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Mokhtari N, Ahmadi N, Moradi S, Farmani S, Kheyrani E, Dolatabadi NF. Experimental and in silico analysis of LINC01279 expression in tumor of patients with breast cancer. J Appl Genet 2024:10.1007/s13353-024-00908-6. [PMID: 39465460 DOI: 10.1007/s13353-024-00908-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 08/18/2024] [Accepted: 09/22/2024] [Indexed: 10/29/2024]
Abstract
Breast cancer (BC) is characterized by the increase of malignant cells in the breast. The malignant cells begin in the lining of the breast milk glands or ducts (ductal epithelium). BC is the most frequent cancer in women, but it may also occur in males. Long non-coding RNAs (lncRNA) have been demonstrated to control the development and incidence of cancer. However, some lncRNAs experience potential changes in BC, but their role has not been well studied. LINC01279 is known as a valuable biomarker in gastric cancer but has not yet been studied in BC. Changes in LINC01279 expression levels in BC samples were investigated by microarray. Q-PCR was also used to evaluate the expression of LINC01279 in the tumor and normal adjacent samples of 30 BC patients. The LINC01279 co-expressed gene module was discovered using weighted gene correlation network analysis (WGCNA) on the relevant dataset. The top ten hub genes were determined using gene ontology (GO) functional enrichments on the co-expressed gene module. The results of the bioinformatics study showed an increase in LINC01279 expression levels (log2FC = 3.228749561, adj.P.Val = 1.69E - 12) in tumor samples compared to normal marginal tissue. Q-PCR results also showed a significant increase in LINC01279 expression (P-value = 0.0005) in tumor samples. WGCNA analysis identified that the black module is the LINC01279 co-expressed module, and functional annotation analysis of black module genes enriched in significant cancer-related pathways and processes, including cell growth and/or maintenance, regulation of immune response, regulation of cell proliferation, and epithelial-to-mesenchymal transition (EMT). Regarding the real-time PCR results, the analysis of expression patterns has illuminated a distinct association between the heightened expression levels of LINC01279, and the stages of cancer progression as well as the metastatic potential of tumors. However, intriguingly, our observations have failed to reveal any statistically significant correlations between the relative expression of LINC01279 and tumor grade classification, or the presence of ER, PR, and HER2 biomarkers. The present study could provide a new perspective on the molecular regulatory. Processes associated with BC pathogenic mechanisms are linked to the LINC01279, although further research is needed on the possible role of this lncRNA in BC.
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Affiliation(s)
- Negar Mokhtari
- Department of Cellular and Molecular Biology, Islamic Azad University, Najafabad Branch, Isfahan, Iran
| | - Najmeh Ahmadi
- Departmant of Medical Laboratory Sciences, School of Paramedical Sciences, Gerash University of Medical Sciences, Gerash, Iran
| | - Sahar Moradi
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Isfahan, Iran
| | - Shiva Farmani
- Department of Biology, Faculty of Basic Sciences, Yazd University, Yazd, Iran
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Xu W, Tan X, Li ML, Xu H, Villegas J, Fu H. Von Willebrand factor and hematogenous cancer metastasis under flow. Front Cell Dev Biol 2024; 12:1435718. [PMID: 39282473 PMCID: PMC11401050 DOI: 10.3389/fcell.2024.1435718] [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: 05/20/2024] [Accepted: 08/05/2024] [Indexed: 09/19/2024] Open
Abstract
Hematogenous metastasis involves cancer cell migration to different locations from the primary tumor through the blood circulation. Von Willebrand factor (VWF) has been shown to play an important role in tumor cell adhesion to and extravasation from the endothelial cell lining of blood vessel walls during cancer metastasis. VWF may contribute to this process by interacting with tumor cells, endothelial cells, and platelets through various cell membrane receptors, such as platelet glycoprotein (GP)Ibα, P-selectin, ανβ3 and αIIbβ3 integrins, and glycocalyx. Blood flow can mechanically extend and activate VWF to bind platelets and associate intermolecularly with other VWF molecules in plasma or on the surface of endothelial cells, cancer cells, or platelets. This suggests a mechanoregulatory role of VWF in mediating the interactions between VWF and these cells to promote cancer cell adhesion to blood vessels. In this review, we will summarize the current knowledge of VWF function and the role of hydrodynamic forces in hematogenous cancer metastasis.
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Affiliation(s)
- Wenxuan Xu
- Division of Hematology and Oncology, Department of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States
| | - Xi Tan
- Division of Hematology and Oncology, Department of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States
| | - Morgan L Li
- Division of Hematology and Oncology, Department of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States
| | - Hanzhi Xu
- Division of Hematology and Oncology, Department of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States
- Department of Bioengineering, University of Washington, Seattle, WA, United States
| | - Jasmine Villegas
- Division of Hematology and Oncology, Department of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States
- Department of Bioengineering, University of Washington, Seattle, WA, United States
| | - Hongxia Fu
- Division of Hematology and Oncology, Department of Medicine, University of Washington, Seattle, WA, United States
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States
- Department of Bioengineering, University of Washington, Seattle, WA, United States
- Bloodworks Research Institute, Seattle, WA, United States
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Wang X, Zhang X, Zhang C, Qi L, Liu J. Plasma von Willebrand factor levels in patients with cancer: A meta‑analysis. Oncol Lett 2024; 28:399. [PMID: 38979552 PMCID: PMC11228924 DOI: 10.3892/ol.2024.14532] [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: 02/06/2024] [Accepted: 06/17/2024] [Indexed: 07/10/2024] Open
Abstract
von Willebrand Factor (VWF) is well recognized for being dysregulated in various malignancies and has emerged as a potential biomarker for cancer detection. The present meta-analysis aimed to elucidate the association between plasma VWF and the incidence and metastasis of cancer. For this purpose, a comprehensive search was conducted across multiple databases from their inception until March 3, 2023. This culminated in the selection of 15 original studies on various types of cancer, including a collective sample of 1,403 individuals. The standardized mean difference (SMD) and 95% confidence intervals (CIs) were employed as statistical parameters to determine the association between plasma VWF and the incidence and metastasis of cancer. These were estimated using a random-effects model. The pooled data revealed that the plasma VWF levels of patients with cancer were significantly elevated compared with those of healthy controls (SMD, 0.98; 95% CI, 0.59-1.36), and a significant association was observed between plasma VWF levels and cancer metastasis (SMD, 0.69; 95% CI, 0.33-1.06). The symmetry of the Begg's funnel plots indicated that no significant bias was present in the analyses of VWF in cancer and its metastasis. In summary, the results of the present meta-analysis support the hypothesis that increased plasma VWF levels may serve as a biomarker for cancer and metastatic progression.
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Affiliation(s)
- Xitan Wang
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
- Institute of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
| | - Xiaoyu Zhang
- Department of Medical Physiology, School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Chaonan Zhang
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
- Institute of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
| | - Li Qi
- Department of Infectious Diseases, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Ju Liu
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
- Institute of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
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Steyn C, Mishi R, Fillmore S, Verhoog MB, More J, Rohlwink UK, Melvill R, Butler J, Enslin JMN, Jacobs M, Sauka-Spengler T, Greco M, Quiñones S, Dulla CG, Raimondo JV, Figaji A, Hockman D. Cell type-specific gene expression dynamics during human brain maturation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.09.29.560114. [PMID: 37808657 PMCID: PMC10557738 DOI: 10.1101/2023.09.29.560114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
The human brain undergoes protracted post-natal maturation, guided by dynamic changes in gene expression. Most studies exploring these processes have used bulk tissue analyses, which mask cell type-specific gene expression dynamics. Here, using single nucleus (sn)RNA-seq on temporal lobe tissue, including samples of African ancestry, we build a joint paediatric and adult atlas of 75 cell subtypes, which we verify with spatial transcriptomics. We explore the differences between paediatric and adult cell types, revealing the genes and pathways that change during brain maturation. Our results highlight excitatory neuron subtypes, including the LTK and FREM subtypes, that show elevated expression of genes associated with cognition and synaptic plasticity in paediatric tissue. The new resources we present here improve our understanding of the brain during its development and contribute to global efforts to build an inclusive brain cell map.
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Affiliation(s)
- Christina Steyn
- Division of Cell Biology, Department of Human Biology, University of Cape Town, Cape Town, South Africa
- Neuroscience Institute, University of Cape Town, Cape Town, South Africa
| | - Ruvimbo Mishi
- Division of Cell Biology, Department of Human Biology, University of Cape Town, Cape Town, South Africa
- Neuroscience Institute, University of Cape Town, Cape Town, South Africa
| | - Stephanie Fillmore
- Division of Cell Biology, Department of Human Biology, University of Cape Town, Cape Town, South Africa
- Neuroscience Institute, University of Cape Town, Cape Town, South Africa
| | - Matthijs B Verhoog
- Division of Cell Biology, Department of Human Biology, University of Cape Town, Cape Town, South Africa
- Neuroscience Institute, University of Cape Town, Cape Town, South Africa
| | - Jessica More
- Division of Cell Biology, Department of Human Biology, University of Cape Town, Cape Town, South Africa
- Neuroscience Institute, University of Cape Town, Cape Town, South Africa
| | - Ursula K Rohlwink
- Neuroscience Institute, University of Cape Town, Cape Town, South Africa
- Division of Neurosurgery, Department of Surgery, University of Cape Town, Cape Town, South Africa
| | - Roger Melvill
- Division of Neurosurgery, Department of Surgery, University of Cape Town, Cape Town, South Africa
| | - James Butler
- Neuroscience Institute, University of Cape Town, Cape Town, South Africa
- Division of Neurology, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Johannes M N Enslin
- Neuroscience Institute, University of Cape Town, Cape Town, South Africa
- Division of Neurosurgery, Department of Surgery, University of Cape Town, Cape Town, South Africa
| | - Muazzam Jacobs
- Neuroscience Institute, University of Cape Town, Cape Town, South Africa
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
- Division of Immunology, Department of Pathology University of Cape Town
- National Health Laboratory Service, South Africa
| | - Tatjana Sauka-Spengler
- Radcliffe Department of Medicine, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
- Stowers Institute for Medical Research, Kansas City, MO, USA
| | - Maria Greco
- Single Cell Facility, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
| | - Sadi Quiñones
- Department of Neuroscience, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA
- Graduate School of Biomedical Science, Tufts University School of Medicine, Boston, MA, USA
| | - Chris G Dulla
- Department of Neuroscience, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA
| | - Joseph V Raimondo
- Division of Cell Biology, Department of Human Biology, University of Cape Town, Cape Town, South Africa
- Neuroscience Institute, University of Cape Town, Cape Town, South Africa
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Anthony Figaji
- Neuroscience Institute, University of Cape Town, Cape Town, South Africa
- Division of Neurosurgery, Department of Surgery, University of Cape Town, Cape Town, South Africa
| | - Dorit Hockman
- Division of Cell Biology, Department of Human Biology, University of Cape Town, Cape Town, South Africa
- Neuroscience Institute, University of Cape Town, Cape Town, South Africa
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Lu Y, Qi Y, Gu J, Tao Q, Zhu Y, Zhang H, Liang X. Vascular endothelial-derived Von Willebrand factor inhibits lung cancer progression through the αvβ3/ERK1/2 axis. Toxicol Appl Pharmacol 2023; 468:116516. [PMID: 37068611 DOI: 10.1016/j.taap.2023.116516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 04/11/2023] [Accepted: 04/12/2023] [Indexed: 04/19/2023]
Abstract
Lung cancer remains a common malignant tumor causing death due to the rapid industrialization and serious pollution of the environment. The Von Willebrand Factor (vWF) protein is an endothelial marker and is widely used to diagnose cancer and other inflammations, however its exact mechanism of action remains largely unexplored. In particular, how it plays two opposing roles in tumor development is not clear. Our study aimed to the impact of endothelial-derived vWF on tumor development by co-culturing human umbilical vein endothelial cells (HUVECs) with lung cancer cells (95D and A549). A knockdown of endothelial-derived vWF assisted lung cancer cell in proliferation, migration and inhibited apoptosis in vitro, while overexpression of endothelial-derived vWF inhibited the proliferation, migration and induced apoptosis of lung cancer cells. The results of further experiments indicated that the vWF secreted by endothelial cells could affect lung cancer cell migration and apoptosis via its binding to integrin αvβ3 on the surface of lung cancer cells. Furthermore, a novel finding was the fact that endothelial-derived vWF inhibited lung cancer cell apoptosis by phosphorylating ERK1/2. At the same time, we established experimental lung metastasis model and xenograft model in normal mice and vWF-/- mice, and found that knockout of vWF in mice significantly promoted lung cancer growth and metastasis. In conclusion, our research found that endothelial-derived vWF could directly combine to αvβ3 on the exterior of A549 and 95D, thereby mediating lung cancer proliferation, migration and apoptosis and inhibiting the development of lung cancer.
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Affiliation(s)
- Yuxin Lu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Yingxue Qi
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Jiayi Gu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Qianying Tao
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Yifei Zhu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Haibin Zhang
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
| | - Xin Liang
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
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Tao Q, Lu Y, Qi Y, Yu D, Gu J, Zhu Y, Shi C, Liang X. Hypoxia promotes the expression of Von Willebrand factor in breast cancer cells by up-regulating the transcription factor YY1 and down-regulating the hsa-miR-424. Eur J Pharmacol 2022; 934:175308. [DOI: 10.1016/j.ejphar.2022.175308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 09/22/2022] [Accepted: 09/29/2022] [Indexed: 11/03/2022]
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Denis CV, Roullet S, Perrin J. Von Willebrand factor and cancer: Another piece of the puzzle. J Thromb Haemost 2022; 20:2207-2210. [PMID: 35906726 PMCID: PMC9796339 DOI: 10.1111/jth.15810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 07/01/2022] [Indexed: 01/01/2023]
Affiliation(s)
- Cécile V. Denis
- Laboratory for Hemostasis, Inflammation & Thrombosis (HITh)Unité Mixte de Recherche (UMR)‐1176, Institut National de la Santé et de la Recherche Médicale (Inserm), Université Paris‐SaclayLe Kremlin‐BicêtreFrance
| | - Stéphanie Roullet
- Laboratory for Hemostasis, Inflammation & Thrombosis (HITh)Unité Mixte de Recherche (UMR)‐1176, Institut National de la Santé et de la Recherche Médicale (Inserm), Université Paris‐SaclayLe Kremlin‐BicêtreFrance
| | - Julien Perrin
- INSERM, UMR_S 1116Vandœuvre‐lès‐NancyFrance
- Université de Lorraine, DCACNancyFrance
- CHRU Nancy, Service d’hématologie Biologique, Pôle LaboratoiresNancyFrance
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Huang L, Guan S, Feng L, Wei J, Wu L. Integrated analysis identified NPNT as a potential key regulator in tumor metastasis of hepatocellular carcinoma. Gene 2022; 825:146436. [PMID: 35304239 DOI: 10.1016/j.gene.2022.146436] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 02/12/2022] [Accepted: 03/11/2022] [Indexed: 01/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the lethal malignancies worldwide. Tumor metastasis is the main cause of HCC related death. Although progress has been made in the mechanism study of HCC in the past decades, the underlying mechanism of HCC metastasis has not been fully illustrated. In the present study, bioinformatic analysis including weighted gene co-expression network analysis (WGCNA), differentially expressed gene analysis, and gene enrichment analysis were applied to discover genes correlated with HCC metastasis. Immunohistochemistry (IHC) assays were applied to detect the expression of NPNT in HCC samples. Cell transfection, wound healing, matrigel transwell assays, and western blot assays were utilized to evaluate the effects of NPNT on cell migration and invasion and signaling pathway variation. We found that NPNT was up-regulated in HCC tumor tissues compared with normal tissues. Especially, NPNT was highly expressed in metastatic tumor compared with non-metastatic HCC tumors. Down-regulation of NPNT via siRNA transfection inhibited cell migration, invasion, and FAK/PI3K/AKT signaling pathway in HCC. Our results demonstrate that NPNT is a potential key regulator in HCC metastasis.
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Affiliation(s)
- Lingkun Huang
- Medical College, Guangxi University, Nanning 530004, China
| | - Shuzhen Guan
- Medical College, Guangxi University, Nanning 530004, China
| | - Lin Feng
- Department of Pathology, the first Medical Center of PLA General Hospital, Beijing, China
| | - Jinrui Wei
- Guangxi Scientific Research Center of Traditional Chinese Medicine, Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Lichuan Wu
- Medical College, Guangxi University, Nanning 530004, China.
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The Intriguing Connections between von Willebrand Factor, ADAMTS13 and Cancer. Healthcare (Basel) 2022; 10:healthcare10030557. [PMID: 35327035 PMCID: PMC8953111 DOI: 10.3390/healthcare10030557] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/06/2022] [Accepted: 03/14/2022] [Indexed: 12/21/2022] Open
Abstract
von Willebrand factor (VWF) is a complex and large protein that is cleaved by ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13), and together they serve important roles in normal hemostasis. Malignancy can result in both a deficiency or excess of VWF, leading to aberrant hemostasis with either increased bleeding or thrombotic complications, as respectively seen with acquired von Willebrand syndrome and cancer-associated venous thromboembolism. There is emerging evidence to suggest VWF also plays a role in inflammation, angiogenesis and tumor biology, and it is likely that VWF promotes tumor metastasis. High VWF levels have been documented in a number of malignancies and in some cases correlate with more advanced disease and poor prognosis. Tumor cells can induce endothelial cells to release VWF and certain tumor cells have the capacity for de novo expression of VWF, leading to a proinflammatory microenvironment that is likely conducive to tumor progression, metastasis and micro-thrombosis. VWF can facilitate tumor cell adhesion to endothelial cells and aids with the recruitment of platelets into the tumor microenvironment, where tumor/platelet aggregates are able to form and facilitate hematogenous spread of cancer. As ADAMTS13 moderates VWF level and activity, it too is potentially involved in the pathophysiology of these events. VWF and ADAMTS13 have been explored as tumor biomarkers for the detection and prognostication of certain malignancies; however, the results are underdeveloped and so currently not utilized for clinical use. Further studies addressing the basic science mechanisms and real word epidemiology are required to better appreciate the intriguing connections between VWF, ADAMTS13 and malignancy. A better understanding of the role VWF and ADAMTS13 play in the promotion and inhibition of cancer and its metastasis will help direct further translational studies to aid with the development of novel cancer prognostic tools and treatment modalities.
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Gu J, Qi Y, Lu Y, Tao Q, Yu D, Jiang C, Liu J, Liang X. Lung adenocarcinoma-derived vWF promotes tumor metastasis by regulating PHKG1-mediated glycogen metabolism. Cancer Sci 2022; 113:1362-1376. [PMID: 35150045 PMCID: PMC8990721 DOI: 10.1111/cas.15298] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 01/20/2022] [Accepted: 02/01/2022] [Indexed: 11/29/2022] Open
Abstract
Tumor metastasis is a series of complicated biological events. Hematogenous metastasis mediated by von Willebrand factor (vWF) is critical in tumor metastasis. However, the source of vWF and its role in tumor metastasis are controversial, and the further mechanism involved in mediating tumor metastasis is still unclear. In this study, we first demonstrated that lung adenocarcinoma cells could express vWF de novo and promotes tumor metastasis. Through the analysis of transcriptome sequencing, metastasis promotion effect of vWF may be related to phosphorylase kinase subunit G1 (PHKG1), a catalytic subtype of phosphorylase kinase PhK. PHKG1 was highly expressed in lung adenocarcinoma patients and led to poor prognosis. Further experiments found that lung adenocarcinoma-derived vWF induced the up-regulation of PHKG1 through the PI3K/AKT pathway to promote glycogenolysis. Glycogen was funneled into glycolysis, leading to increased metastasis. Tumor metastasis assayed in vitro and in vivo showed that knockdown of PHKG1 or synergistic injection of phosphorylase inhibition based on the overexpression of vWF could inhibit metastasis. In summary, our research proved that lung adenocarcinoma-derived vWF may mediate tumor metastasis by regulating PHKG1 to promote glycogen metabolism, and suggested potential targets for inhibition of lung adenocarcinoma metastasis.
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Affiliation(s)
- Jiayi Gu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Yingxue Qi
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Yuxin Lu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Qianying Tao
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Die Yu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.,Central laboratory, General Surgery, Putuo Hospital, and Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, PR China
| | - Chunchun Jiang
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Jianwen Liu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Xin Liang
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China
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11
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Ao T, Mochizuki S, Kajiwara Y, Yonemura K, Shiraishi T, Nagata K, Shinto E, Okamoto K, Nearchou IP, Shimazaki H, Kishi Y, Okada Y, Ueno H. Cancer-associated fibroblasts at the unfavorable desmoplastic stroma promote colorectal cancer aggressiveness: potential role of ADAM9. Int J Cancer 2022; 150:1706-1721. [PMID: 35080810 DOI: 10.1002/ijc.33947] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 12/10/2021] [Accepted: 01/04/2022] [Indexed: 11/11/2022]
Abstract
The tumor microenvironment plays a key role in cancer aggressiveness. Desmoplastic reaction (DR), morphologically classified as Mature, Intermediate and Immature types, has previously been shown to be highly prognostic in colorectal cancer (CRC) and it consists to a large extent of cancer-associated fibroblasts (CAFs). The aim of this study was to characterize the molecular background of DR and understand the effects of CAFs in tumor aggressiveness. The prognostic significance of DR was initially examined in 1,497 patients. Then CAFs originating from patient tissues with different DR types were isolated and their impact on tumor growth was examined both in vitro and in vivo. DR was shown to be highly prognostic, with patients within the Immature DR group conferring the worst relapse-free survival. The conditioned media of CAFs from tumor with Immature-type DR (CAFsImmature ) significantly increased proliferation and migration of CRC cell lines and growth of CRC-derived organoids compared to that of CAFs from Mature-type DR (CAFsMature ). Subcutaneous or orthotopic implantation of CRC cells together with CAFsImmature in mice significantly promoted tumor growth and dissemination compared to implantation with CAFsMature . Systematic examination of the expression of "a disintegrin and metalloproteinases" (ADAMs) in CAFs isolated from CRC tissues showed that the secreted isoform of ADAM9 (ADAM9s) was significantly higher in CAFsImmature than in CAFsMature . Knockdown of ADAM9s in CAFsImmature abrogated the promoting effects on CRC cell proliferation and migration. CAFs-derived ADAM9s is implicated in deteriorating survival in CRC patients with Immature-type DR by increasing tumor cell proliferation and dissemination. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Tadakazu Ao
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Satsuki Mochizuki
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Yoshiki Kajiwara
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Keisuke Yonemura
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Takehiro Shiraishi
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Ken Nagata
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Eiji Shinto
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Koichi Okamoto
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Ines P Nearchou
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Hideyuki Shimazaki
- Department of Laboratory Medicine, National Defence Medical College, Tokorozawa, Saitama, Japan
| | - Yoji Kishi
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Yasunori Okada
- Department of Pathophysiology for Locomotive and Neoplastic Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hideki Ueno
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
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12
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Alavi P, Rathod AM, Jahroudi N. Age-Associated Increase in Thrombogenicity and Its Correlation with von Willebrand Factor. J Clin Med 2021; 10:4190. [PMID: 34575297 PMCID: PMC8472522 DOI: 10.3390/jcm10184190] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/08/2021] [Accepted: 09/10/2021] [Indexed: 02/07/2023] Open
Abstract
Endothelial cells that cover the lumen of all blood vessels have the inherent capacity to express both pro and anticoagulant molecules. However, under normal physiological condition, they generally function to maintain a non-thrombogenic surface for unobstructed blood flow. In response to injury, certain stimuli, or as a result of dysfunction, endothelial cells release a highly adhesive procoagulant protein, von Willebrand factor (VWF), which plays a central role in formation of platelet aggregates and thrombus generation. Since VWF expression is highly restricted to endothelial cells, regulation of its levels is among the most important functions of endothelial cells for maintaining hemostasis. However, with aging, there is a significant increase in VWF levels, which is concomitant with a significant rise in thrombotic events. It is not yet clear why and how aging results in increased VWF levels. In this review, we have aimed to discuss the age-related increase in VWF, its potential mechanisms, and associated coagulopathies as probable consequences.
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Affiliation(s)
| | | | - Nadia Jahroudi
- Department of Medicine, University of Alberta, Edmonton, AB T6G 2S2, Canada; (P.A.); (A.M.R.)
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13
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Mojzisch A, Brehm MA. The Manifold Cellular Functions of von Willebrand Factor. Cells 2021; 10:2351. [PMID: 34572000 PMCID: PMC8466076 DOI: 10.3390/cells10092351] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 08/26/2021] [Accepted: 09/02/2021] [Indexed: 12/13/2022] Open
Abstract
The plasma glycoprotein von Willebrand factor (VWF) is exclusively synthesized in endothelial cells (ECs) and megakaryocytes, the precursor cells of platelets. Its primary function lies in hemostasis. However, VWF is much more than just a "fishing hook" for platelets and a transporter for coagulation factor VIII. VWF is a true multitasker when it comes to its many roles in cellular processes. In ECs, VWF coordinates the formation of Weibel-Palade bodies and guides several cargo proteins to these storage organelles, which control the release of hemostatic, inflammatory and angiogenic factors. Leukocytes employ VWF to assist their rolling on, adhesion to and passage through the endothelium. Vascular smooth muscle cell proliferation is supported by VWF, and it regulates angiogenesis. The life cycle of platelets is accompanied by VWF from their budding from megakaryocytes to adhesion, activation and aggregation until the end in apoptosis. Some tumor cells acquire the ability to produce VWF to promote metastasis and hide in a shell of VWF and platelets, and even the maturation of osteoclasts is regulated by VWF. This review summarizes the current knowledge on VWF's versatile cellular functions and the resulting pathophysiological consequences of their dysregulation.
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Affiliation(s)
- Angelika Mojzisch
- Dermatology and Venerology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
| | - Maria A. Brehm
- School of Life Sciences, University of Siegen, 57076 Siegen, Germany
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14
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Sobol NT, Solernó LM, Beltrán B, Vásquez L, Ripoll GV, Garona J, Alonso DF. Anticancer activity of repurposed hemostatic agent desmopressin on AVPR2-expressing human osteosarcoma. Exp Ther Med 2021; 21:566. [PMID: 33850538 PMCID: PMC8027742 DOI: 10.3892/etm.2021.9998] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 12/03/2020] [Indexed: 01/15/2023] Open
Abstract
Osteosarcoma is the most prevalent primary bone malignancy. Due to its high aggressiveness, novel treatment strategies are urgently required to improve survival of patients with osteosarcoma, especially those with advanced disease. Desmopressin (dDAVP) is a widely used blood-saving agent that has been repurposed as an adjuvant agent for cancer management due to its antiangiogenic and antimetastatic properties. dDAVP acts as a selective agonist of the vasopressin membrane receptor type 2 (AVPR2) present in the microvascular endothelium and in some cancer cells, including breast, lung, colorectal and neuroendocrine tumor cells. Despite the fact that dDAVP has demonstrated its antitumor efficacy in a wide variety of tumor types, exploration of its potential anti-osteosarcoma activity has, to the best of our knowledge, not yet been conducted. Therefore, the aim of the present study was to evaluate the preclinical antitumor activity of dDAVP in osteosarcoma. Human MG-63 and U-2 OS osteosarcoma cell lines were used to assess in vitro and in vivo therapeutic effects of dDAVP. At low micromolar concentrations, dDAVP reduced AVPR2-expressing MG-63 cell growth in a concentration-dependent manner. In contrast, dDAVP exhibited no direct cytostatic effect on AVPR2-negative U-2 OS cells. As it would be expected for canonical AVPR2-activation, dDAVP raised intracellular cAMP levels in osteosarcoma cells, and coincubation with phosphodiesterase-inhibitor rolipram indicated synergistic antiproliferative activity. Cytostatic effects were associated with increased apoptosis, reduced mitotic index and impairment of osteosarcoma cell chemotaxis, as evaluated by TUNEL-labeling, mitotic body count in DAPI-stained cultures and Transwell migration assays. Intravenous administration of dDAVP (12 µg/kg; three times per week) to athymic mice bearing rapidly growing MG-63 xenografts, was indicated to be capable of reducing tumor progression after a 4-week treatment. No major alterations in animal weight, biochemical or hematological parameters were associated with dDAVP treatment, confirming its good tolerability and safety. Finally, AVPR2 expression was detected by immunohistochemistry in 66% of all evaluated chemotherapy-naive human conventional osteosarcoma biopsies. Taking these findings into account, repurposed agent dDAVP may represent an interesting therapeutic tool for the management of osteosarcoma. Further preclinical exploration of dDAVP activity on orthotopic or metastatic osteosarcoma models are required.
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Affiliation(s)
- Natasha Tatiana Sobol
- Center of Molecular and Translational Oncology, National University of Quilmes, Bernal B1876BXD, Buenos Aires, Argentina
| | - Luisina María Solernó
- Center of Molecular and Translational Oncology, National University of Quilmes, Bernal B1876BXD, Buenos Aires, Argentina
| | - Brady Beltrán
- Precision Medicine Research Center, School of Medicine, University of San Martín de Porres, Lima 15024, Perú
| | - Liliana Vásquez
- Precision Medicine Research Center, School of Medicine, University of San Martín de Porres, Lima 15024, Perú
| | - Giselle Vanina Ripoll
- Center of Molecular and Translational Oncology, National University of Quilmes, Bernal B1876BXD, Buenos Aires, Argentina
- National Council of Scientific and Technical Research (CONICET), Buenos Aires C1425FQB, Argentina
| | - Juan Garona
- Center of Molecular and Translational Oncology, National University of Quilmes, Bernal B1876BXD, Buenos Aires, Argentina
- National Council of Scientific and Technical Research (CONICET), Buenos Aires C1425FQB, Argentina
| | - Daniel Fernando Alonso
- Center of Molecular and Translational Oncology, National University of Quilmes, Bernal B1876BXD, Buenos Aires, Argentina
- National Council of Scientific and Technical Research (CONICET), Buenos Aires C1425FQB, Argentina
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15
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Apanovich N, Apanovich P, Mansorunov D, Kuzevanova A, Matveev V, Karpukhin A. The Choice of Candidates in Survival Markers Based on Coordinated Gene Expression in Renal Cancer. Front Oncol 2021; 11:615787. [PMID: 34046336 PMCID: PMC8144703 DOI: 10.3389/fonc.2021.615787] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 03/25/2021] [Indexed: 12/18/2022] Open
Abstract
We aimed to identify and investigate genes that are essential for the development of clear cell renal cell carcinoma (ccRCC) and sought to shed light on the mechanisms of its progression and create prognostic markers for the disease. We used real-time PCR to study the expression of 20 genes that were preliminarily selected based on their differential expression in ccRCC, in 68 paired tumor/normal samples. Upon ccRCC progression, seven genes that showed an initial increase in expression showed decreased expression. The genes whose expression levels did not significantly change during progression were associated mainly with metabolic and inflammatory processes. The first group included CA9, NDUFA4L2, EGLN3, BHLHE41, VWF, IGFBP3, and ANGPTL4, whose expression levels were coordinately decreased during tumor progression. This expression coordination and gene function is related to the needs of tumor development at different stages. Specifically, the high correlation coefficient of EGLN3 and NDUFA4L2 expression may indicate the importance of the coordinated regulation of glycolysis and mitochondrial metabolism. A panel of CA9, EGLN3, BHLHE41, and VWF enabled the prediction of survival for more than 3.5 years in patients with ccRCC, with a probability close to 90%. Therefore, a coordinated change in the expression of a gene group during ccRCC progression was detected, and a new panel of markers for individual survival prognosis was identified.
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Affiliation(s)
- Natalya Apanovich
- Laboratory of Molecular Genetics of Complex Inherited Diseases, Research Centre for Medical Genetics, Moscow, Russia
| | - Pavel Apanovich
- Laboratory of Molecular Genetics of Complex Inherited Diseases, Research Centre for Medical Genetics, Moscow, Russia
| | - Danzan Mansorunov
- Laboratory of Molecular Genetics of Complex Inherited Diseases, Research Centre for Medical Genetics, Moscow, Russia
| | - Anna Kuzevanova
- Laboratory of Molecular Genetics of Complex Inherited Diseases, Research Centre for Medical Genetics, Moscow, Russia
| | - Vsevolod Matveev
- Department of Oncourology, Federal State Budgetary Institution “N.N. Blokhin National Medical Research Center of Oncology” of the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Alexander Karpukhin
- Laboratory of Molecular Genetics of Complex Inherited Diseases, Research Centre for Medical Genetics, Moscow, Russia
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16
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Kawai T, Elliott KJ, Scalia R, Eguchi S. Contribution of ADAM17 and related ADAMs in cardiovascular diseases. Cell Mol Life Sci 2021; 78:4161-4187. [PMID: 33575814 PMCID: PMC9301870 DOI: 10.1007/s00018-021-03779-w] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/23/2020] [Accepted: 01/27/2021] [Indexed: 02/06/2023]
Abstract
A disintegrin and metalloproteases (ADAMs) are key mediators of cell signaling by ectodomain shedding of various growth factors, cytokines, receptors and adhesion molecules at the cellular membrane. ADAMs regulate cell proliferation, cell growth, inflammation, and other regular cellular processes. ADAM17, the most extensively studied ADAM family member, is also known as tumor necrosis factor (TNF)-α converting enzyme (TACE). ADAMs-mediated shedding of cytokines such as TNF-α orchestrates immune system or inflammatory cascades and ADAMs-mediated shedding of growth factors causes cell growth or proliferation by transactivation of the growth factor receptors including epidermal growth factor receptor. Therefore, increased ADAMs-mediated shedding can induce inflammation, tissue remodeling and dysfunction associated with various cardiovascular diseases such as hypertension and atherosclerosis, and ADAMs can be a potential therapeutic target in these diseases. In this review, we focus on the role of ADAMs in cardiovascular pathophysiology and cardiovascular diseases. The main aim of this review is to stimulate new interest in this area by highlighting remarkable evidence.
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Affiliation(s)
- Tatsuo Kawai
- Cardiovascular Research Center, Lewis Katz School of Medicine At Temple University, Philadelphia, PA, USA
| | - Katherine J Elliott
- Cardiovascular Research Center, Lewis Katz School of Medicine At Temple University, Philadelphia, PA, USA
| | - Rosario Scalia
- Cardiovascular Research Center, Lewis Katz School of Medicine At Temple University, Philadelphia, PA, USA
| | - Satoru Eguchi
- Cardiovascular Research Center, Lewis Katz School of Medicine At Temple University, Philadelphia, PA, USA.
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17
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ADAM28 from both endothelium and gastric cancer cleaves von Willebrand Factor to eliminate von Willebrand Factor-induced apoptosis of gastric cancer cells. Eur J Pharmacol 2021; 898:173994. [PMID: 33675784 DOI: 10.1016/j.ejphar.2021.173994] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 02/26/2021] [Accepted: 02/28/2021] [Indexed: 11/20/2022]
Abstract
Disintegrin and metalloproteinase 28 (ADAM28) is a member of the disintegrin and metalloprotease domain (ADAM) family. It is associated with the growth and metastasis of various malignancies in vivo, but its role in gastric cancer remains unclear. The purpose of this study was to investigate the effect of ADAM28 derived from gastric cancer and endothelium on gastric cancer cells and its related mechanisms. In this study, Western blot analysis and q-PCR results showed that ADAM28 was up-regulated in gastric cancer cell lines. The TCGA database showed that patients with high ADAM28 expression had significantly shorter overall survival than those with low ADAM28 expression. By MTT analysis, wound healing assay, and flow cytometry, we found that overexpression/knockdown of ADAM28 expression in gastric cancer cells can regulate cell proliferation, apoptosis and migration in vitro. In addition, overexpression/knockdown of ADAM28 in human umbilical vein endothelial cells (HUVECs) in the upper ventricle can regulate the apoptosis of lower ventricular gastric cancer cells in the co-culture system. Furthermore, ELISA demonstrated that knockdown of ADAM28 from endothelial cells increased the expression of von Willebrand Factor (vWF) in the supernatant. We found that ADAM28 both from gastric cancer cells and HUVECs eliminated vWF-induced apoptosis of gastric cancer cells by cleaving vWF, and the addition of the vWF knockdown plasmid eliminated the increase of integrin β3, p-TP53 and c-Casp3 caused by ADAM28 knockdown. In conclusion, ADAM28 from endothelium and gastric cancer may cleave vWF to eliminate vWF-induced apoptosis of gastric cancer cells and play an pro-metastasis effect.
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18
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Goh CY, Patmore S, Smolenski A, Howard J, Evans S, O'Sullivan J, McCann A. The role of von Willebrand factor in breast cancer metastasis. Transl Oncol 2021; 14:101033. [PMID: 33571850 PMCID: PMC7876567 DOI: 10.1016/j.tranon.2021.101033] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 01/12/2021] [Accepted: 01/28/2021] [Indexed: 01/16/2023] Open
Abstract
VWF plays an important role in breast tumour progression and metastasis. Patients with metastatic breast cancer have significantly elevated plasma VWF. Increased levels of highly adhesive VWF may regulate platelet-tumour interactions. VWF may protect disseminated tumour cells from chemotherapy. Breast cancer is the most common female cancer globally, with approximately 12% of patients eventually developing metastatic disease. Critically, limited effective treatment options exist for metastatic breast cancer. Recently, von Willebrand factor (VWF), a haemostatic plasma glycoprotein, has been shown to play an important role in tumour progression and metastasis. In breast cancer, a significant rise in the plasma levels of VWF has been reported in patients with malignant disease compared to benign conditions and healthy controls, with an even greater increase seen in patients with disseminated disease. Direct interactions between VWF, tumour cells, platelets and endothelial cells may promote haematogenous dissemination and thus the formation of metastatic foci. Intriguingly, patients with metastatic disease have unusually large VWF multimers. This observation has been proposed to be a result of a dysfunctional or deficiency of VWF-cleaving protease activity, ADAMTS-13 activity, which may then regulate the platelet-tumour adhesive interactions in the metastatic process. In this review, we provide an overview of VWF in orchestrating the pathological process of breast cancer dissemination, and provide supporting evidence of the role of VWF in mediating metastatic breast cancer.
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Affiliation(s)
- Chia Yin Goh
- UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Dublin 4, Ireland; UCD School of Medicine, College of Health and Agricultural Sciences (CHAS), University College Dublin, Belfield, Dublin, Dublin 4, Ireland.
| | - Sean Patmore
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Dublin 2, Ireland
| | - Albert Smolenski
- UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Dublin 4, Ireland; UCD School of Medicine, College of Health and Agricultural Sciences (CHAS), University College Dublin, Belfield, Dublin, Dublin 4, Ireland
| | - Jane Howard
- UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Dublin 4, Ireland
| | - Shane Evans
- UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Dublin 4, Ireland; UCD School of Medicine, College of Health and Agricultural Sciences (CHAS), University College Dublin, Belfield, Dublin, Dublin 4, Ireland
| | - Jamie O'Sullivan
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Dublin 2, Ireland
| | - Amanda McCann
- UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Dublin 4, Ireland; UCD School of Medicine, College of Health and Agricultural Sciences (CHAS), University College Dublin, Belfield, Dublin, Dublin 4, Ireland
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19
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Patmore S, Dhami SPS, O'Sullivan JM. Von Willebrand factor and cancer; metastasis and coagulopathies. J Thromb Haemost 2020; 18:2444-2456. [PMID: 32573945 DOI: 10.1111/jth.14976] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 06/05/2020] [Accepted: 06/12/2020] [Indexed: 12/16/2022]
Abstract
Von Willebrand factor (VWF) is a multimeric procoagulant plasma glycoprotein that mediates platelet adhesion along the endothelium. In addition to its role maintaining normal hemostasis, more recently novel biological functions for VWF have been described, including inflammation, angiogenesis, and metastasis. Significantly increased plasma VWF levels have been reported across a variety of cancer patient cohorts. Given that VWF is established as a risk factor for venous thrombosis, this is of direct clinical importance. Moreover, elevated VWF has also been observed localized within the tumor microenvironment, correlating with advanced disease stage and poorer clinical outcome. Critically, evidence suggests that elevated VWF levels in cancer patients may not only contribute to cancer associated coagulopathies but may also mediate cancer progression and metastasis. Studies have shown that VWF can promote pro-inflammatory signaling, regulate angiogenesis and vascular permeability, which may facilitate tumor cell growth and extravasation across the vessel wall. Endothelial secreted VWF multimers contribute to the adhesion and transendothelial migration of tumor cells key for tumor dissemination. In support of this, VWF inhibition attenuated metastasis in vivo. Perhaps most intriguingly, specific tumor cells have been reported to acquire de novo VWF expression which increases tumor-platelet heteroaggregates and confers enhanced metastatic activity. Current knowledge on the roles of VWF in cancer and in particular its contribution to metastasis and cancer associated coagulopathies is summarized in this review.
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Affiliation(s)
- Sean Patmore
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Sukhraj Pal S Dhami
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Jamie M O'Sullivan
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
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20
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Hubeau C, Rocks N, Cataldo D. ADAM28: Another ambivalent protease in cancer. Cancer Lett 2020; 494:18-26. [PMID: 32861707 DOI: 10.1016/j.canlet.2020.08.031] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 08/05/2020] [Accepted: 08/21/2020] [Indexed: 01/10/2023]
Abstract
Emergence of novel therapeutic options in a perspective of personalized therapy of cancer relies on the discovery of precise molecular mechanisms involved in the switch from a localized tumor to invasive metastasis spread. Pro-tumor functions have been mostly ascribed to proteolytic enzymes from the metalloproteinase family including A Disintegrin And Metalloproteinases (ADAMs). Particularly, when expressed by cancer cells, ADAM28 protease supports cancer cell proliferation, survival and migration as well as metastatic progression. In sharp contrast, ADAM28 derived from the tumor microenvironment has shown to exert strong protective effects against deleterious metastasis dissemination. Indeed, depletion of host-derived ADAM28 (ADAM28 KO mice) accelerates colonization lung tissues, increases tumor foci implantation, and impairs T cell immune response. In this review, we outline specific ADAM28 functions when specifically expressed by carcinoma cells or by tumor microenvironment. Finally, we discuss about future research strategies that could be pursued to highlight new functions of this protease in cancer.
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Affiliation(s)
- Céline Hubeau
- Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Liège, Liège, Belgium
| | - Natacha Rocks
- Laboratory of Pharmaceutical Technology and Biopharmacy, CIRM, University of Liège, Liège, Belgium
| | - Didier Cataldo
- Laboratory of Tumor and Development Biology, GIGA-Cancer, University of Liège, Liège, Belgium; Department of Respiratory Diseases, CHU of Liège, University of Liège, Liège, Belgium.
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21
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Zou Y, Zhao X, Li Y, Duan S. miR-552: an important post-transcriptional regulator that affects human cancer. J Cancer 2020; 11:6226-6233. [PMID: 33033505 PMCID: PMC7532495 DOI: 10.7150/jca.46613] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 08/14/2020] [Indexed: 12/12/2022] Open
Abstract
MiR-552 is a small non-coding RNA located on chromosome 1p34.3, and its expression level is significantly up-regulated in tissues or cells of various tumors. miR-552 can target multiple genes. These targeted genes play important regulatory roles in biological processes such as gene transcription and translation, cell cycle progression, cell proliferation, apoptosis, cell migration, and invasion. Besides, miR-552 may affect the efficacy of various anticancer drugs by targeting genes such as TP53 and RUNX3. This review summarizes the biological functions and clinical expressions of miR-552 in human cancer. Our goal is to explore the potential value of miR-552 in the diagnosis, prognosis, and treatment of human cancer.
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Affiliation(s)
- Yuhao Zou
- Medical Genetics Center, Ningbo University School of Medicine, Ningbo, Zhejiang, China
| | - Xin Zhao
- Medical Genetics Center, Ningbo University School of Medicine, Ningbo, Zhejiang, China
| | - Yin Li
- Medical Genetics Center, Ningbo University School of Medicine, Ningbo, Zhejiang, China
| | - Shiwei Duan
- Medical Genetics Center, Ningbo University School of Medicine, Ningbo, Zhejiang, China
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22
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Zhai W, Lu H, Dong S, Fang J, Yu Z. Identification of potential key genes and key pathways related to clear cell renal cell carcinoma through bioinformatics analysis. Acta Biochim Biophys Sin (Shanghai) 2020; 52:853-863. [PMID: 32556097 DOI: 10.1093/abbs/gmaa068] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Revised: 10/17/2019] [Accepted: 12/26/2019] [Indexed: 12/16/2022] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is a common malignancy of the genitourinary system and is associated with high mortality rates. However, the molecular mechanism of ccRCC pathogenesis is still unclear, which translates to few effective diagnostic and prognostic biomarkers. In this study, we conducted a bioinformatics analysis on three Gene Expression Omnibus datasets and identified 437 differentially expressed genes (DEGs) related to ccRCC development and prognosis, of which 311 and 126 genes are respectively down-regulated and up-regulated. The protein-protein interaction network of these DEGs consists of 395 nodes and 1872 interactions and 2 prominent modules. The Staphylococcus aureus infection and complement and coagulation cascades are significantly enriched in module 1 and are likely involved in ccRCC progression. Forty-two hub genes were screened, of which von Willebrand factor, TIMP metallopeptidase inhibitor 1, plasminogen, formimidoyltransferase cyclodeaminase, solute carrier family 34 member 1, hydroxyacid oxidase 2, alanine-glyoxylate aminotransferase 2, phosphoenolpyruvate carboxykinase 1, and 3-hydroxy-3-methylglutaryl-CoA synthase 2 are possibly related to the prognosis of ccRCC. The differential expression of all nine genes was confirmed by quantitative real-time polymerase chain reaction analysis of the ccRCC and normal renal tissues. These key genes are potential biomarkers for the diagnosis and prognosis of ccRCC and warrant further investigation.
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Affiliation(s)
- Wenxin Zhai
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Haijiao Lu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200000, China
| | - Shenghua Dong
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Jing Fang
- Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
| | - Zhuang Yu
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao 266000, China
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23
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Sorenmo K, Durham AC, Evans B, Scavello H, Stefanovski D. A prospective randomized trial of desmopressin in canine mammary carcinoma. Vet Comp Oncol 2020; 18:796-803. [PMID: 32441479 DOI: 10.1111/vco.12619] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 05/13/2020] [Accepted: 05/14/2020] [Indexed: 11/28/2022]
Abstract
Metastatic disease represents a serious and often fatal development in patients with solid tumours, including women with breast cancer and dogs with mammary tumours. Therefore, preventing and treating metastatic disease has remained a priority in cancer research. Desmopressin, a synthetic derivative of vasopressin, traditionally used to treat patients with bleeding disorders, has been proposed as a potential anti-metastatic agent due to its effect on haemostasis as well as multiple other anti-proliferative and anti-angiogenic mechanisms. The purpose of this study was to retest desmopressin in dogs with mammary carcinomas. A prospective randomized study was performed. Twenty-four dogs with mammary carcinomas were enrolled; 12 dogs received perioperative desmopressin and 12 received placebo. All dogs underwent standard pre-surgical staging followed by complete resection of all tumours. Intact dogs were spayed. All tumours were graded and classified according to the published guidelines. Follow-up was performed every 4 months the first year and every 6 months thereafter. Necropsies were requested on all dogs. There was no difference in time to primary metastasis or survival between desmopressin treated dogs and the placebo arm (P = .43 and .73, respectively). The distribution of negative prognostic factors, including tumour grade, stage, and high vs low bioscore (refined flexible bioscoring) category between arms was not statistically different, even though more dogs in the placebo arm had grade 3 tumours and high bioscores. Based on the results of this study, perioperative desmopressin does not prevent metastasis in dogs with mammary carcinomas.
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Affiliation(s)
- Karin Sorenmo
- Department of Biomedical Sciences School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Penn Vet Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Amy C Durham
- Penn Vet Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Brolin Evans
- Department of Clinical Sciences & Advanced Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Heather Scavello
- Veterinary Clinical Investigation Center (VCIC), University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Darko Stefanovski
- Department of Clinical Studies-New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Garona J, Pifano M, Ripoll G, Alonso DF. Development and therapeutic potential of vasopressin synthetic analog [V 4Q 5]dDAVP as a novel anticancer agent. VITAMINS AND HORMONES 2020; 113:259-289. [PMID: 32138951 DOI: 10.1016/bs.vh.2019.08.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Since its discovery, arginine vasopressin (AVP) was subjected to several modifications with the aim of obtaining novel derivatives with increased potency and selectivity for biomedical use. Desmopressin (dDAVP) is a first generation synthetic analog of AVP with hemostatic and antimetastatic activity. dDAVP acts as a selective agonist of the arginine vasopressin type 2 receptor (AVPR2) present in microvascular endothelium and cancer cells. Considering its selective effects on AVPR2-expressing malignant and vascular tissue, and interesting antitumor profile, dDAVP was used as a lead compound for the development of novel peptide analogs with enhanced anticancer efficacy. After conducting different structure-activity relationship studies to determine key aminoacidic positions for its antitumor activity against AVPR2-expressing malignant cells, dDAVP was rationally modified and a wide panel of synthetic analogs with different sequence and structural modifications was assessed. As a result of this structure-based drug derivatization novel AVP analog [V4Q5]dDAVP (1-deamino-4-valine-5-glutamine-8-d-arginine vasopressin) was selected as the most active candidate and further developed. [V4Q5]dDAVP was evaluated in highly aggressive and metastatic cancer preclinical models deploying enhanced cytostatic, antimetastatic and angiostatic effects in comparison to parental peptide dDAVP. In addition, novel compound demonstrated good tolerability as evaluated in several toxicological studies, and cooperative therapeutic effects after combination with standard-of-care chemotherapy. In summary, due to its ability to inhibit growth and tumor-associated angiogenesis, as well as impairing progression of metastatic disease, AVP analogs such as novel [V4Q5]dDAVP are promising compounds for further development as coadjuvant agents for the management of advance or recurrent cancers.
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Affiliation(s)
- Juan Garona
- Laboratory of Molecular Oncology, Science and Technology Department, National University of Quilmes, Buenos Aires, Argentina.
| | - Marina Pifano
- Laboratory of Molecular Oncology, Science and Technology Department, National University of Quilmes, Buenos Aires, Argentina
| | - Giselle Ripoll
- Laboratory of Molecular Oncology, Science and Technology Department, National University of Quilmes, Buenos Aires, Argentina
| | - Daniel F Alonso
- Laboratory of Molecular Oncology, Science and Technology Department, National University of Quilmes, Buenos Aires, Argentina
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Takaya H, Namisaki T, Kitade M, Kaji K, Nakanishi K, Tsuji Y, Shimozato N, Moriya K, Seki K, Sawada Y, Saikawa S, Sato S, Kawaratani H, Akahane T, Noguchi R, Matsumoto M, Yoshiji H. VWF/ADAMTS13 ratio as a potential biomarker for early detection of hepatocellular carcinoma. BMC Gastroenterol 2019; 19:167. [PMID: 31638892 PMCID: PMC6802329 DOI: 10.1186/s12876-019-1082-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 09/20/2019] [Indexed: 02/08/2023] Open
Abstract
Background To investigate the von Willebrand factor to ADAMTS13 ratio as a potential biomarker for early detection of hepatocellular carcinoma (HCC) in cirrhosis. Methods Serum levels of alpha-fetoprotein, des-γ-carboxy prothrombin, Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (alpha-fetoprotein-L3%), vascular endothelial growth factor, and vascular endothelial growth factor receptor-2, as well as the plasma levels of von Willebrand factor antigen (von Willebrand factor: Ag) and ADAMTS13 activity (ADAMTS13:AC), were evaluated in 41 cirrhotic patients with HCC undergoing radiofrequency ablation and in 20 cirrhotic patients without HCC. The diagnostic accuracy of each biomarker was evaluated using the receiver operating characteristic curve analysis. Results The von Willebrand factor: Ag and von Willebrand factor: Ag/ADAMTS13:AC ratios were significantly higher in cirrhotic patients with HCC than in those without HCC (p < 0.05 and p < 0.01, respectively), whereas ADAMTS13:AC was significantly lower in those with HCC than those without HCC (p < 0.05). However, no relationship was observed between the von Willebrand factor: Ag/ADAMTS13:AC ratio and serum tumor markers such as alpha-fetoprotein, des-γ-carboxy prothrombin, and alpha-fetoprotein-L3%. Multivariate regression analysis identified von Willebrand factor: Ag/ADAMTS13:AC ratio and alpha-fetoprotein-L3% as significant factors of HCC development. Receiver operating characteristic analysis showed that the von Willebrand factor: Ag/ADAMTS13:AC ratio and alpha-fetoprotein-L3% had a better performance than alpha-fetoprotein, des-γ-carboxy prothrombin, alpha-fetoprotein-L3%, vascular endothelial growth factor, and vascular endothelial growth factor receptor-2, von Willebrand factor: Ag, and ADAMTS13:AC. The von Willebrand factor: Ag/ADAMTS13:AC ratio was exclusively correlated with tumor volume and stage as well as serum vascular endothelial growth factor levels. Conclusions The von Willebrand factor: Ag/ADAMTS13:AC ratio can potentially serve as a novel biomarker for early diagnosis of HCC in cirrhotic patients.
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Affiliation(s)
- Hiroaki Takaya
- Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Tadashi Namisaki
- Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan.
| | - Mitsuteru Kitade
- Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Kosuke Kaji
- Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Keisuke Nakanishi
- Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Yuki Tsuji
- Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Naotaka Shimozato
- Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Kei Moriya
- Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Kenichiro Seki
- Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Yasuhiko Sawada
- Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Soichiro Saikawa
- Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Shinya Sato
- Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Hideto Kawaratani
- Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Takemi Akahane
- Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Ryuichi Noguchi
- Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
| | - Masanori Matsumoto
- Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Nara, 634-8522, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan
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Wei L, Wen JY, Chen J, Ma XK, Wu DH, Chen ZH, Huang JL. Oncogenic ADAM28 induces gemcitabine resistance and predicts a poor prognosis in pancreatic cancer. World J Gastroenterol 2019; 25:5590-5603. [PMID: 31602160 PMCID: PMC6785518 DOI: 10.3748/wjg.v25.i37.5590] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 09/05/2019] [Accepted: 09/09/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pancreatic cancer is a major cause of cancer-related death, with a 5-year overall survival rate being below 5%. The main causes of poor prognosis in pancreatic cancer include easy metastasis, high recurrence rate, and robust drug resistance. Gemcitabine is a first-line drug for patients with unresectable pancreatic cancer. However, due to drug resistance, the clinical effect is not satisfactory. ADAM28 is reported as a tumor promoter in some cancers, but its role in pancreatic cancer and gemcitabine chemoresistance in pancreatic cancer has not been elucidated.
AIM To identify if ADAM28 can act as an important target to reverse the gemcitabine drug resistance in pancreatic cancer.
METHODS RNA-sequence analysis was applied to explore the potential targets involved in the gemcitabine of pancreatic cancer. SW1990 pancreatic cancer cells were treated with an increased dose of gemcitabine, and the mRNA levels of ADAM28 were evaluated by RT-PCR. The protein and mRNA levels of ADAM28 were confirmed in the gemcitabine resistant and parallel SW1990 cells. The ADAM28 expression was also assessed in TCGA and GEO databases, and the results were confirmed in the collected tumor and adjacent normal tissues. The overall survival (OS) rate and relapse-free survival (RFS) rate of pancreatic cancer patients with high ADAM28 level and low ADAM28 level in TCGA were evaluated with Kaplan-Meier Plotter. Furthermore, the OS rate was calculated in pancreatic cancer patients with high tumor mutation burden (TMB) and low TMB. CCK-8 assay was used to examine the effect of ADAM28 on the viability of SW1990 cells. The ADAM28 and its co-expressed genes were analyzed in the cBioPortal for cancer genomics and subjected to GSEA pathway analysis. The correlations of ADAM28 with GSTP1, ABCC1, GSTM4, and BCL2 were analyzed based on TCGA data on pancreatic cancer.
RESULTS RNA-sequence analysis identified that ADAM28 was overexpressed in gemcitabine-resistant cells, and gemcitabine treatment could induce the expression of ADAM28. The mRNA and protein levels of ADAM28 were elevated in gemcitabine-resistant SW1990 cells compared with parallel cells. Also, the expression of ADAM28 was upregulated in pancreatic tumor tissues against normal pancreatic tissues. Notably, ADAM28 was highly expressed in the classical type than in the basal tumor type. Furthermore, the high expression of ADAM28 was associated with low OS and RFS rates. Interestingly, the high levels of ADAM28 was associated with a significantly lower OS rate in the high TMB patients, but not in the low TMB patients. Moreover, overexpression of ADAM28 could reduce the cell viability inhibition by gemcitabine, and knockdown of ADAM28 could enhance the proliferation inhibition by gemcitabine. The GSEA analysis showed that ADAM28 was related to the regulation of drug metabolism, and ADAM28 was significantly positively correlated with GSTP1, ABCC1, GSTM4, and BCL2.
CONCLUSION This study demonstrates that ADAM28 is overexpressed in pancreatic cancer, and closely involved in the regulation of gemcitabine resistance. Overexpression of ADAM28 is a novel prognostic biomarker in pancreatic cancer.
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Affiliation(s)
- Li Wei
- Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Jing-Yun Wen
- Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Jie Chen
- Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Xiao-Kun Ma
- Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Dong-Hao Wu
- Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Zhan-Hong Chen
- Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
| | - Jiang-Long Huang
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
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Suraj J, Kurpińska A, Zakrzewska A, Sternak M, Stojak M, Jasztal A, Walczak M, Chlopicki S. Early and late endothelial response in breast cancer metastasis in mice: simultaneous quantification of endothelial biomarkers using a mass spectrometry-based method. Dis Model Mech 2019; 12:dmm.036269. [PMID: 30683749 PMCID: PMC6451429 DOI: 10.1242/dmm.036269] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 01/17/2019] [Indexed: 12/11/2022] Open
Abstract
The endothelium plays an important role in cancer metastasis, but the mechanisms involved are still not clear. In the present work, we characterised the changes in endothelial function at early and late stages of breast cancer progression in an orthotopic model of murine mammary carcinoma (4T1 cells). Endothelial function was analysed based on simultaneous microflow liquid chromatography–tandem mass spectrometry using multiple reaction monitoring (microLC/MS-MRM) quantification of 12 endothelium-related biomarkers, including those reflecting glycocalyx disruption – syndecan-1 (SDC-1), endocan (ESM-1); endothelial inflammation – vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E-selectin (E-sel); endothelial permeability – fms-like tyrosine kinase 1 (FLT-1), angiopoietin 2 (Angpt-2); and haemostasis – von Willebrand factor (vWF), tissue plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), as well as those that are pathophysiologically linked to endothelial function – adrenomedullin (ADM) and adiponectin (ADN). The early phase of metastasis in mouse plasma was associated with glycocalyx disruption (increased SDC-1 and ESM-1), endothelial inflammation [increased soluble VCAM-1 (sVCAM-1)] and increased vascular permeability (Angpt-2). During the late phase of metastasis, additional alterations in haemostasis (increased PAI-1 and vWF), as well as a rise in ADM and substantial fall in ADN concentration, were observed. In conclusion, in a murine model of breast cancer metastasis, we identified glycocalyx disruption, endothelial inflammation and increased endothelial permeability as important events in early metastasis, while the late phase of metastasis was additionally characterised by alterations in haemostasis. Summary: A microLC/MS-MRM-based approach for simultaneous determination of endothelium-related biomarkers identified glycocalyx disruption, endothelial inflammation and increased endothelial permeability as important events in early pulmonary metastasis in a murine model of breast cancer metastasis.
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Affiliation(s)
- Joanna Suraj
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland.,Jagiellonian University Medical College, Faculty of Pharmacy, Chair and Department of Toxicology, Medyczna 9, 30-688 Krakow, Poland
| | - Anna Kurpińska
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland
| | - Agnieszka Zakrzewska
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland
| | - Magdalena Sternak
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland
| | - Marta Stojak
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland
| | - Agnieszka Jasztal
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland
| | - Maria Walczak
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland .,Jagiellonian University Medical College, Faculty of Pharmacy, Chair and Department of Toxicology, Medyczna 9, 30-688 Krakow, Poland
| | - Stefan Chlopicki
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland .,Jagiellonian University Medical College, Faculty of Medicine, Chair of Pharmacology, Grzegorzecka 16, 31-531 Krakow, Poland
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Garona J, Sobol NT, Solernó LM, Alonso DF. Potential Use of Desmopressin During Hepatic Resection for Colorectal Liver Metastases. J Surg Res 2019; 237:1-2. [PMID: 30694785 DOI: 10.1016/j.jss.2018.12.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 10/23/2018] [Accepted: 12/10/2018] [Indexed: 12/18/2022]
Affiliation(s)
- Juan Garona
- Laboratory of Molecular Oncology, National University of Quilmes, Bernal, Buenos Aires, Argentina; National Council of Scientific and Technical Research (CONICET), Buenos Aires, Argentina
| | - Natasha T Sobol
- Laboratory of Molecular Oncology, National University of Quilmes, Bernal, Buenos Aires, Argentina
| | - Luisina M Solernó
- Laboratory of Molecular Oncology, National University of Quilmes, Bernal, Buenos Aires, Argentina
| | - Daniel F Alonso
- Laboratory of Molecular Oncology, National University of Quilmes, Bernal, Buenos Aires, Argentina; National Council of Scientific and Technical Research (CONICET), Buenos Aires, Argentina.
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29
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Gérard C, Hubeau C, Carnet O, Bellefroid M, Sounni NE, Blacher S, Bendavid G, Moser M, Fässler R, Noel A, Cataldo D, Rocks N. Microenvironment-derived ADAM28 prevents cancer dissemination. Oncotarget 2018; 9:37185-37199. [PMID: 30647853 PMCID: PMC6324684 DOI: 10.18632/oncotarget.26449] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 11/26/2018] [Indexed: 01/25/2023] Open
Abstract
Previous studies have linked cancer cell-associated ADAM28 expression with tumor progression and metastatic dissemination. However, the role of host-derived ADAM28 in cancer dissemination processes remains unclear. Genetically engineered-mice fully deficient for ADAM28 unexpectedly display increased lung colonization by pulmonary, melanoma or breast tumor cells. In experimental tumor cell dissemination models, host ADAM28 deficiency is further associated with a decreased lung infiltration by CD8+ T lymphocytes. Notably, naive ADAM28-deficient mice already display a drastic reduction of CD8+ T cells in spleen which is further observed in lungs. Interestingly, ex vivo CD8+ T cell characterization revealed that ADAM28-deficiency does not impact proliferation, migration nor activation of CD8+ T cells. Our data highlight a functional role of ADAM28 in T cell mobilization and point to an unexpected protective role for host ADAM28 against metastasis.
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Affiliation(s)
- Catherine Gérard
- Laboratory of Tumor and Development Biology, GIGA-Cancer and GIGA-I3, GIGA-Research, University of Liege, Liege, Belgium
| | - Céline Hubeau
- Laboratory of Tumor and Development Biology, GIGA-Cancer and GIGA-I3, GIGA-Research, University of Liege, Liege, Belgium
| | - Oriane Carnet
- Laboratory of Tumor and Development Biology, GIGA-Cancer and GIGA-I3, GIGA-Research, University of Liege, Liege, Belgium
| | - Marine Bellefroid
- Laboratory of Tumor and Development Biology, GIGA-Cancer and GIGA-I3, GIGA-Research, University of Liege, Liege, Belgium
| | - Nor Eddine Sounni
- Laboratory of Tumor and Development Biology, GIGA-Cancer and GIGA-I3, GIGA-Research, University of Liege, Liege, Belgium
| | - Silvia Blacher
- Laboratory of Tumor and Development Biology, GIGA-Cancer and GIGA-I3, GIGA-Research, University of Liege, Liege, Belgium
| | - Guillaume Bendavid
- Laboratory of Tumor and Development Biology, GIGA-Cancer and GIGA-I3, GIGA-Research, University of Liege, Liege, Belgium.,ENT Department, University Hospital of Liege, Liege, Belgium
| | - Markus Moser
- Max-Planck-Institute of Biochemistry, Department of Molecular Medicine, Martinsried, Germany
| | - Reinhard Fässler
- Max-Planck-Institute of Biochemistry, Department of Molecular Medicine, Martinsried, Germany
| | - Agnès Noel
- Laboratory of Tumor and Development Biology, GIGA-Cancer and GIGA-I3, GIGA-Research, University of Liege, Liege, Belgium
| | - Didier Cataldo
- Laboratory of Tumor and Development Biology, GIGA-Cancer and GIGA-I3, GIGA-Research, University of Liege, Liege, Belgium.,Department of Respiratory Diseases, CHU Liege and University of Liege, Liege, Belgium
| | - Natacha Rocks
- Laboratory of Tumor and Development Biology, GIGA-Cancer and GIGA-I3, GIGA-Research, University of Liege, Liege, Belgium
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30
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Chevalier MT, Garona J, Sobol NT, Farina HG, Alonso DF, Álvarez VA. In vitro and in vivo evaluation of desmopressin-loaded poly(D,L-lactic-co-glycolic acid) nanoparticles for its potential use in cancer treatment. Nanomedicine (Lond) 2018; 13:2835-2849. [PMID: 30430901 DOI: 10.2217/nnm-2018-0065] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIM To develop and characterize the antitumor activity of poly(D,L-lactic-co-glycolic acid) nanoparticles loaded with hemostatic and anticancer drug desmopressin (dDAVP). MATERIALS & METHODS After full physicochemical characterization, anticancer activity of dDAVP-loaded poly(D,L-lactic-co-glycolic acid) nanoparticles (NPdDAVP) was evaluated in vitro and in vivo on a highly aggressive breast cancer model. RESULTS After efficiently loading desmopressin in poly(D,L-lactic-co-glycolic acid) matrix, NPdDAVP exhibited suitable physicochemical characteristics for biomedical applications. NPdDAVP displayed a potent cytostatic effect in vitro, inhibiting tumor cell proliferation and colony forming ability. Moreover, intravenous treatment using nanoparticulated-dDAVP inhibited tumor progression and prolonged survival in animals bearing rapidly-growing mammary tumors. CONCLUSION Within the framework of promising dDAVP repurposing studies, these findings support further preclinical development of the NPdDAVP for the management of highly aggressive cancer.
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Affiliation(s)
- Merari T Chevalier
- Grupo de Materiales Compuestos Termoplásticos, Instituto de Investigaciones de Ciencia y Tecnología de Materiales (INTEMA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Mar del Plata (UNMdP), Colón 10890 (7600), Mar del Plata, Argentina
| | - Juan Garona
- Laboratorio de Oncología Molecular (LOM), Departamento de Ciencia y Tecnología (DCyT), Universidad Nacional de Quilmes (UNQ), Roque Saenz Peña 352 (B1876BXD), Buenos Aires, Argentina
| | - Natasha T Sobol
- Laboratorio de Oncología Molecular (LOM), Departamento de Ciencia y Tecnología (DCyT), Universidad Nacional de Quilmes (UNQ), Roque Saenz Peña 352 (B1876BXD), Buenos Aires, Argentina
| | - Hernan G Farina
- Laboratorio de Oncología Molecular (LOM), Departamento de Ciencia y Tecnología (DCyT), Universidad Nacional de Quilmes (UNQ), Roque Saenz Peña 352 (B1876BXD), Buenos Aires, Argentina
| | - Daniel F Alonso
- Laboratorio de Oncología Molecular (LOM), Departamento de Ciencia y Tecnología (DCyT), Universidad Nacional de Quilmes (UNQ), Roque Saenz Peña 352 (B1876BXD), Buenos Aires, Argentina
| | - Vera A Álvarez
- Grupo de Materiales Compuestos Termoplásticos, Instituto de Investigaciones de Ciencia y Tecnología de Materiales (INTEMA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Mar del Plata (UNMdP), Colón 10890 (7600), Mar del Plata, Argentina
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31
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Shi L, Li S, Maurer K, Zhang Z, Petri M, Sullivan KE. Enhancer RNA and NFκB-dependent P300 regulation of ADAMDEC1. Mol Immunol 2018; 103:312-321. [PMID: 30352365 PMCID: PMC6260809 DOI: 10.1016/j.molimm.2018.09.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 09/21/2018] [Accepted: 09/27/2018] [Indexed: 01/27/2023]
Abstract
We observed increased expression of ADAMDEC1 RNA in monocytes from patients with systemic lupus erythematosus. The precise role of ADAMDEC1 is uncertain and uniquely among metalloproteinases it utilizes a zinc-coordinating aspartic acid residue which allows it to escape inhibition by tissue inhibitor of metalloprotease-3 (TIMP-3). A closely related gene encodes the protein ADAM28, which is not up-regulated in lupus. We leveraged the ability to look at both gene's promoters and enhancers simultaneously. ADAMDEC1 was up-regulated by LPS while ADAM28 was not upregulated in the short term. We identified MAP kinases and NFκB as critical cell pathways regulating the expression of ADAMDEC1. These same pathways were implicated in driving the expression of the ADAMDEC1 upstream enhancer RNAs. We demonstrated that binding of the enhancer RNAs produced from the upstream enhancer were critically important and that p300 bound to both the RNA from the enhancer and the DNA at the enhancer. P300 binding to the enhancer was dependent on NFκB. These data define the critical pathways regulating the expression of ADAMDEC1 and extend our knowledge of the roles of enhancer RNAs and mechanistically links p300 and enhancer RNAs.
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Affiliation(s)
- Lihua Shi
- The Division of Allergy Immunology at The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA, 19104, United states.
| | - Song Li
- The Division of Allergy Immunology at The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA, 19104, United states.
| | - Kelly Maurer
- The Division of Allergy Immunology at The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA, 19104, United states.
| | - Zhe Zhang
- The Department of Biomedical and Health informatics at the Children's Hospital of Philadelphia, 3535 Market St, Philadelphia, PA, 19104, United states.
| | - Michelle Petri
- Division of Rheumatology, Johns Hopkins University School of Medicine, 1830 E. Monument Street, Baltimore, MD, 21205, United states.
| | - Kathleen E Sullivan
- The Division of Allergy Immunology at The Children's Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA, 19104, United states.
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32
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Zhang T, Guo J, Gu J, Wang Z, Wang G, Li H, Wang J. Identifying the key genes and microRNAs in colorectal cancer liver metastasis by bioinformatics analysis and in vitro experiments. Oncol Rep 2018; 41:279-291. [PMID: 30542696 PMCID: PMC6278419 DOI: 10.3892/or.2018.6840] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 10/16/2018] [Indexed: 12/20/2022] Open
Abstract
Colorectal cancer (CRC) is one of the principal causes of cancer‑associated mortality worldwide. The high incidence of liver metastasis is the leading risk factor of mortality in patients with CRC, and the mechanisms of CRC liver metastasis are poorly understood. In the present study, 7 datasets, including 3 gene expression profile datasets and 4 microRNA (miRNA) expression profile datasets were downloaded from the NCBI Gene Expression Omnibus (GEO) database to identify potential key genes and miRNAs, which may be candidate biomarkers for CRC liver metastasis. Differentially expressed (DE) genes (DEGs) and DE miRNAs of primary CRC tumor tissues and liver metastatic CRC tumor tissues were selected using the GEO2R tool. Gene Ontology and Kyoto Encyclopedia of Gene and Genome pathway enrichment analyses were conducted using the Database for Annotation, Visualization and Integrated Discovery online database. Furthermore, Cytoscape with cytoHubba and the Molecular Complex Detection (MCODE) plug‑in were used to visualize a protein‑protein interaction (PPI) network for these DEGs, and to screen hub genes and gene modules in the PPI network. In addition, the online databases, TargetScan, miRanda, PITA, miRWalk and miRDB, were used to identify the target genes of the DE miRNAs. In the present study, 141 DEGs (97 upregulated and 44 downregulated) and 3 DE miRNAs (2 upregulated and 1 downregulated) were screened from the 3 gene expression microarray datasets and 4 miRNA expression microarray datasets, respectively. In total, 10 hub genes with a high degree of connectivity were selected from the PPI network, including albumin (ALB), coagulation factor II (F2), thrombin, apolipoprotein H (APOH), serpin family C member 1 (SERPINC1), apolipoprotein A1 (APOA1), α‑1‑microglobulin/bikunin precursor (AMBP), apolipoprotein C3 (APOC3), plasminogen (PLG), α‑2 HS glycoprotein (AHSG) and apolipoprotein B (APOB). The most important module was detected in the PPI network using the MCODE plug‑in. A total of 20 DEGs were identified to be potential target genes of these DE miRNAs, and novel miRNA‑DEGs regulatory axes were constructed. In vitro experiments were performed to demonstrate that miR‑885 promoted CRC cell migration by, at least partially, decreasing the expression of von Willebrand factor (vWF) and insulin‑like growth factor binding protein 5 (IGFBP5). In conclusion, by using integrated bioinformatics analysis and in vitro experiments, key candidate genes were identified and novel miRNA‑mRNA regulatory axes in CRC liver metastasis were constructed, which may improve understanding of the molecular mechanisms underlying CRC liver metastasis.
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Affiliation(s)
- Tao Zhang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jianrong Guo
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jian Gu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zheng Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Guobin Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Huili Li
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jiliang Wang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Mojiri A, Alavi P, Jahroudi N. Von Willebrand factor contribution to pathophysiology outside of von Willebrand disease. Microcirculation 2018; 26:e12510. [PMID: 30365187 DOI: 10.1111/micc.12510] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 10/12/2018] [Accepted: 10/19/2018] [Indexed: 12/13/2022]
Abstract
VWF is a procoagulant protein that plays a central role in the initiation of platelets aggregate formation and thrombosis. While von Willebrand disease has long been known to result from qualitative and quantitative deficiencies of VWF, it is recently that contribution of elevated levels of VWF to various pathological conditions including thrombosis, inflammation, angiogenesis, and cancer metastasis has been appreciated. Here, we discuss contribution of elevated levels of VWF to various thrombotic and nonthrombotic pathological conditions.
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Affiliation(s)
- Anahita Mojiri
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Parnian Alavi
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Nadia Jahroudi
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
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Zhang JM, Wang CC, Zhang GC, Jiang Q, Yang SM, Fu HX, Wang QM, Zhu XL, Zhu HH, Jiang H, Wang Y, Lv M, Lu J, Chen H, Han W, Chang YJ, Kong Y, Xu LP, Liu KY, Huang XJ, Zhang XH. ADAM28 promotes tumor growth and dissemination of acute myeloid leukemia through IGFBP-3 degradation and IGF-I-induced cell proliferation. Cancer Lett 2018; 442:193-201. [PMID: 30429106 DOI: 10.1016/j.canlet.2018.10.028] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Accepted: 10/09/2018] [Indexed: 10/28/2022]
Abstract
ADAM28 has been shown to relate with tumor proliferation and prognosis. The expression of ADAM28 is up-regulated in acute myeloid leukemia (AML). However, the mechanism by which ADAM28 regulates the leukemic cell and the prognostic relevance with AML remain unknown. Here, we found that the expression level of ADAM28 was significantly elevated in AML patients suffering a relapse compared with those remaining in complete remission (CR). ADAM28 promoted the proliferation, migration and invasion in leukemic cells in vitro. Additionally, the increased expression of ADAM28 led to more IGFBP-3 degradation and IGF-I-induced cell proliferation. In a xenotransplantation mouse model, knockout of ADAM28 alleviated HL-60 cells growth and dissemination. The cumulative incidence of relapse (CIR) was significantly higher in patients with high ADAM28 expression. When separately considering the impact of ADAM28 on prognosis within the risk stratifications, patients with high ADAM28 expression levels had a significantly higher CIR in the favorable and intermediate-risk group but not in poor-risk group. Taken together, these data suggest a pivotal role for ADAM28 in regulating the proliferation and invasion of leukemic cells and in the prediction of relapse in AML patients.
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Affiliation(s)
- Jia-Min Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Chen-Cong Wang
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Gao-Chao Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Qian Jiang
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Shen-Miao Yang
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Hai-Xia Fu
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Qian-Ming Wang
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Xiao-Lu Zhu
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Hong-Hu Zhu
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Hao Jiang
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Yu Wang
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Meng Lv
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Jin Lu
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Huan Chen
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Wei Han
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Ying-Jun Chang
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Yuan Kong
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Lan-Ping Xu
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Kai-Yan Liu
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China
| | - Xiao-Hui Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, China; Collaborative Innovation Center of Hematology, Peking University, Beijing, China.
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Mochizuki S, Shimoda M, Abe H, Miyamae Y, Kuramoto J, Aramaki-Hattori N, Ishii K, Ueno H, Miyakoshi A, Kojoh K, Okada Y. Selective Inhibition of ADAM28 Suppresses Lung Carcinoma Cell Growth and Metastasis. Mol Cancer Ther 2018; 17:2427-2438. [PMID: 30190423 DOI: 10.1158/1535-7163.mct-17-1198] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 04/13/2018] [Accepted: 08/29/2018] [Indexed: 11/16/2022]
Abstract
ADAM28 (a disintegrin and metalloproteinase 28) is overexpressed by carcinoma cells in non-small cell lung carcinomas (NSCLC) and plays an important role in cancer cell proliferation and metastasis by reactivation of insulin-like growth factor-1 (IGF-1) and escaping from von Willebrand factor (VWF)-induced apoptosis through digestion of IGF-binding protein-3 and VWF, respectively. To aim for new target therapy of NSCLC patients, we developed human neutralizing antibodies 211-12 and 211-14 against ADAM28, which showed IC50 values of 62.4 and 37.5 nmol/L, respectively. Antibody 211-14 recognized the junctional region between cysteine-rich domain and secreted-specific domain and showed a KD value of 94.7 pmol/L for the epitope-containing peptide. This antibody detected monkey and human secreted-form ADAM28s, although it was not reactive with mouse membrane-anchored ADAM28m. Antibody 211-14 effectively inhibited IGF-1-stimulated cell proliferation of lung adenocarcinoma cell lines with ADAM28 expression, including PC-9 cells, and promoted VWF-induced cell death in these cell lines. In lung metastasis models, antibody 211-14 significantly reduced tumor growth and metastases of PC-9 cells and prolonged survivals in the antibody-treated mice compared with the control IgG-treated ones. Combination therapy of the antibody and docetaxel was more effective than that of bevacizumab and docetaxel and showed further elongation of survival time compared with monotherapy. No adverse effects were observed even after administration of 10-fold more than effective dose of anti-ADAM28 antibody to normal mice. Our data demonstrate that antibody 211-14 is a neutralizing antibody specific to ADAM28s and suggest that this antibody may be a useful treatment remedy for NSCLC patients. Mol Cancer Ther; 17(11); 2427-38. ©2018 AACR.
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Affiliation(s)
- Satsuki Mochizuki
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan. .,Department of Surgery, National Defense Medical College, Saitama, Japan
| | - Masayuki Shimoda
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Hitoshi Abe
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Yuka Miyamae
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Junko Kuramoto
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Noriko Aramaki-Hattori
- Department of Plastic and Reconstructive Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Ken Ishii
- Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Hideki Ueno
- Department of Surgery, National Defense Medical College, Saitama, Japan
| | | | | | - Yasunori Okada
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan. .,Department of Pathophysiology for Locomotive and Neoplastic Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan
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Sasaki A, Abe H, Mochizuki S, Shimoda M, Okada Y. SOX4, an epithelial-mesenchymal transition inducer, transactivates ADAM28 gene expression and co-localizes with ADAM28 at the invasive front of human breast and lung carcinomas. Pathol Int 2018; 68:449-458. [PMID: 29882245 DOI: 10.1111/pin.12685] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 05/11/2018] [Indexed: 12/21/2022]
Abstract
ADAM28 (a disintegrin and metalloproteinase 28) is abundantly expressed by carcinoma cells in the human breast and non-small cell lung carcinomas, and plays a role in carcinoma cell growth and metastasis. Although Src is an inducer of ADAM28 gene expression through the PI3K/AKT/mTOR and MEK/ERK pathways, direct transcriptional regulators for ADAM28 gene expression remain unknown. In this study, we performed the luciferase reporter assay and found that SOX4 (SRY-related HMG-box 4), an inducer of epithelial-mesenchymal transition (EMT), is a transcriptional activator for the ADAM28 gene. This activation required the SOX4-binding consensus sequence at the 5'-untranslated region of the mouse and human ADAM28 genes. Forced expression of SOX4 promoted the ADAM28 gene expression and migration in human breast and lung carcinoma cell lines. In the human breast and lung carcinoma tissues, ADAM28 and SOX4 were co-expressed at the invasive front of carcinoma cell nests. Our data demonstrate that SOX4 transactivates ADAM28 gene expression through direct binding to the ADAM28 promoter region and suggest the possibility that ADAM28 plays a role in invasion through SOX4-mediated EMT in the human breast and lung carcinomas.
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Affiliation(s)
- Aya Sasaki
- Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Hitoshi Abe
- Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Satsuki Mochizuki
- Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Masayuki Shimoda
- Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Yasunori Okada
- Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
- Department of Pathophysiology for Locomotive and Neoplastic Diseases, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
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Garona J, Sobol NT, Pifano M, Segatori VI, Gomez DE, Ripoll GV, Alonso DF. Preclinical Efficacy of [V4 Q5 ]dDAVP, a Second Generation Vasopressin Analog, on Metastatic Spread and Tumor-Associated Angiogenesis in Colorectal Cancer. Cancer Res Treat 2018; 51:438-450. [PMID: 29879760 PMCID: PMC6473275 DOI: 10.4143/crt.2018.040] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 05/30/2018] [Indexed: 12/29/2022] Open
Abstract
Purpose Control of metastatic spread of colorectal cancer (CRC) remains as a major therapeutic challenge. [V4 Q5 ]dDAVP is a vasopressin peptide analog with previously reported anticancer activity against carcinoma tumors. By acting as a selective agonist of arginine vasopressin type 2 membrane receptor (AVPR2) present in endothelial and tumor cells, [V4Q5]dDAVP is able to impair tumor aggressiveness and distant spread. Our aim was to evaluate the potential therapeutic benefits of [V4Q5]dDAVP on highly aggressive CRC disease using experimental models with translational relevance. Materials and Methods Murine CT-26 and human Colo-205 AVPR2-expressing CRC cell lines were used to test the preclinical efficacy of [V4Q5]dDAVP, both in vitro and in vivo. Results In syngeneic mice surgically implanted with CT-26 cells in the spleen, sustained intravenous treatment with [V4Q5]dDAVP (0.3 µg/kg) dramatically impaired metastatic progression to liver without overt signs of toxicity, and also reduced experimental lung colonization. The compound inhibited in vivo angiogenesis driven by Colo-205 cells in athymic mice, as well as in vitro endothelial cell migration and capillary tube formation. [V4Q5]dDAVP exerted AVPR2-dependent cytostatic activity in vitro (IC50 1.08 µM) and addition to 5-fluorouracil resulted in synergistic antiproliferative effects both in CT-26 and Colo-205 cells. Conclusion The present preclinical study establishes for the first time the efficacy of [V4Q5]dDAVP on CRC. These encouraging results suggest that the novel second generation vasopressin analog could be used for the management of aggressive CRC as an adjuvant agent during surgery or to complement standard chemotherapy, limiting tumor angiogenesis and metastasis and thus protecting the patient from CRC recurrence.
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Affiliation(s)
- Juan Garona
- Laboratory of Molecular Oncology, Science and Technology Department, National University of Quilmes, Buenos Aires, Argentina
| | - Natasha T Sobol
- Laboratory of Molecular Oncology, Science and Technology Department, National University of Quilmes, Buenos Aires, Argentina
| | - Marina Pifano
- Laboratory of Molecular Oncology, Science and Technology Department, National University of Quilmes, Buenos Aires, Argentina
| | - Valeria I Segatori
- Laboratory of Molecular Oncology, Science and Technology Department, National University of Quilmes, Buenos Aires, Argentina
| | - Daniel E Gomez
- Laboratory of Molecular Oncology, Science and Technology Department, National University of Quilmes, Buenos Aires, Argentina
| | - Giselle V Ripoll
- Laboratory of Molecular Oncology, Science and Technology Department, National University of Quilmes, Buenos Aires, Argentina
| | - Daniel F Alonso
- Laboratory of Molecular Oncology, Science and Technology Department, National University of Quilmes, Buenos Aires, Argentina
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Luo T, Chen X, Zeng S, Guan B, Hu B, Meng Y, Liu F, Wong T, Lu Y, Yun C, Hocher B, Yin L. Bioinformatic identification of key genes and analysis of prognostic values in clear cell renal cell carcinoma. Oncol Lett 2018; 16:1747-1757. [PMID: 30008862 PMCID: PMC6036467 DOI: 10.3892/ol.2018.8842] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 05/22/2018] [Indexed: 12/29/2022] Open
Abstract
The present study aimed to identify new key genes as potential biomarkers for the diagnosis, prognosis or targeted therapy of clear cell renal cell carcinoma (ccRCC). Three expression profiles (GSE36895, GSE46699 and GSE71963) were collected from Gene Expression Omnibus. GEO2R was used to identify differentially expressed genes (DEGs) in ccRCC tissues and normal samples. The Database for Annotation, Visualization and Integrated Discovery was utilized for functional and pathway enrichment analysis. STRING v10.5 and Molecular Complex Detection were used for protein-protein interaction (PPI) network construction and module analysis, respectively. Regulation network analyses were performed with the WebGestal tool. UALCAN web-portal was used for expression validation and survival analysis of hub genes in ccRCC patients from The Cancer Genome Atlas (TCGA). A total of 65 up- and 164 downregulated genes were identified as DEGs. DEGs were enriched with functional terms and pathways compactly related to ccRCC pathogenesis. Seventeen hub genes and one significant module were filtered out and selected from the PPI network. The differential expression of hub genes was verified in TCGA patients. Kaplan-Meier plot showed that high mRNA expression of enolase 2 (ENO2) was associated with short overall survival in ccRCC patients (P=0.023). High mRNA expression of cyclin D1 (CCND1) (P<0.001), fms related tyrosine kinase 1 (FLT1) (P=0.004), plasminogen (PLG) (P<0.001) and von Willebrand factor (VWF) (P=0.008) appeared to serve as favorable factors in survival. These findings indicate that the DEGs may be key genes in ccRCC pathogenesis and five genes, including ENO2, CCND1, PLT1, PLG and VWF, may serve as potential prognostic biomarkers in ccRCC.
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Affiliation(s)
- Ting Luo
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Xiaoyi Chen
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Shufei Zeng
- Department of Nephrology, Charité-Universitätsmedizin Berlin, Campus Mitte, D-10117 Berlin, Germany
| | - Baozhang Guan
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Bo Hu
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Yu Meng
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Fanna Liu
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Taksui Wong
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Yongpin Lu
- Department of Nephrology, Charité-Universitätsmedizin Berlin, Campus Mitte, D-10117 Berlin, Germany
| | - Chen Yun
- Department of Nephrology, Charité-Universitätsmedizin Berlin, Campus Mitte, D-10117 Berlin, Germany
| | - Berthold Hocher
- Institute of Nutritional Sciences, University of Potsdam, D-14558 Potsdam, Germany
| | - Lianghong Yin
- Department of Nephrology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong 510632, P.R. China
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Takaya H, Kawaratani H, Tsuji Y, Nakanishi K, Saikawa S, Sato S, Sawada Y, Kaji K, Okura Y, Shimozato N, Kitade M, Akahane T, Moriya K, Namisaki T, Mitoro A, Matsumoto M, Fukui H, Yoshiji H. von Willebrand factor is a useful biomarker for liver fibrosis and prediction of hepatocellular carcinoma development in patients with hepatitis B and C. United European Gastroenterol J 2018; 6:1401-1409. [PMID: 30386613 DOI: 10.1177/2050640618779660] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 05/05/2018] [Indexed: 12/13/2022] Open
Abstract
Background Several noninvasive biomarkers are available for diagnosing liver fibrosis stage and predicting hepatocellular carcinoma (HCC) development in patients with chronic hepatitis and liver cirrhosis. However, these biomarkers are not sufficiently accurate. Recently, von Willebrand factor (VWF) has been related to angiogenesis and apoptosis. Furthermore, VWF is associated with hepatic spare ability and HCC. Objective We aimed to determine whether VWF is a potential biomarker for liver fibrosis and HCC development. Methods Two hundred and twelve patients with chronic hepatitis B and C were recruited. VWF antigen (VWF: Ag) levels in each patient were determined via enzyme-linked immunosorbent assay. Univariable and multivariable analyses were used to determine the risk factor of HCC. Results The VWF: Ag levels were higher in patients with severe liver fibrosis stage and/or HCC development than in those without. The area under the curve of VWF: Ag for diagnosis of severe liver fibrosis stage was 0.721. Multivariable analysis showed that only VWF: Ag was a predictive biomarker for HCC development. Conclusions VWF: Ag is related to liver fibrosis and may be useful for predicting HCC development. VWF is a potentially useful biomarker to diagnose severe liver fibrosis and predict HCC development.
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Affiliation(s)
- Hiroaki Takaya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Hideto Kawaratani
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Yuki Tsuji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Keisuke Nakanishi
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Soichiro Saikawa
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Shinya Sato
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Yasuhiko Sawada
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Kosuke Kaji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Yasushi Okura
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Naotaka Shimozato
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Mitsuteru Kitade
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Takemi Akahane
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Kei Moriya
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Tadashi Namisaki
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Akira Mitoro
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Masanori Matsumoto
- Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan
| | - Hiroshi Fukui
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
| | - Hitoshi Yoshiji
- Third Department of Internal Medicine, Nara Medical University, Kashihara, Japan
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Search of vasopressin analogs with antiproliferative activity on small-cell lung cancer: drug design based on two different approaches. Future Med Chem 2018; 10:879-894. [PMID: 29589487 DOI: 10.4155/fmc-2017-0178] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
AIM Development of compounds with therapeutic application requires the interaction of different disciplines. Several tumors express vasopressin (AVP; arginine vasopressin) receptors with contrasting effects depending on receptor subtype. Desmopressin (dDAVP) is an AVP-selective analog with antiproliferative properties. In this work, an evolutionary approach and a rational strategy were applied in order to design novel AVP analogs. RESULTS We designed two novel analogs; dDInotocin (dDINT, insect analog), and [V4Q5]dDAVP, and demonstrated the importance of the dDAVP conformational loop for its antiproliferative activity. [V4Q5] dDAVP showed major cytostatic effect on lung cancer cells than dDAVP and its cytostatic effect was abolished by V2R blockade. CONCLUSION Combination of these strategies could provide the basis for future studies for the development of improved compounds with potential therapeutic applications.
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Ueno M, Shiomi T, Mochizuki S, Chijiiwa M, Shimoda M, Kanai Y, Kataoka F, Hirasawa A, Susumu N, Aoki D, Okada Y. ADAM9 is over-expressed in human ovarian clear cell carcinomas and suppresses cisplatin-induced cell death. Cancer Sci 2018; 109:471-482. [PMID: 29247567 PMCID: PMC5797829 DOI: 10.1111/cas.13469] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 12/05/2017] [Accepted: 12/12/2017] [Indexed: 12/13/2022] Open
Abstract
ADAMs (a disintegrin and metalloproteinases) are involved in various biological events such as cell adhesion, migration and invasion, membrane protein shedding and proteolysis. However, there have been no systematic studies on the expression of ADAMs in human ovarian carcinomas. We therefore examined mRNA expression of all the proteolytic ADAM species including ADAM8, 9, 10, 12, 15, 17, 19, 20, 21, 28, 30, 33 and ADAMDEC1 in human ovarian carcinomas, and found that prototype membrane-anchored ADAM9m, but not secreted isoform ADAM9s, is significantly over-expressed in carcinomas than in control non-neoplastic ovarian tissue. Among the histological subtypes of serous, endometrioid, mucinous and clear cell carcinomas, ADAM9m expression was highest in clear cell carcinomas. Immunohistochemistry showed that all the clear cell carcinoma samples displayed ADAM9m primarily on the carcinoma cell membrane. By immunoblotting, ADAM9m was detected mainly in an active form in the clear cell carcinoma tissues. When two clear cell carcinoma cell lines (RMG-I and TOV21G cells) with ADAM9m expression were treated with cisplatin, viability was significantly reduced and apoptosis increased in ADAM9m knockdown cells compared with mock transfectants. In addition, treatment of the cells with neutralizing anti-ADAM9m antibody significantly decreased viability compared with non-immune IgG, whereas ADAM9m over-expression significantly increased viability compared with mock transfectants. Our data show, to the best of our knowledge, for the first time, that ADAM9m is over-expressed in an activated form in human ovarian clear cell carcinomas, and suggest that ADAM9m plays a key role in cisplatin resistance.
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Affiliation(s)
- Mari Ueno
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Takayuki Shiomi
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Satsuki Mochizuki
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Miyuki Chijiiwa
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Masayuki Shimoda
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Yae Kanai
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Fumio Kataoka
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Akira Hirasawa
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Nobuyuki Susumu
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Daisuke Aoki
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Yasunori Okada
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan.,Department of Pathophysiology for Locomotive and Neoplastic Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan
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Escalona RM, Chan E, Kannourakis G, Findlay JK, Ahmed N. The Many Facets of Metzincins and Their Endogenous Inhibitors: Perspectives on Ovarian Cancer Progression. Int J Mol Sci 2018; 19:E450. [PMID: 29393911 PMCID: PMC5855672 DOI: 10.3390/ijms19020450] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 01/23/2018] [Accepted: 01/24/2018] [Indexed: 02/07/2023] Open
Abstract
Approximately sixty per cent of ovarian cancer patients die within the first five years of diagnosis due to recurrence associated with chemoresistance. The metzincin family of metalloproteinases is enzymes involved in matrix remodeling in response to normal physiological changes and diseased states. Recently, there has been a mounting awareness of these proteinases and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), as superb modulators of cellular communication and signaling regulating key biological processes in cancer progression. This review investigates the role of metzincins and their inhibitors in ovarian cancer. We propose that understanding the metzincins and TIMP biology in ovarian cancer may provide valuable insights in combating ovarian cancer progression and chemoresistance-mediated recurrence in patients.
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Affiliation(s)
- Ruth M Escalona
- Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC 3052, Australia.
- The Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.
- Fiona Elsey Cancer Research Institute, Ballarat, VIC 3353, Australia.
| | - Emily Chan
- Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC 3052, Australia.
| | - George Kannourakis
- Fiona Elsey Cancer Research Institute, Ballarat, VIC 3353, Australia.
- Federation University Australia, Ballarat, VIC 3010, Australia.
| | - Jock K Findlay
- Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC 3052, Australia.
- The Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.
| | - Nuzhat Ahmed
- Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC 3052, Australia.
- The Hudson Institute of Medical Research, Clayton, VIC 3168, Australia.
- Fiona Elsey Cancer Research Institute, Ballarat, VIC 3353, Australia.
- Federation University Australia, Ballarat, VIC 3010, Australia.
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Garona J, Sobol NT, Alonso DF. Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy in Colorectal Cancer: Potential use of Perioperative Desmopressin to Reduce Allogenic Blood Transfusion Rates. J Gastrointest Surg 2017; 21:1971-1973. [PMID: 28840437 DOI: 10.1007/s11605-017-3551-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 08/16/2017] [Indexed: 01/31/2023]
Affiliation(s)
- Juan Garona
- Laboratory of Molecular Oncology, National University of Quilmes, R. Saenz Peña 352, Bernal, B1876BXD, Buenos Aires, Argentina.,National Council of Scientific and Technical Research (CONICET), Buenos Aires, Argentina
| | - Natasha T Sobol
- Laboratory of Molecular Oncology, National University of Quilmes, R. Saenz Peña 352, Bernal, B1876BXD, Buenos Aires, Argentina
| | - Daniel F Alonso
- Laboratory of Molecular Oncology, National University of Quilmes, R. Saenz Peña 352, Bernal, B1876BXD, Buenos Aires, Argentina. .,National Council of Scientific and Technical Research (CONICET), Buenos Aires, Argentina.
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Abstract
Von Willebrand factor (VWF) is a plasma glycoprotein best known for its crucial hemostatic role in serving as a molecular bridge linking platelets to subendothelial components following vascular injury. In addition, VWF functions as chaperone for coagulation factor VIII. In pathological settings, VWF is recognized as a risk factor for both arterial and venous thrombosis, as well as a molecular player that directly promotes the thrombotic process. Recent years have seen the emergence of the concept of immuno-thrombosis by which inflammatory cells participate in thrombotic processes. In return, reports about the involvement of hemostatic proteins or cells (such as platelets) in inflammatory responses have become increasingly common, emphasizing the intricate link between hemostasis and inflammation. However, evidence of a link between VWF and inflammation arose much earlier than these recent developments. At first, VWF was considered only as a marker of inflammation in various pathologies, due to its acute release by the activated endothelium. Later on, a more complex role of VWF in inflammation was uncovered, owing to its capacity to direct the biogenesis of specific endothelial organelles, the Weibel-Palade bodies that contain known inflammation players such as P-selectin. Finally, a more direct link between VWF and inflammation has become apparent with the discovery that VWF is able to recruit leukocytes, either via direct leukocyte binding or by recruiting platelets which in turn will attract leukocytes. This review will focus on these different aspects of the connection between VWF and inflammation, with particular emphasis on VWF-leukocyte interactions.
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Affiliation(s)
- C Kawecki
- Institut National de la Santé et de la Recherche Médicale, UMR_S 1176, Univ. Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
- Laboratory for Vascular Translational Science, Institut National de la Santé et de la Recherche Médicale Paris, UMR 1148, Paris, France
- Paris7 Denis Diderot University, Paris, France
| | - P J Lenting
- Institut National de la Santé et de la Recherche Médicale, UMR_S 1176, Univ. Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | - C V Denis
- Institut National de la Santé et de la Recherche Médicale, UMR_S 1176, Univ. Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
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Abstract
INTRODUCTION Trophoblast progenitor cell differentiation towards the extravillous trophoblast (EVT) lineage initiates within proximal regions of anchoring columns of first trimester placental villi. While molecular processes controlling the initial stages of progenitor cell differentiation along the EVT pathway have been described, much remains unknown about factors important in distal column cell differentiation into invasive EVTs. ADAMs are proteases that regulate growth factor signaling, cell-matrix adhesion, and matrix proteolysis, and thus impact many processes relevant in placentation. Global gene expression studies identified the ADAM subtype, ADAM28, to be highly expressed in EVT-like trophoblasts, suggesting that it may play a role in EVT function. This study aims to test the functional importance of ADAM28 in column cell outgrowth and maintenance. METHODS ADAM28 mRNA levels and protein localization were determined by qPCR and immunofluorescence microscopy analyses in purified placental villi cell populations and tissues. ADAM28 function in trophoblast column outgrowth was examined using ADAM28-targetting siRNAs in Matrigel-imbedded placental explant cultures. RESULTS Within placental villi, ADAM28 mRNA levels were highest in HLA-G+ column trophoblasts, and consistent with this, ADAM28 was preferentially localized to HLA-G+ trophoblasts within distal anchoring columns and decidual tissue. siRNA-directed loss of ADAM28 impaired trophoblast column outgrowth and resulted in increased apoptosis in matrix-invading trophoblasts. DISCUSSION Our findings suggest that ADAM28 promotes column outgrowth by providing survival cues within anchoring column cells. This study also provides insight into a possible role for ADAM28 in driving differentiation of column trophoblasts into invasive HLA-G+ EVT subsets.
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Affiliation(s)
- L C De Luca
- British Columbia's Children's Hospital Research Institute, Vancouver, Canada; Department of Obstetrics & Gynecology, The University of British Columbia, Vancouver, Canada
| | - H T Le
- British Columbia's Children's Hospital Research Institute, Vancouver, Canada; Department of Obstetrics & Gynecology, The University of British Columbia, Vancouver, Canada
| | - D L Mara
- British Columbia's Children's Hospital Research Institute, Vancouver, Canada
| | - A G Beristain
- British Columbia's Children's Hospital Research Institute, Vancouver, Canada; Department of Obstetrics & Gynecology, The University of British Columbia, Vancouver, Canada.
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Guo R, Yang J, Liu X, Wu J, Chen Y. Increased von Willebrand factor over decreased ADAMTS-13 activity is associated with poor prognosis in patients with advanced non-small-cell lung cancer. J Clin Lab Anal 2017; 32. [PMID: 28374895 DOI: 10.1002/jcla.22219] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 02/27/2017] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Hypercoagulability induced by the imbalance between von Willebrand factor (VWF) secretion and its cleaving protease (ADAMTS-13) has been correlated with cancer metastasis. The aim of this study was to explore the prognostic significance of the VWF/ADAMTS-13 ratio in advanced non-small-cell lung cancer (NSCLC). METHODS Pre-treatment sera/plasma levels of VWF, ADAMTS-13, VWF/ADAMTS-13 ratio, factor (F) VIII, and other clinical/laboratory parameters were measured in 119 patients with advanced NSCLC and 102 healthy controls. All patients were followed up to determine the predictive value of these parameters for prognosis of advanced NSCLC. RESULTS Elevated VWF, VWF/ADAMTS-13 ratio, and reduced ADAMTS-13 were significantly correlated with the stage and grade of advanced NSCLC and the final status of disease (P<.05). VWF levels and the VWF/ADAMTS-13 ratio were also associated with response to chemotherapy (P<.05). Multivariate analysis identified the VWF/ADAMTS-13 ratio and D-dimer as significant independent predictors of patient mortality. The area under the curve showed that the VWF/ADAMTS-13 ratio was more useful than VWF, ADAMTS-13, and D-dimer to predict mortality. Kaplan-Meier analysis showed that a low VWF/ADAMTS-13 ratio was significantly predictive of improved survival (P=.004). CONCLUSION These results suggest that the imbalance between VWF secretion and ADAMTS-13 may play a critical role in the hypercoagulability state in advanced NSCLC. Moreover, elevation of the plasma VWF/ADAMTS-13 ratio may serve as an independent predictive factor for mortality in patients with advanced NSCLC.
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Affiliation(s)
- Renyong Guo
- Department of Laboratory Medicine, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Jiezuan Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xia Liu
- Department of Intensive Care Unit, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jianping Wu
- Department of Laboratory Medicine, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Yu Chen
- Department of Laboratory Medicine, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, Zhejiang, China
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Mojiri A, Stoletov K, Lorenzana Carrillo MA, Willetts L, Jain S, Godbout R, Jurasz P, Sergi CM, Eisenstat DD, Lewis JD, Jahroudi N. Functional assessment of von Willebrand factor expression by cancer cells of non-endothelial origin. Oncotarget 2017; 8:13015-13029. [PMID: 28035064 PMCID: PMC5355073 DOI: 10.18632/oncotarget.14273] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 11/30/2016] [Indexed: 02/04/2023] Open
Abstract
Von Willebrand factor (VWF) is a highly adhesive procoagulant molecule that mediates platelet adhesion to endothelial and subendothelial surfaces. Normally it is expressed exclusively in endothelial cells (ECs) and megakaryocytes. However, a few studies have reported VWF detection in cancer cells of non-endothelial origin, including osteosarcoma. A role for VWF in cancer metastasis has long been postulated but evidence supporting both pro- and anti-metastatic roles for VWF has been presented. We hypothesized that the role of VWF in cancer metastasis is influenced by its cellular origin and that cancer cell acquisition of VWF expression may contribute to enhanced metastatic potential. We demonstrated de novo expression of VWF in glioma as well as osteosarcoma cells. Endothelial monolayer adhesion, transmigration and extravasation capacities of VWF expressing cancer cells were shown to be enhanced compared to non-VWF expressing cells, and were significantly reduced as a result of VWF knock down. VWF expressing cancer cells were also detected in patient tumor samples of varying histologies. Analyses of the mechanism of transcriptional activation of the VWF in cancer cells demonstrated a pattern of trans-activating factor binding and epigenetic modifications consistent overall with that observed in ECs. These results demonstrate that cancer cells of non-endothelial origin can acquire de novo expression of VWF, which can enhance processes, including endothelial and platelet adhesion and extravasation, that contribute to cancer metastasis.
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Affiliation(s)
- Anahita Mojiri
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | | | | | - Lian Willetts
- Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
| | - Saket Jain
- Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
| | - Roseline Godbout
- Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
| | - Paul Jurasz
- Department of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Consolato M. Sergi
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
| | - David D. Eisenstat
- Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
- Departments of Medical Genetics and Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - John D. Lewis
- Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
| | - Nadia Jahroudi
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
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Nanjo S, Arai S, Wang W, Takeuchi S, Yamada T, Hata A, Katakami N, Okada Y, Yano S. MET Copy Number Gain Is Associated with Gefitinib Resistance in Leptomeningeal Carcinomatosis of EGFR-mutant Lung Cancer. Mol Cancer Ther 2017; 16:506-515. [PMID: 28138027 DOI: 10.1158/1535-7163.mct-16-0522] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 11/16/2016] [Accepted: 11/19/2016] [Indexed: 01/13/2023]
Abstract
Leptomeningeal carcinomatosis occurs frequently in EGFR-mutant lung cancer, and develops acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). This study aimed to clarify the mechanism of EGFR-TKI resistance in leptomeningeal carcinomatosis and seek for a novel therapeutic strategy. We examined EGFR mutations, including the T790M gatekeeper mutation, in 32 re-biopsy specimens from 12 leptomeningeal carcinomatosis and 20 extracranial lesions of EGFR-mutant lung cancer patients who became refractory to EGFR-TKI treatment. All the 32 specimens had the same baseline EGFR mutations, but the T790M mutation was less frequent in leptomeningeal carcinomatosis specimens than in extracranial specimens (8% vs. 55%, P < 0.01). To study molecular mechanisms of acquired EGFR-TKI resistance in leptomeningeal carcinomatosis, we utilized our previously developed mouse model of leptomeningeal carcinomatosis with the EGFR-mutant lung cancer cell line PC-9/ffluc cells, in which acquired resistance to gefitinib was induced by continuous oral treatment. Compared with subcutaneously inoculated gefitinib-resistant tumors, the T790M mutation was less frequent in leptomeningeal carcinomatosis that acquired resistance to gefitinib. PC-9/LMC-GR cells were established from the gefitinib-resistant leptomeningeal carcinomatosis model, and they were found to be intermediately resistant to gefitinib and osimertinib (third-generation EGFR-TKI). Although EGFR-T790M was negative, gefitinib resistance of PC-9/LMC-GR cells was related to MET copy number gain with MET activation. Moreover, combined use of EGFR-TKI and crizotinib, a MET inhibitor, dramatically regressed leptomeningeal carcinomatosis with acquired resistance to gefitinib or osimertinib. These findings suggest that combination therapy with MET inhibitors may be promising for controlling leptomeningeal carcinomatosis that acquires resistance to EGFR-TKIs. Mol Cancer Ther; 16(3); 506-15. ©2017 AACR.
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Affiliation(s)
- Shigeki Nanjo
- Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan.,Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Chuo-ku, Kobe, Japan
| | - Sachiko Arai
- Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan
| | - Wei Wang
- Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan.,Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, P.R. China
| | - Shinji Takeuchi
- Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan
| | - Tadaaki Yamada
- Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan
| | - Akito Hata
- Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Chuo-ku, Kobe, Japan
| | - Nobuyuki Katakami
- Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Chuo-ku, Kobe, Japan
| | - Yasunori Okada
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan.,Department of Pathophysiology for Locomotive and Neoplastic Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Seiji Yano
- Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan.
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Riku M, Inaguma S, Ito H, Tsunoda T, Ikeda H, Kasai K. Down-regulation of the zinc-finger homeobox protein TSHZ2 releases GLI1 from the nuclear repressor complex to restore its transcriptional activity during mammary tumorigenesis. Oncotarget 2016; 7:5690-701. [PMID: 26744317 PMCID: PMC4868714 DOI: 10.18632/oncotarget.6788] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 12/24/2015] [Indexed: 12/21/2022] Open
Abstract
Although breast cancer is one of the most common malignancies, the molecular mechanisms underlying its development and progression are not fully understood. To identify key molecules involved, we screened publicly available microarray datasets for genes differentially expressed between breast cancers and normal mammary glands. We found that three of the genes predicted in this analysis were differentially expressed among human mammary tissues and cell lines. Of these genes, we focused on the role of the zinc-finger homeobox protein TSHZ2, which is down-regulated in breast cancer cells. We found that TSHZ2 is a nuclear protein harboring a bipartite nuclear localization signal, and we confirmed its function as a C-terminal binding protein (CtBP)-dependent transcriptional repressor. Through comprehensive screening, we identified TSHZ2-suppressing genes such as AEBP1 and CXCR4, which are conversely up-regulated by GLI1, the downstream transcription factor of Hedgehog signaling. We found that GLI1 forms a ternary complex with CtBP2 in the presence of TSHZ2 and that the transcriptional activity of GLI1 is suppressed by TSHZ2 in a CtBP-dependent manner. Indeed, knockdown of TSHZ2 increases the expression of AEBP1 and CXCR4 in TSHZ2-expressing immortalized mammary duct epithelium. Concordantly, immunohistochemical staining of mammary glands revealed that normal duct cells expresses GLI1 in the nucleus along with TSHZ2 and CtBP2, whereas invasive ductal carcinoma cells, which does not express TSHZ2, show the increase in the expression of AEBP1 and CXCR4 and in the cytoplasmic localization of GLI1. Thus, we propose that down-regulation of TSHZ2 is crucial for mammary tumorigenesis via the activation of GLI1.
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Affiliation(s)
- Miho Riku
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan
| | - Shingo Inaguma
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan
| | - Hideaki Ito
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan
| | - Takumi Tsunoda
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan
| | - Hiroshi Ikeda
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan
| | - Kenji Kasai
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan
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50
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Nanjo S, Ebi H, Arai S, Takeuchi S, Yamada T, Mochizuki S, Okada Y, Nakada M, Murakami T, Yano S. High efficacy of third generation EGFR inhibitor AZD9291 in a leptomeningeal carcinomatosis model with EGFR-mutant lung cancer cells. Oncotarget 2016; 7:3847-56. [PMID: 26716903 PMCID: PMC4826174 DOI: 10.18632/oncotarget.6758] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Accepted: 11/29/2015] [Indexed: 11/25/2022] Open
Abstract
Leptomeningeal carcinomatosis (LMC) remarkably decreases the quality of life of EGFR-mutant lung cancer patients. In contrast to the lesions outside the central nervous system (CNS), molecular mechanisms of EGFR tyrosine kinase inhibitor (TKI) resistance in CNS lesions including LMC are largely unknown. In this study, we established an in vivo imaging model for LMC with EGFR mutant lung cancer cell lines harboring an exon 19 deletion in EGFR and evaluated the effect of first generation EGFR-TKIs, erlotinib, second generation afatinib, and third generation AZD9291. In PC-9/ffluc model, erlotinib treatment slowed the development of LMC. Importantly, treatment with afatinib or AZD9291 apparently delayed the development of LMC. Moreover, treatment with a higher dose of AZD9291, also associated with inhibited phosphorylation of EGFR downstream molecule S6, regressed LMC refractory to the aforementioned EGFR-TKI treatments. These observations suggest that the third generation EGFR-TKI AZD9291 may be an effective treatment for first or second generation EGFR-TKI resistant LMC caused by EGFR-mutant lung cancer.
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Affiliation(s)
- Shigeki Nanjo
- Department of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan
| | - Hiromichi Ebi
- Department of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan
| | - Sachiko Arai
- Department of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan
| | - Shinji Takeuchi
- Department of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan
| | - Tadaaki Yamada
- Department of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan
| | - Satsuki Mochizuki
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Yasunori Okada
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Mitsutoshi Nakada
- Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
| | - Takashi Murakami
- Laboratory of Tumor Biology, Takasaki University of Health and Welfare, Takasaki, Japan
| | - Seiji Yano
- Department of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan
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