesion molecules. Here, we summarize the recent reports on mechanisms how H. pylori utilizes a variety of extracellular proteases, involving the proteases Hp0169 and high temperature requirement A (HtrA) of bacterial origin, and host matrix-metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs) and tissue inhibitors of metalloproteinases (TIMPs). H. pylori-regulated proteases represent predictive biomarkers and attractive targets for therapeutic interventions in gastric cancer.
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43
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Espinoza-Sánchez NA, Chimal-Ramírez GK, Mantilla A, Fuentes-Pananá EM. IL-1β, IL-8, and Matrix Metalloproteinases-1, -2, and -10 Are Enriched upon Monocyte-Breast Cancer Cell Cocultivation in a Matrigel-Based Three-Dimensional System. Front Immunol 2017; 8:205. [PMID: 28337194 PMCID: PMC5340783 DOI: 10.3389/fimmu.2017.00205] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 02/14/2017] [Indexed: 12/21/2022] Open
Abstract
Breast cancer remains the first cancer-related cause of death in women worldwide, particularly in developing countries in which most cases are diagnosed in late stages. Although most cancer studies are based in the genetic or epigenetic changes of the tumor cells, immune cells within the tumor stroma often cooperate with cancer progression. Particularly, monocytes are attracted to the tumor primary site in which they are differentiated into tumor-associated macrophages that facilitate tumor cell invasion and metastasis. In this study, we used three-dimensional cultures to form acini-like structures to analyze the inflammatory secretion profile of tumor cells individually or in co-culture with monocytes. Breast cancer cell lines and primary isolates from eight Mexican patients with breast cancer were used. We found high levels of RANTES/CCL5, MCP-1/CCL2, and G-CSF in the breast cancer individual cultures, supporting an important recruitment capacity of monocytes, but also of neutrophils. The co-cultures of the tumor cells and monocytes were significantly enriched with the potent pro-inflammatory cytokines interleukin (IL)-1β and IL-8, known to support malignant progression. We also found that the interaction of tumor cells with monocytes promoted high levels of matrix metalloproteinases (MMP)-1, MMP-2, and MMP-10. Our study supports that a key event for malignant progression is the recruitment of different immune cell populations, which help to sustain and enhance a chronic inflammatory microenvironment that highly favors tumor malignancy.
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Affiliation(s)
- Nancy Adriana Espinoza-Sánchez
- Unidad de Investigación en Virología y Cáncer, Hospital Infantil de México Federico Gómez, Ciudad de México, México; Programa de Doctorado en Ciencias Biomédicas, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, México
| | - Gloria Karina Chimal-Ramírez
- Unidad de Investigación en Virología y Cáncer, Hospital Infantil de México Federico Gómez , Ciudad de México , México
| | - Alejandra Mantilla
- Departamento de Patología, Hospital de Oncología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social , Ciudad de México , México
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Interacting post-muscarinic receptor signaling pathways potentiate matrix metalloproteinase-1 expression and invasion of human colon cancer cells. Biochem J 2017; 474:647-665. [PMID: 28008134 DOI: 10.1042/bcj20160704] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 12/16/2016] [Accepted: 12/21/2016] [Indexed: 12/26/2022]
Abstract
M3 muscarinic receptor (M3R) expression is increased in colon cancer; M3R activation stimulates colon cancer cell invasion via cross-talk with epidermal growth factor receptors (EGFR), post-EGFR activation of mitogen-activated protein kinase (MAPK) extracellular signal-related kinase 1/2 (ERK1/2), and induction of matrix metalloproteinase-1 (MMP1) expression. MMP1 expression is strongly associated with tumor metastasis and adverse outcomes. Here, we asked whether other MAPKs regulate M3R agonist-induced MMP1 expression. In addition to activating ERK1/2, we found that treating colon cancer cells with acetylcholine (ACh) stimulated robust time- and dose-dependent phosphorylation of p38 MAPK. Unlike ERK1/2 activation, ACh-induced p38 phosphorylation was EGFR-independent and blocked by inhibiting protein kinase C-α (PKC-α). Inhibiting activation of PKC-α, EGFR, ERK1/2, or p38-α/β alone attenuated, but did not abolish ACh-induced MMP1 expression, a finding that predicted potentiating interactions between these pathways. Indeed, ACh-induced MMP1 expression was abolished by incubating cells with either an EGFR or MEK/ERK1/2 inhibitor combined with a p38-α/β inhibitor. Activating PKC-α and EGFR directly with the combination of phorbol 12-myristate 13-acetate (PMA) and EGF potentiated MMP1 gene and protein expression, and cell invasion. PMA- and ACh-induced MMP1 expression were strongly diminished by inhibiting Src and abolished by concurrently inhibiting both p38-α/β and Src, indicating that Src mediates the cross-talk between PKC-α and EGFR signaling. Using siRNA knockdown, we identified p38-α as the relevant p38 isoform. Collectively, these studies uncover novel functional interactions between post-muscarinic receptor signaling pathways that augment MMP1 expression and drive colon cancer cell invasion; targeting these potentiating interactions has therapeutic potential.
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Solomonov I, Zehorai E, Talmi-Frank D, Wolf SG, Shainskaya A, Zhuravlev A, Kartvelishvily E, Visse R, Levin Y, Kampf N, Jaitin DA, David E, Amit I, Nagase H, Sagi I. Distinct biological events generated by ECM proteolysis by two homologous collagenases. Proc Natl Acad Sci U S A 2016; 113:10884-9. [PMID: 27630193 PMCID: PMC5047162 DOI: 10.1073/pnas.1519676113] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
It is well established that the expression profiles of multiple and possibly redundant matrix-remodeling proteases (e.g., collagenases) differ strongly in health, disease, and development. Although enzymatic redundancy might be inferred from their close similarity in structure, their in vivo activity can lead to extremely diverse tissue-remodeling outcomes. We observed that proteolysis of collagen-rich natural extracellular matrix (ECM), performed uniquely by individual homologous proteases, leads to distinct events that eventually affect overall ECM morphology, viscoelastic properties, and molecular composition. We revealed striking differences in the motility and signaling patterns, morphology, and gene-expression profiles of cells interacting with natural collagen-rich ECM degraded by different collagenases. Thus, in contrast to previous notions, matrix-remodeling systems are not redundant and give rise to precise ECM-cell crosstalk. Because ECM proteolysis is an abundant biochemical process that is critical for tissue homoeostasis, these results improve our fundamental understanding its complexity and its impact on cell behavior.
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Affiliation(s)
- Inna Solomonov
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Eldar Zehorai
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Dalit Talmi-Frank
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel; Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Sharon G Wolf
- Department of Chemical Research Support, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Alla Shainskaya
- Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Alina Zhuravlev
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Elena Kartvelishvily
- Department of Chemical Research Support, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Robert Visse
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, OX3 7FY, United Kingdom
| | - Yishai Levin
- Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Nir Kampf
- Department of Materials and Interfaces, Weizmann Institute of Science, Rehovot 76100, Israel
| | | | - Eyal David
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Ido Amit
- Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Hideaki Nagase
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, OX3 7FY, United Kingdom
| | - Irit Sagi
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel;
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Wenham RM, Calingaert B, Ali S, McClean K, Whitaker R, Bentley R, Lancaster JM, Schildkraut J, Marks J, Berchuck A. Matrix Metalloproteinase-1 Gene Promoter Polymorphism and Risk of Ovarian Cancer. ACTA ACUST UNITED AC 2016. [DOI: 10.1016/s1071-55760300141-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
| | | | | | | | | | | | | | | | - Jeffrey Marks
- Departments of Obstetrics and Gynecology/Division of Gynecologic Oncology, Pathology, Community and Family Medicine, and Surgery, Duke University Medical Center, Durham, North Carolina
| | - Andrew Berchuck
- Departments of Obstetrics and Gynecology/Division of Gynecologic Oncology, Pathology, Community and Family Medicine, and Surgery, Duke University Medical Center, Durham, North Carolina; Division of Gynecologic Oncology, Duke University Medical Center, Box 3079, Durham NC 27710
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47
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Ha NH, Park DG, Woo BH, Kim DJ, Choi JI, Park BS, Kim YD, Lee JH, Park HR. Porphyromonas gingivalis increases the invasiveness of oral cancer cells by upregulating IL-8 and MMPs. Cytokine 2016; 86:64-72. [PMID: 27468958 DOI: 10.1016/j.cyto.2016.07.013] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Revised: 07/06/2016] [Accepted: 07/16/2016] [Indexed: 12/14/2022]
Abstract
Recent studies indicate that chronic inflammation promotes the aggressiveness of cancers. However, the direct molecular mechanisms underlying a functional link between chronic periodontitis, the most common form of oral inflammatory diseases, and the malignancy of oral cancer remain unknown. To elucidate the role of chronic periodontitis in progression of oral cancer, we examined the effect of Porphyromonas gingivalis (P. gingivalis), a major pathogen that causes chronic periodontitis, on the invasiveness of oral squamous cell carcinoma (OSCC) cells, including SCC-25, OSC-20 and SAS cells. Exposures to P. gingivalis promoted the invasive ability of OSC-20 and SAS cells via the upregulation of matrix metalloproteinases (MMPs), specifically MMP-1 and MMP-2. However, P. gingivalis-infected SCC-25 cells did not exhibit changes in their invasive properties or the low expression levels of MMPs. In an effort to delineate the molecular players that control the invasiveness, we first assessed the level of interleukin-8 (IL-8), a well-known inflammatory cytokine, in P. gingivalis-infected OSCC cells. IL-8 secretion was substantially increased in the OSC-20 and SAS cells, but not in the SCC-25 cells, following P. gingivalis infection. When IL-8 was directly applied to SCC-25 cells, their invasive ability and MMP level were significantly increased. Furthermore, the downregulation of IL-8 in P. gingivalis-infected OSC-20 and SAS cells attenuated their invasive potentials and MMP levels. Taken together, our findings strongly suggest that P. gingivalis infection plays an important role in the promotion of the invasive potential of OSCC cells via the upregulation of IL-8 and MMPs.
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Affiliation(s)
- Na Hee Ha
- Department of Oral Pathology & BK21 PLUS Project, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan 50612, South Korea.
| | - Dae Gun Park
- Department of Oral Pathology & BK21 PLUS Project, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan 50612, South Korea.
| | - Bok Hee Woo
- Department of Oral Pathology & BK21 PLUS Project, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan 50612, South Korea.
| | - Da Jeong Kim
- Department of Oral Pathology & BK21 PLUS Project, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan 50612, South Korea.
| | - Jeom Il Choi
- Department of Periodontology, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan 50612, South Korea.
| | - Bong Soo Park
- Department of Oral Anatomy, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan 50612, South Korea.
| | - Yong Deok Kim
- Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan 50612, South Korea; Institute of Translational Dental Sciences, Pusan National University, 49 Busandaehak-Ro, Yangsan 50612, South Korea.
| | - Ji Hye Lee
- Department of Oral Pathology & BK21 PLUS Project, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan 50612, South Korea; Institute of Translational Dental Sciences, Pusan National University, 49 Busandaehak-Ro, Yangsan 50612, South Korea.
| | - Hae Ryoun Park
- Department of Oral Pathology & BK21 PLUS Project, School of Dentistry, Pusan National University, 49 Busandaehak-Ro, Yangsan 50612, South Korea; Institute of Translational Dental Sciences, Pusan National University, 49 Busandaehak-Ro, Yangsan 50612, South Korea.
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Yan S, Yang B, Shang C, Ma Z, Tang Z, Liu G, Shen W, Zhang Y. Platelet-rich plasma promotes the migration and invasion of synovial fibroblasts in patients with rheumatoid arthritis. Mol Med Rep 2016; 14:2269-75. [DOI: 10.3892/mmr.2016.5500] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 07/06/2016] [Indexed: 11/06/2022] Open
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Banday MZ, Sameer AS, Mir AH, Mokhdomi TA, Chowdri NA, Haq E. Matrix metalloproteinase (MMP) -2, -7 and -9 promoter polymorphisms in colorectal cancer in ethnic Kashmiri population - A case-control study and a mini review. Gene 2016; 589:81-89. [PMID: 27222481 DOI: 10.1016/j.gene.2016.05.028] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2016] [Revised: 04/12/2016] [Accepted: 05/17/2016] [Indexed: 12/11/2022]
Abstract
Matrix metalloproteinases (MMPs) are proteolytic enzymes that play a pivotal role in the transformation and progression of tumors at all stages, especially during the invasion and metastasis. The aim of this study was to determine the genetic association of MMP2, MMP7 and MMP9 promoter polymorphisms with colorectal cancer (CRC) susceptibility and development risk in ethnic Kashmiri population. The genotype frequencies of MMP2-1306C/T, MMP7-181A/G and MMP9-1562C/T SNPs were compared between 142 CRC patients and 184 healthy controls by using PCR-RFLP method. The association between all the three MMP promoter polymorphisms and the modulation of risk of CRC was found to be significant (p≤0.05). The heterozygous genotype (CT) of MMP2-1306C/T SNP and variant genotype (GG) of MMP7-181A/G SNP showed a significant association with decreased risk for the development of CRC [OR, 0.61 (95%CI, 0.37-1.01); p=0.05 and OR, 0.43 (95%CI, 0.20-0.90); p=0.02, respectively] whereas the heterozygous genotype (CT) of MMP9-1562C/T SNP showed a significant association with increased risk for the development of colorectal cancer [OR, 1.88 (95%CI, 1.11-3.18); p=0.02]. Further, the less common MMP9-1562T allele was found to be significantly associated with an increased risk of colorectal cancer [OR, 1.74 (95%CI, 1.15-2.62); p=0.007]. Our results suggest that these MMP2, MMP7 and MMP9 promoter polymorphisms play a role as one of the key modulators of the risk of developing colorectal cancer in Kashmiri population.
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Affiliation(s)
- Mujeeb Zafar Banday
- Department of Biotechnology, University of Kashmir, Hazratbal, Srinagar, Kashmir, India
| | - Aga Syed Sameer
- Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Ashaq Hussain Mir
- Department of Biotechnology, University of Kashmir, Hazratbal, Srinagar, Kashmir, India
| | - Taseem A Mokhdomi
- Department of Biotechnology, University of Kashmir, Hazratbal, Srinagar, Kashmir, India
| | - Nissar A Chowdri
- Department of Surgery, Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India
| | - Ehtishamul Haq
- Department of Biotechnology, University of Kashmir, Hazratbal, Srinagar, Kashmir, India.
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Chude-Okonkwo UAK, Malekian R, Maharaj BTS. Molecular Communication Model for Targeted Drug Delivery in Multiple Disease Sites_newline With Diversely Expressed Enzymes. IEEE Trans Nanobioscience 2016; 15:230-45. [DOI: 10.1109/tnb.2016.2526783] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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