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Priya S, Kma L. Identification of novel microRNAs: Biomarkers for pathogenesis of hepatocellular carcinoma in mice model. Biochem Biophys Rep 2025; 41:101896. [PMID: 39881957 PMCID: PMC11774814 DOI: 10.1016/j.bbrep.2024.101896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 11/26/2024] [Accepted: 12/09/2024] [Indexed: 01/31/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the most fatal cancer that has affected both male and female populations globally. With poor diagnosis and patient survival rates, it has become a global need for scientists to come to the aid. The main objective of the study was to profile the miRNAs in the serum of Control and DEN-treated mice at different time intervals (4 Weeks, 8 Weeks, 12 Weeks, and 16 Weeks) and identify HCC-associated miRNA as putative early biomarkers along with the miRNA regulated candidate gene which may be involved in HCC. Our study group involves 4,8,12, & 16 weeks 16-week-old treated male mice. Each group was sacrificed and analyzed for the stages of HCC. We employed in silico techniques for the small RNA-Seq and bioinformatics pipeline for further analysis. Our analysis revealed over 400 differentially expressed miRNAs in each treated sample and 10 novel miRNAs. The downstream analysis of these differentially expressed miRNAs, and their target genes opened an arena of different biological processes and pathways that these miRNAs affect during the development of HCC. The work has a promising role as the miRNAs predicted through this study can be used as biomarkers for early detection of HCC.
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Affiliation(s)
- Shivani Priya
- Department of Chemistry & Biochemistry, Sharda School of Basic Sciences & Research, Sharda University, Noida, UP, India
| | - Lakhon Kma
- Department of Biochemistry, North Eastern Hill University, Shillong, India
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Liu B, Zhu L, Bian L, Wen D, Cui X. Recent advances in the dual effects of activin A on tumors. Biochem Biophys Res Commun 2025; 747:151301. [PMID: 39799865 DOI: 10.1016/j.bbrc.2025.151301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 01/01/2025] [Accepted: 01/08/2025] [Indexed: 01/15/2025]
Abstract
Activin A, a gonadal protein, not only stimulates the pituitary to secrete follicle-stimulating hormone (FSH) but also plays a crucial role in regulating various cell behaviors, such as cell proliferation, differentiation, apoptosis, migration, and invasion. Studies have shown an association between activin A expression and tumor progression, highlighting its dual role in cancer. Similar to transforming growth factor-beta (TGF-β), activin A can have both pro-tumor and anti-tumor effects, for instance, it inhibits the migration of lung adenocarcinoma cells, while promotes the migration of triple-negative breast cancer cells. Therefore, activin A exerts context-dependent effects on different tumor cells. This review explores the biological functions of activin A in tumor progression and treatment, focusing on its influence on tumor cell proliferation, apoptosis, and metastasis. The aim is to offer insights and potential directions for future clinical cancer treatments.
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Affiliation(s)
- Boyang Liu
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Jilin, Changchun, 130021, PR China; Department of Scientific Research, Jilin Jianzhu University, Jilin, Changchun, 130118, PR China
| | - Linjing Zhu
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Jilin, Changchun, 130021, PR China
| | - Linfang Bian
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, 130021, PR China
| | - Dezhong Wen
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Jilin, Changchun, 130021, PR China.
| | - Xueling Cui
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Jilin, Changchun, 130021, PR China.
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Sinn K, Elbeialy A, Mosleh B, Aigner C, Schelch K, Laszlo V, Dome B, Hoda MA, Grusch M. High circulating activin A plasma levels are associated with tumour stage and poor survival in treatment-naive lung squamous cell cancer patients. Transl Oncol 2025; 51:102153. [PMID: 39405924 PMCID: PMC11525229 DOI: 10.1016/j.tranon.2024.102153] [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: 07/01/2024] [Revised: 09/09/2024] [Accepted: 10/07/2024] [Indexed: 11/03/2024] Open
Abstract
OBJECTIVES Lung squamous cell carcinoma (LUSC) is associated with a poor prognosis and a lack of specific treatment options. The dysregulation of activin A (ActA) has been reported in various malignancies. Herein, we investigated the diagnostic and prognostic significance of ActA in LUSC. MATERIALS AND METHODS ActA concentrations were measured using ELISA in plasma samples of 128 LUSC patients (stage I-IV) and 73 controls, and correlated those values with clinicopathological parameters and survival. RESULTS ActA plasma levels were significantly higher in therapy-naive LUSC patients compared to controls (444.1 ± 310.9 pg/mL vs 338.9 ± 145.5 pg/mL, p = 0.010). ActA levels significantly correlated with advanced stage as well as with T and N factors. High circulating ActA levels were significantly increased in metastatic disease patients compared to M0 disease. Further, patients with ActA levels above a computationally established optimal cut-off value of 443.0 pg/mL had a significantly worse median overall (OS, 17.63 vs 64.77 months, HR 0.391, 95 % CI 0.200-0.762, p < 0.001) and median disease-/progression-free survival (DFS/PFS; 11.57 vs 30.20 months, HR 0.502, 95 % CI 0.248-1.019, p = 0.020). Multivariate analysis revealed that high ActA levels were an independent prognostic factor for shorter OS (p = 0.001) and DFS/PFS (p = 0.018). A newly developed score combining CRP and ActA levels was also an independent prognostic factor for OS and DFS/PFS. CONCLUSION Measurement of circulating ActA levels may help identify advanced-stage LUSC patients, and this value could serve as a prognostic parameter in LUSC. Thus, ActA may be a novel blood-based biomarker for identifying LUSC patients with distant metastasis.
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Affiliation(s)
- Katharina Sinn
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Ahmed Elbeialy
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Berta Mosleh
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Clemens Aigner
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Karin Schelch
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria; Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Viktoria Laszlo
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Balazs Dome
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria; Department of Tumour Biology, National Korányi Institute of Pulmonology, Budapest, Hungary; Department of Thoracic Surgery, National Institute of Oncology, Semmelweis University, Budapest, Hungary; Department of Translational Medicine, Lund University, Lund, Sweden
| | - Mir Alireza Hoda
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Michael Grusch
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
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Wang XL, Yang M, Wang Y. Roles of transforming growth factor-β signaling in liver disease. World J Hepatol 2024; 16:973-979. [PMID: 39086528 PMCID: PMC11287609 DOI: 10.4254/wjh.v16.i7.973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 03/04/2024] [Accepted: 05/24/2024] [Indexed: 07/26/2024] Open
Abstract
In this editorial we expand the discussion on the article by Zhang et al published in the recent issue of the World Journal of Hepatology. We focus on the diagnostic and therapeutic targets identified on the basis of the current understanding of the molecular mechanisms of liver disease. Transforming growth factor-β (TGF-β) belongs to a structurally related cytokine super family. The family members display different time- and tissue-specific expression patterns associated with autoimmunity, inflammation, fibrosis, and tumorigenesis; and, they participate in the pathogenesis of many diseases. TGF-β and its related signaling pathways have been shown to participate in the progression of liver diseases, such as injury, inflammation, fibrosis, cirrhosis, and cancer. The often studied TGF-β/Smad signaling pathway has been shown to promote or inhibit liver fibrosis under different circumstances. Similarly, the early immature TGF-β molecule functions as a tumor suppressor, inducing apoptosis; but, its interaction with the mitogenic molecule epidermal growth factor alters this effect, activating anti-apoptotic signals that promote liver cancer development. Overall, TGF-β signaling displays contradictory effects in different liver disease stages. Therefore, the use of TGF-β and related signaling pathway molecules for diagnosis and treatment of liver diseases remains a challenge and needs further study. In this editorial, we aim to review the evidence for the use of TGF-β signaling pathway molecules as diagnostic or therapeutic targets for different liver disease stages.
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Affiliation(s)
- Xiao-Ling Wang
- Clinical Laboratory, Shanxi Academy of Traditional Chinese Medicine, Taiyuan 030012, Shanxi Province, China.
| | - Meng Yang
- Clinical Laboratory, Shanxi Academy of Traditional Chinese Medicine, Taiyuan 030012, Shanxi Province, China
| | - Ying Wang
- Clinical Laboratory, Shanxi Academy of Traditional Chinese Medicine, Taiyuan 030012, Shanxi Province, China
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Mekala S, Rai R, Reed SL, Bowen B, Michalopoulos GK, Locker J, Raeman R, Oertel M. Antagonizing Activin A/p15 INK4b Signaling as Therapeutic Strategy for Liver Disease. Cells 2024; 13:649. [PMID: 38607090 PMCID: PMC11011318 DOI: 10.3390/cells13070649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/09/2024] [Accepted: 02/01/2024] [Indexed: 04/13/2024] Open
Abstract
BACKGROUND/AIM Activin A is involved in the pathogenesis of human liver diseases, but its therapeutic targeting is not fully explored. Here, we tested the effect of novel, highly specific small-molecule-based activin A antagonists (NUCC-474/555) in improving liver regeneration following partial hepatectomy and halting fibrosis progression in models of chronic liver diseases (CLDs). METHODS Cell toxicity of antagonists was determined in rat hepatocytes and Huh-7 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. Hepatocytes and hepatic stellate cells (HSCs) were treated with activin A and NUCC-555 and analyzed by reverse transcription-polymerase chain reaction and immunohistochemistry. Partial hepatectomized Fisher (F)344 rats were treated with NUCC-555, and bromodeoxyuridine (BrdU) incorporation was determined at 18/24/36/120/240 h. NUCC-555 was administered into thioacetamide- or carbon tetrachloride-treated F344 rats or C57BL/6 mice, and the fibrosis progression was studied. RESULTS NUCC-474 showed higher cytotoxicity in cultured hepatic cells; therefore, NUCC-555 was used in subsequent studies. Activin A-stimulated overexpression of cell cycle-/senescence-related genes (e.g., p15INK4b, DEC1, Glb1) was near-completely reversed by NUCC-555 in hepatocytes. Activin A-mediated HSC activation was blocked by NUCC-555. In partial hepatectomized rats, antagonizing activin A signaling resulted in a 1.9-fold and 2.3-fold increase in BrdU+ cells at 18 and 24 h, respectively. Administration of NUCC-555 in rats and mice with progressing fibrosis significantly reduced collagen accumulation (7.9-fold), HSC activation indicated by reduced alpha smooth muscle actin+ and vimentin+ cells, and serum aminotransferase activity. CONCLUSIONS Our studies demonstrate that activin A antagonist NUCC-555 promotes liver regeneration and halts fibrosis progression in CLD models, suggesting that blocking activin A signaling may represent a new approach to treating people with CLD.
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Affiliation(s)
- Sowmya Mekala
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USA (R.R.); (G.K.M.); (R.R.)
| | - Ravi Rai
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USA (R.R.); (G.K.M.); (R.R.)
| | - Samantha Loretta Reed
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USA (R.R.); (G.K.M.); (R.R.)
| | - Bill Bowen
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USA (R.R.); (G.K.M.); (R.R.)
| | - George K. Michalopoulos
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USA (R.R.); (G.K.M.); (R.R.)
- Pittsburgh Liver Research Center (PLRC), University of Pittsburgh, Pittsburgh, PA 15261, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Joseph Locker
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USA (R.R.); (G.K.M.); (R.R.)
- Pittsburgh Liver Research Center (PLRC), University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Reben Raeman
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USA (R.R.); (G.K.M.); (R.R.)
- Pittsburgh Liver Research Center (PLRC), University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Michael Oertel
- Department of Pathology, Division of Experimental Pathology, University of Pittsburgh, 200 Lothrop Street—BST S-404, Pittsburgh, PA 15261, USA (R.R.); (G.K.M.); (R.R.)
- Pittsburgh Liver Research Center (PLRC), University of Pittsburgh, Pittsburgh, PA 15261, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
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Abou Kors T, Hofmann L, Betzler A, Payer K, Bens M, Truong J, von Witzleben A, Thomas J, Kraus JM, Kalaajieh R, Huber D, Ezić J, Benckendorff J, Greve J, Schuler PJ, Ottensmeier CH, Kestler HA, Hoffmann TK, Theodoraki MN, Brunner C, Laban S. INHBA is Enriched in HPV-negative Oropharyngeal Squamous Cell Carcinoma and Promotes Cancer Progression. CANCER RESEARCH COMMUNICATIONS 2024; 4:571-587. [PMID: 38329386 PMCID: PMC10901070 DOI: 10.1158/2767-9764.crc-23-0258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 12/15/2023] [Accepted: 02/06/2024] [Indexed: 02/09/2024]
Abstract
Patients with oropharyngeal squamous cell carcinoma (OPSCC) caused by human papilloma virus (HPV) exhibit a better prognosis than those with HPV-negative OPSCC. This study investigated the distinct molecular pathways that delineate HPV-negative from HPV-positive OPSCC to identify biologically relevant therapeutic targets. Bulk mRNA from 23 HPV-negative and 39 HPV-positive OPSCC tumors (n = 62) was sequenced to uncover the transcriptomic profiles. Differential expression followed by gene set enrichment analysis was performed to outline the top enriched biological process in the HPV-negative compared with HPV-positive entity. INHBA, the highest overexpressed gene in the HPV-negative tumor, was knocked down. Functional assays (migration, proliferation, cell death, stemness) were conducted to confirm the target's oncogenic role. Correlation analyses to reveal its impact on the tumor microenvironment were performed. We revealed that epithelial-to-mesenchymal transition (EMT) is the most enriched process in HPV-negative compared with HPV-positive OPSCC, with INHBA (inhibin beta A subunit) being the top upregulated gene. INHBA knockdown downregulated the expression of EMT transcription factors and attenuated migration, proliferation, stemness, and cell death resistance of OPSCC cells. We uncovered that INHBA associates with a pro-tumor microenvironment by negatively correlating with antitumor CD8+ T and B cells while positively correlating with pro-tumor M1 macrophages. We identified three miRNAs that are putatively involved in repressing INHBA expression. Our results indicate that the upregulation of INHBA is tumor-promoting. We propose INHBA as an attractive therapeutic target for the treatment of INHBA-enriched tumors in patients with HPV-negative OPSCC to ameliorate prognosis. SIGNIFICANCE Patients with HPV-negative OPSCC have a poorer prognosis due to distinct molecular pathways. This study reveals significant transcriptomic differences between HPV-negative and HPV-positive OPSCC, identifying INHBA as a key upregulated gene in HPV-negative OPSCC's oncogenic pathways. INHBA is crucial in promoting EMT, cell proliferation, and an immunosuppressive tumor environment, suggesting its potential as a therapeutic target for HPV-negative OPSCC.
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Affiliation(s)
- Tsima Abou Kors
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Linda Hofmann
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Annika Betzler
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Kathrina Payer
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Martin Bens
- Fritz Lipmann Institute, Leibniz Institute on Aging, University of Jena, Jena, Germany
| | - Jens Truong
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Adrian von Witzleben
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Jaya Thomas
- Cancer Sciences Unit, University of Southampton, Faculty of Medicine, Southampton, United Kingdom
| | - Johann M Kraus
- Institute for Medical Systems Biology, Ulm University, Ulm, Germany
| | - Randa Kalaajieh
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Diana Huber
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Jasmin Ezić
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | | | - Jens Greve
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Patrick J Schuler
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Christian H Ottensmeier
- Institute of Systems, Molecular and Integrative Biology, Liverpool Head and Neck Center, University of Liverpool, Faculty of Medicine, Liverpool, United Kingdom
| | - Hans A Kestler
- Institute for Medical Systems Biology, Ulm University, Ulm, Germany
| | - Thomas K Hoffmann
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Marie-Nicole Theodoraki
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Cornelia Brunner
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Simon Laban
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
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Santol J, Pereyra D, Haegele S, Ammon D, Ortmayr G, Pirabe A, Jonas JP, Schuster S, Kim S, Nguyen T, Gruenberger T, Assinger A, Starlinger P. The Ratio of Activin A and Follistatin-Like 3 Is Associated With Posthepatectomy Liver Failure and Morbidity in Patients Undergoing Liver Resection. GASTRO HEP ADVANCES 2023; 2:642-651. [PMID: 39129875 PMCID: PMC11307668 DOI: 10.1016/j.gastha.2023.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 02/28/2023] [Indexed: 08/13/2024]
Abstract
Background and Aims Activin A is a key regulator in liver regeneration, but data evaluating its role in humans after hepatic surgery are limited. In this study we explore the predictive role of circulating activin A, its antagonist follistatin-like 3 (FSTL-3), and their ratio for posthepatectomy liver failure (PHLF) and monitor their levels after surgery, to evaluate their role in human liver regeneration. Methods Activin A and FSTL-3 levels were assessed in 59 patients undergoing liver surgery. Using receiver operating characteristic analysis, we evaluated the predictive potential of activin A, FSTL-3, and their ratio. Results While perioperative dynamics of activin A and FSTL3 were significantly affected by hepatic resection (activin A P = .045, FSTL-3 P = .005), their functionally relevant ratio did not significantly change (P = .528). Neither activin A nor FSTL-3 alone but only their ratio exhibited a significant predictive potential for PHLF (area under the curve: 0.789, P = .038). Patients with low preoperative activin A/FSTL-3 ratio were found to more frequently suffer from PHLF (0.017) and morbidity (0.005). Conclusion Activin A/FSTL-3 ratio predicts PHLF and morbidity. Its significance in preoperative patient assessment needs to be further validated in larger, independent cohorts.
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Affiliation(s)
- Jonas Santol
- Department of Surgery, Vienna Health Network, HPB Center, Clinic Favoriten and Sigmund Freud Private University, Vienna, Austria
- Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - David Pereyra
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Stefanie Haegele
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Daphni Ammon
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Gregor Ortmayr
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Anita Pirabe
- Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Jan Philipp Jonas
- Department of Surgery, Vienna Health Network, HPB Center, Clinic Favoriten and Sigmund Freud Private University, Vienna, Austria
- Department of Visceral and Transplantation Surgery, University Hospital Zurich, Zurich, Switzerland
| | - Stefan Schuster
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Sarang Kim
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Toni Nguyen
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Thomas Gruenberger
- Department of Surgery, Vienna Health Network, HPB Center, Clinic Favoriten and Sigmund Freud Private University, Vienna, Austria
| | - Alice Assinger
- Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Patrick Starlinger
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
- Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
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Xu ZB, Gan MF, Yu HY, Mo LC, Xia YH, Yu QX, Zheng JM. The Significance of INHBE Expression in the Cancer Cells of Clear-Cell Renal Cell Carcinoma. Urol Int 2021; 106:376-386. [PMID: 34515260 DOI: 10.1159/000518161] [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: 01/29/2021] [Accepted: 06/22/2021] [Indexed: 11/19/2022]
Abstract
BACKGROUND Activins and inhibins are structurally related dimeric glycoprotein hormones belonging to the transforming growth factor-β superfamily but whether they are also involved in malignancy is far from clear. No study has reported the expression of INHBE in kidney cancer. The purpose of this study was to examine the expressions of INHBE in the tumor tissue of patients with clear-cell renal cell carcinoma (ccRCC) and to explore the pathologic significance. METHODS The INHBE mRNA expression in the tumor tissue of ccRCC patients was analyzed by using RNA sequencing data from the TCGA database. To examine the expression of inhibin βE protein, 241 ccRCC patients were recruited and immunohistochemistry was performed on the tumor tissue of these patients along with 39 normal renal samples. The association between the inhibin βE expression level and patient's clinicopathological indices was evaluated. RESULTS In the normal renal tissue, inhibin βE was found to be expressed mainly by renal tubular epithelial cells. In the tumor tissue, inhibin βE was expressed mainly in cancer cells. The expressions of INHBE mRNA and protein in the tumor tissue of ccRCC patients increased significantly compared with those in normal renal samples. There was a significant correlation between the level of inhibin βE in the tumor tissue and tumor grade. Patients with a lower inhibin βE expression in the tumor tissue were found to have a longer overall survival and disease-specific survival. CONCLUSIONS INHBE might be involved in the pathogenesis of ccRCC and function as a tumor promoter.
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Affiliation(s)
- Zi-Bin Xu
- Department of Urology, Taizhou Hospital, Wenzhou Medical University, Linhai, China
| | - Mei-Fu Gan
- Department of Pathology, Taizhou Hospital, Wenzhou Medical University, Linhai, China
| | - Hong-Yuan Yu
- Department of Urology, Taizhou Hospital, Wenzhou Medical University, Linhai, China
| | - Li-Cai Mo
- Department of Urology, Taizhou Hospital, Wenzhou Medical University, Linhai, China
| | - Yu-Hui Xia
- Department of Pathology, Taizhou Hospital, Wenzhou Medical University, Linhai, China
| | - Qing-Xin Yu
- Department of Pathology, Taizhou Hospital, Wenzhou Medical University, Linhai, China
| | - Jing-Min Zheng
- Department of Urology, Taizhou Hospital, Wenzhou Medical University, Linhai, China.,Department of Pathology, Taizhou Hospital, Wenzhou Medical University, Linhai, China
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Adu-Gyamfi EA, Ding YB, Wang YX. Regulation of placentation by the transforming growth factor beta superfamily†. Biol Reprod 2021; 102:18-26. [PMID: 31566220 DOI: 10.1093/biolre/ioz186] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 08/18/2019] [Accepted: 09/09/2019] [Indexed: 12/12/2022] Open
Abstract
During pregnancy, there is increased expression of some cytokines at the fetal-maternal interface; and the clarification of their roles in trophoblast-endometrium interactions is crucial to understanding the mechanism of placentation. This review addresses the up-to-date reported mechanisms by which the members of the transforming growth factor beta superfamily regulate trophoblast proliferation, differentiation, and invasion of the decidua, which are the main phases of placentation. The available information shows that these cytokines regulate placentation in somehow a synergistic and an antagonistic manner; and that dysregulation of their levels can lead to aberrant placentation. Nevertheless, prospective studies are needed to reconcile some conflicting reports; and identify some unknown mediators involved in the actions of these cytokines before their detailed mechanistic regulation of human placentation could be fully characterized. The TGF beta superfamily are expressed in the placenta, and regulate the process of placentation through the activation of several signaling pathways.
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Affiliation(s)
- Enoch Appiah Adu-Gyamfi
- Department of Reproductive Sciences, School of Public Health, Chongqing Medical University, Chongqing, People's Republic of China.,Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, Chongqing, People's Republic of China
| | - Yu-Bin Ding
- Department of Reproductive Sciences, School of Public Health, Chongqing Medical University, Chongqing, People's Republic of China.,Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, Chongqing, People's Republic of China
| | - Ying-Xiong Wang
- Department of Reproductive Sciences, School of Public Health, Chongqing Medical University, Chongqing, People's Republic of China.,Joint International Research Laboratory of Reproduction & Development, Chongqing Medical University, Chongqing, People's Republic of China
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10
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Abdel Mouti M, Pauklin S. TGFB1/INHBA Homodimer/Nodal-SMAD2/3 Signaling Network: A Pivotal Molecular Target in PDAC Treatment. Mol Ther 2021; 29:920-936. [PMID: 33429081 PMCID: PMC7934636 DOI: 10.1016/j.ymthe.2021.01.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 10/17/2020] [Accepted: 01/02/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer remains a grueling disease that is projected to become the second-deadliest cancer in the next decade. Standard treatment of pancreatic cancer is chemotherapy, which mainly targets the differentiated population of tumor cells; however, it paradoxically sets the roots of tumor relapse by the selective enrichment of intrinsically chemoresistant pancreatic cancer stem cells that are equipped with an indefinite capacity for self-renewal and differentiation, resulting in tumor regeneration and an overall anemic response to chemotherapy. Crosstalk between pancreatic tumor cells and the surrounding stromal microenvironment is also involved in the development of chemoresistance by creating a supportive niche, which enhances the stemness features and tumorigenicity of pancreatic cancer cells. In addition, the desmoplastic nature of the tumor-associated stroma acts as a physical barrier, which limits the intratumoral delivery of chemotherapeutics. In this review, we mainly focus on the transforming growth factor beta 1 (TGFB1)/inhibin subunit beta A (INHBA) homodimer/Nodal-SMAD2/3 signaling network in pancreatic cancer as a pivotal central node that regulates multiple key mechanisms involved in the development of chemoresistance, including enhancement of the stem cell-like properties and tumorigenicity of pancreatic cancer cells, mediating cooperative interactions between pancreatic cancer cells and the surrounding stroma, as well as regulating the deposition of extracellular matrix proteins within the tumor microenvironment.
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Affiliation(s)
- Mai Abdel Mouti
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Headington, University of Oxford, Oxford OX3 7LD, UK
| | - Siim Pauklin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Headington, University of Oxford, Oxford OX3 7LD, UK.
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11
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Jiang L, Liu B, Qi Y, Zhu L, Cui X, Liu Z. Antagonistic effects of activin A and TNF-α on the activation of L929 fibroblast cells via Smad3-independent signaling. Sci Rep 2020; 10:20623. [PMID: 33244088 PMCID: PMC7693280 DOI: 10.1038/s41598-020-77783-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 11/17/2020] [Indexed: 02/07/2023] Open
Abstract
Fibroblasts play an important role in inflammation and tissue fibrosis. Both activin A and TNF-α can activate immune cells, however, the roles and relationship of them in activating fibroblasts in inflammation remain unclear. Here, this study revealed that TNF-α promoted the release of NO and IL-6 by L929 fibroblast cells, but co-treatment with activin A attenuated these effects. In contrast, activin A induced cell migration and increased the production of tissue fibrosis-related TGF-β1 and fibronectin, while TNF-α inhibited these function changes of L929 cells induced by activin A. Moreover, this study revealed that activin A and TNF-α regulated the activities of L929 cells via ERK1/2/MAPK pathway, rather than Smad3-dependent signaling pathway. Taken together, these data indicate that activin A and TNF-α exert mutually antagonistic effects on regulating fibroblasts activities, and the balance between their action may determine the process and outcome of fibroblasts-mediated inflammation.
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Affiliation(s)
- Lingling Jiang
- Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China.,Department of General Dentistry, School and Hospital of Stomatology, Jilin University, Changchun, 130021, Jilin, China
| | - Boyang Liu
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun, 130021, Jilin, China.,Department of Scientific Research, Jilin Jianzhu University, Changchun, 130118, Jilin, China
| | - Yan Qi
- Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China
| | - Linru Zhu
- Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China
| | - Xueling Cui
- Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun, 130021, Jilin, China
| | - Zhonghui Liu
- Department of Immunology, College of Basic Medical Sciences, Jilin University, 126 Xinmin Street, Changchun, 130021, Jilin, China.
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12
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Oh S, Lee J. Sarcopenia and blood myokine levels as prognostic biomarkers in patients with liver cirrhosis or hepatocellular carcinoma. Clin Mol Hepatol 2020; 26:476-479. [PMID: 33053929 PMCID: PMC7641548 DOI: 10.3350/cmh.2020.0192] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 08/28/2020] [Indexed: 12/22/2022] Open
Affiliation(s)
- Sooyeon Oh
- Chaum Life Center, Department of Internal Medicine, CHA University School of Medicine, Seoul, Korea
| | - Jooho Lee
- Chaum Life Center, Department of Internal Medicine, CHA University School of Medicine, Seoul, Korea.,Division of Gastroenterology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
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13
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Zhang DY, Lei JS, Sun WL, Wang DD, Lu Z. Follistatin Like 5 (FSTL5) inhibits epithelial to mesenchymal transition in hepatocellular carcinoma. Chin Med J (Engl) 2020; 133:1798-1804. [PMID: 32740091 PMCID: PMC7469996 DOI: 10.1097/cm9.0000000000000847] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Background Epithelial to mesenchymal transition (EMT) is a key process in determining distant metastasis and intra-hepatic dissemination of hepatocellular carcinoma (HCC). Follistatin (FST) family members are considered to be an attractive therapeutic targets and prognostic indicators in cancers. As a derivative of FST, Follistatin Like 5 (FSTL5) may play a similar role in HCC cells. This study aimed to investigate the expression and function of FSTL5 in HCC and its role in EMT. Methods FSTL5, E-cadherin and vimentin in HCC, and paracancerous tissues were detected by immunohistochemistry. Correlation of FSTL5 expression with overall survival was assessed. The proliferation and invasion of HCC cell lines SK-Hep1 and MHCC-LM3 were analyzed by cell counting kit-8 and Transwell assays. The expression of FSTL5, E-cadherin, and vimentin in HCC cells was examined by polymerase chain reaction and Western blot analysis. T-test was used to analyze the difference in proliferation and invasion ability between groups. The Spearman rank correlation test was used to detect the correlation between the expression of FSTL5 and E-cadherin or vimentin. Results The expression of FSTL5 in HCC was lower than that in paracancerous tissues (9.97% vs. 82.55%, χ2 = 340.15, P < 0.001). Patients with high FSTL5 expression had a better prognosis (χ2 = 8.22, P = 0.004) and smaller tumor diameter (χ2 = 45.52, P < 0.001), less lymph node metastasis (χ2 = 5.58, P = 0.02), earlier tumor node metastasis stage (χ2 = 11.29, P = 0.001), a reduced number of tumors (χ2 = 5.05, P = 0.02), lower alpha-fetoprotein value (χ2 = 24.36, P < 0.001), more probability of hepatitis carrying (χ2 = 40.9, P < 0.001), and better liver function grade (χ2 = 5.21, P = 0.02). Immunohistochemistry showed that FSTL5 expression in HCC tissues was positively correlated with E-cadherin expression (r = 0.38, P < 0.001) and negatively correlated with vimentin expression (r = −0.385, P < 0.001). Furthermore, over-expression of FSTL5 up-regulated the expression of E-cadherin and down-regulated the expression of vimentin in SK-Hep1 (negative control [NC] vs. FSTL5-interfering group [Lv-FSTL5]: E-cadherin [t = 45.03, P < 0.001], vimentin [t = 67, P < 0.001]) and MHCC-LM3 (NC vs. Lv-FSTL5: E-cadherin [t = 50, P < 0.001], vimentin [t = 72.75, P < 0.001]) cells at mRNA level. The same as protein level. In addition, the over-expression of FSTL5 inhibited the proliferation (NC vs. Lv-FSTL5: SK-Hep1, 3 d [t = 7.324, P = 0.018], 4 d [t = 6.23, P = 0.021], 5 d [t = 10.21, P = 0.003]; MHCC-LM3, 3 d [t = 4.32, P = 0.037], 4 d [t = 7.49, P = 0.012], 5 d [t = 9.3661, P = 0.009]) and invasion (NC vs. Lv-FSTL5: SK-Hep1, t = 21.57, P < 0.001; MHCC-LM3, t = 18.04, P < 0.001) of HCC cells. Conclusions Down-regulation of FSTL5 may contribute to EMT of HCC, and FSTL5 is a potential target in the treatment of HCC.
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Affiliation(s)
- Deng-Yong Zhang
- Department of General Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233000, China
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14
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Upregulation of follistatin and low apoptotic activity in intraductal oncocytic papillary neoplasm of the pancreatobiliary system. Sci Rep 2020; 10:8179. [PMID: 32424306 PMCID: PMC7235027 DOI: 10.1038/s41598-020-64920-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 04/22/2020] [Indexed: 12/17/2022] Open
Abstract
Intraductal oncocytic papillary neoplasm (IOPN) is a rare intraductal tumor of the pancreatobiliary system. Currently, little is known about its distinct characteristics, unlike intraductal papillary mucinous neoplasms (IPMN) and intraductal papillary neoplasms of the bile duct (IPNB). The present study compared 22 IOPNs (18 pancreatic and 4 biliary) with those of 61 IPMNs/8 IPNBs. IOPNs were classified into pure and combined types, depending on the coexistence of IPMN/IPNB. Multiple gene expression analysis (nCounter system) was performed, and hierarchical clustering analysis separated IOPNs(n = 4) and IPMNs(n = 3)/ IPNBs(n = 3), and pathway score analysis supported the result. Volcano plot identified follistatin (FST) as the most upregulated mRNA in IOPN in comparison to the gastric subtype (log2 fold change of 5.34) and the intestinal subtype (that of 5.81) of IPMN/IPNB. The expression of FST in IOPN was also high in quantitative polymerase chain reaction and immunohistochemical analysis. We also found lower apoptotic activity in IOPN, particularly in pure type, compared to high-grade or invasive IPMN/IPNB using immunohistochemistry for cleaved caspase 3. But, combined type IOPN was more similar to IPMN/IPNB than pure IOPN. In conclusion, we proved that IOPN, particularly pure IOPN, is distinct from IPMN/IPNB in FST mRNA overexpression and exhibits lower apoptotic activity.
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15
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Zandsalimi F, Hajihassan Z, Hamidi R. Denovo designing: a novel signal peptide for tat translocation pathway to transport activin A to the periplasmic space of E. coli. Biotechnol Lett 2019; 42:45-55. [PMID: 31679097 DOI: 10.1007/s10529-019-02752-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 10/27/2019] [Indexed: 10/25/2022]
Abstract
OBJECTIVES The twin-arginine translocation (Tat) pathway is one of the bacterial secretory strategies which exports folded proteins across the cytoplasmic membrane. RESULTS In the present study, we designed a novel Tat-signal peptide for secretion of human activin A used as a recombinant protein model here. In doing so, Haloferax volcanii, Halobacterium salinarum, and Escherichia coli Tat specific signal peptides were aligned by ClustalW program to determine conserved and more frequently used residues. After making the initial signal peptide sequence and doing some mutations, efficiency of this designed signal peptide was evaluated using a set of well-known software programs such as TatP, PRED-TAT, and Phobius. Then the best complex between TatC as an initiator protein in Tat secretory machine and the new designed signal peptide connected to activin A with the lowest binding energy was constructed by HADDOCK server, and ΔΔG value of - 5.5 kcal/mol was calculated by FoldX module. After that, efficiency of this novel signal peptide for secretion of human activin A to the periplasmic space of E. coli Rosetta-gami (DE3) strain was experimentally evaluated; to scrutinize the activity of the novel signal peptide, Iranian Bacillus Licheniformis α-Amylase enzyme signal peptide as a Sec pathway signal peptide was used as a positive control. The quantitative analysis of western blotting bands by ImageJ software confirmed the high secretion ability of the new designed signal peptide; translocation of 69% of the produced recombinant activin A to the periplasmic space of E. coli. Circular Dichroism (CD) spectroscopy technique also approved the proper secondary structure of activin A secreted to the periplasmic space. The biological activity of activin A was also confirmed by differentiation of K562 erythroleukemia cells to the red blood cell by measuring the amount of hemoglobin or Fe2+ ion using ICP method. CONCLUSIONS In conclusion, this novel designed signal peptide can be used to secrete any other recombinant proteins to the periplasmic space of E. coli efficiently.
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Affiliation(s)
- Farshid Zandsalimi
- Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran
| | - Zahra Hajihassan
- Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran.
| | - Roghaye Hamidi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
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16
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Morita M, Hashimoto O. Identification and expression of the medaka inhibin βE subunit. Mol Biol Rep 2019; 46:1603-1609. [PMID: 30680594 DOI: 10.1007/s11033-019-04607-y] [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: 10/27/2018] [Accepted: 01/16/2019] [Indexed: 11/24/2022]
Abstract
Activin E, a member of the TGF-β super family, is a protein dimer of mature inhibin βE subunits. Recently, it is reported that hepatic activin E may act as a hepatokine that alter whole body energy/glucose metabolism in human. However, orthologues of the activin E gene have yet to be identified in lower vertebrates, including fish. Here, we cloned the medaka (Oryzias latipes) activin E cDNA from liver. Among all the mammalian inhibin β subunits, the mature medaka activin E amino acid sequence shares the highest homology with mammalian activin E. Recombinant expression studies suggest that medaka activin E, the disulfide-bound mature form of mature inhibin βE subunits, may exert its effects in a way similar to that in mammals. Although activin E mRNA is predominantly expressed in liver in mammals, it is ubiquitously expressed in medaka tissues. Since expression in the liver was enhanced after a high fat diet, medaka activin E may be associated with energy/glucose metabolism, as shown in mice and human.
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Affiliation(s)
- Masahiro Morita
- Kitasato University School of Veterinary Medicine, 35-1 Higashi 23, Towada-shi, Aomori, 034-8628, Japan
| | - Osamu Hashimoto
- Kitasato University School of Veterinary Medicine, 35-1 Higashi 23, Towada-shi, Aomori, 034-8628, Japan.
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17
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Gao X, Zhao P, Hu J, Zhu H, Zhang J, Zhou Z, Zhao J, Tang F. MicroRNA-194 protects against chronic hepatitis B-related liver damage by promoting hepatocyte growth via ACVR2B. J Cell Mol Med 2018; 22:4534-4544. [PMID: 30044042 PMCID: PMC6111826 DOI: 10.1111/jcmm.13714] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 03/03/2018] [Indexed: 12/13/2022] Open
Abstract
Persistent infection with the hepatitis B virus leads to liver cirrhosis and hepatocellular carcinoma. MicroRNAs (miRNAs) play an important role in a variety of biological processes; however, the role of miRNAs in chronic hepatitis B (CHB)‐induced liver damage remains poorly understood. Here, we investigated the role of miRNAs in CHB‐related liver damage. Microarray analysis of the expression of miRNAs in 22 CHB patients and 33 healthy individuals identified miR‐194 as one of six differentially expressed miRNAs. miR‐194 was up‐regulated in correlation with increased liver damage in the plasma or liver tissues of CHB patients. In mice subjected to 2/3 partial hepatectomy, miR‐194 was up‐regulated in liver tissues in correlation with hepatocyte growth and in parallel with the down‐regulation of the activin receptor ACVR2B. Overexpression of miR‐194 in human liver HL7702 cells down‐regulated ACVR2B mRNA and protein expression, promoted cell proliferation, acceleratedG1 to S cell cycle transition, and inhibited apoptosis, whereas knockdown of miR‐194 had the opposite effects. Luciferase reporter assays confirmed that ACVR2B is a direct target of miR‐194, and overexpression of ACVR2B significantly repressed cell proliferation and G1 to S phase transition and induced cell apoptosis. ACVR2B overexpression abolished the effect of miR‐194, indicating that miR‐194 promotes hepatocyte proliferation and inhibits apoptosis by down‐regulating ACVR2B. Taken together, these results indicate that miR‐194 plays a crucial role in hepatocyte proliferation and liver regeneration by targeting ACVR2B and may represent a novel therapeutic target for the treatment of CHB‐related liver damage.
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Affiliation(s)
- Xue Gao
- Department of Pathology, 302 Hospital, Beijing, China
| | - Pan Zhao
- Clinical Trial Center, Beijing 302 Hospital, Beijing, China
| | - Jie Hu
- Liver Surgery Department, Zhongshan Hospital, Fudan University, Shanghai, China.,Liver Cancer Institute, Fudan University, Shanghai, China
| | - Hongguang Zhu
- Department of Pathology, Shanghai Medical College, Fudan University, Shanghai, China.,Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China
| | - Jiming Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhongwen Zhou
- Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China
| | - Jingmin Zhao
- Department of Pathology, 302 Hospital, Beijing, China
| | - Feng Tang
- Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China
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18
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Zabkiewicz C, Resaul J, Hargest R, Jiang WG, Ye L. Increased Expression of Follistatin in Breast Cancer Reduces Invasiveness and Clinically Correlates with Better Survival. Cancer Genomics Proteomics 2018. [PMID: 28647698 DOI: 10.21873/cgp.20035] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND/AIM Activin and its antagonist follistatin (FST) have been implicated in several solid tumours. This study investigated the role of FST in breast cancer. MATERIALS AND METHODS FST expression was examined using reverse transcription polymerase chain reaction (RT-PCR), real-time quantitative polymerase chain reaction (qPCR) and immunohistochemistry in a cohort of breast cancer samples. Expression was correlated to pathological and prognostic parameters in our patient cohort. FST was overexpressed in MCF-7 cells and assays for growth and invasion were performed. RESULTS FST is expressed in breast tissue, in the cytoplasm of mammary epithelial cells. Expression was decreased in breast cancer tissue in comparison to normal mammary tissue. Over-expression of FST in vitro led to significantly increased growth rate and reduced invasion. Higher FST associates with lower-grade tumours and better survival. CONCLUSION Our results suggest a role for FST as a suppressor of invasion and metastasis in breast cancer.
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Affiliation(s)
- Catherine Zabkiewicz
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, U.K
| | - Jeyna Resaul
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, U.K
| | - Rachel Hargest
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, U.K
| | - Wen Guo Jiang
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, U.K.
| | - Lin Ye
- Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, U.K.
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19
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Bubnov RV, Drahulian MV, Buchek PV, Gulko TP. High regenerative capacity of the liver and irreversible injury of male reproductive system in carbon tetrachloride-induced liver fibrosis rat model. EPMA J 2018; 9:59-75. [PMID: 29515688 PMCID: PMC5833895 DOI: 10.1007/s13167-017-0115-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 08/17/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Liver fibrosis (LF) is a chronic disease, associated with many collateral diseases including reproductive dysfunction. Although the normal liver has a large regenerative capacity the complications of LF could be severe and irreversible. Hormone and sex-related issues of LF development and interactions with male reproductive have not been finally studied. The aim was to study the reproductive function of male rats in experimental CCl4-induced liver fibrosis rat model, and the capability for restoration of both the liver and male reproduction system. MATERIALS Studies were conducted on 20 3-month old Wistar male rats. The experimental animals were injected with freshly prepared 50% olive oil solution of carbohydrate tetrachloride (CCl4). On the 8th week after injection we noted the manifestations of liver fibrosis. The rats were left to self-healing of the liver for 8 weeks. All male rats underwent ultrasound and biopsy of the liver and testes on the 8th and 16th weeks. The male rats were mated with healthy females before CCl4 injection, after modeling LF on the 8th week, and after self-healing of the liver. Pregnancy was monitored on ultrasound. RESULTS On the 8th week of experiment we observed ultrasound manifestation of advanced liver fibrosis, including hepatosplenomegaly, portal hypertension. Ultrasound exam of the rat testes showed testicular degeneration, hydrocele, fibrosis, scarring, petrifications, size reduction, and restriction of testicular descent; testes size decreased from 1.24 ± 0.62 ml to 0.61 ± 0.13, p < 0.01. Liver histology showed granular dystrophy of hepatocytes, necrotic areas, lipid inclusions in parenchyma. Rats with liver fibrosis demonstrated severe injury of the reproductive system and altering of fertility: the offspring of male rats with advanced LF was 4.71 ± 0.53 born alive vs 9.55 ± 0.47 born from mating with healthy males, p < 0.001. Eight weeks after last CCl4 injection, we revealed signs of liver regeneration, significant recovery of its structure. The ALT and AST levels significantly decreased and reached background measurements. As a result of the second interbreeding after liver self-healing no significant difference was found vs previous mating. CONCLUSION Carbohydrate tetrachloride induces injury of liver parenchyma evoking fast and severe liver fibrosis, and is associated with irreversible structural and functional changes in testes, reducing fertility, decreasing potential pregnancy rate, and affecting its development. Liver showed high potential to regenerate, however the self-restoring after liver fibrosis was not accompanied with recovery of the reproductive system.
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Affiliation(s)
- Rostyslav V. Bubnov
- Zabolotny Institute of Microbiology and Virology, National Academy of Sciences of Ukraine, Zabolotny Str., 154, Kyiv, 03143 Ukraine
- Clinical Hospital ‘Pheophania’ of State Affairs Department, Zabolotny str., 21, Kyiv, 03143 Ukraine
| | - Maria V. Drahulian
- Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Zabolotny str., 150, Kyiv, 03143 Ukraine
| | - Polina V. Buchek
- Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Zabolotny str., 150, Kyiv, 03143 Ukraine
| | - Tamara P. Gulko
- Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Zabolotny str., 150, Kyiv, 03143 Ukraine
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20
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Activin-A causes Hepatic stellate cell activation via the induction of TNFα and TGFβ in Kupffer cells. Biochim Biophys Acta Mol Basis Dis 2017; 1864:891-899. [PMID: 29287776 DOI: 10.1016/j.bbadis.2017.12.031] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 12/06/2017] [Accepted: 12/22/2017] [Indexed: 01/14/2023]
Abstract
BACKGROUND & AIMS TGFβ superfamily member Activin-A is a multifunctional hormone/cytokine expressed in multiple tissues and cells, where it regulates cellular differentiation, proliferation, inflammation and tissue architecture. High activin-A levels have been reported in alcoholic cirrhosis and non-alcoholic steatohepatitis (NASH). Our aim was to identify the cell types involved in the fibrotic processes induced by activin-A in liver and verify the liver diseases that this molecule can be found increased. METHODS We studied the effect of activin-A on mouse primary Kupffer cells (KCs) and Hepatic Stellate cells (HSCs) and the levels of activin-A and its inhibitor follistatin in the serum of patients from a large panel of liver diseases. RESULTS Activin-A is expressed by mouse hepatocytes, HSCs and Liver Sinusoid Endothelial cells but not KCs. Each cell type expresses different activin receptor combinations. HSCs are unresponsive to activin-A due to downregulation/desensitization of type-II activin receptors, while KCs respond by increasing the expression/production of TNFα και TGFβ1. In the presence of KCs or conditioned medium from activin-A treated KCs, HSCs switch to a profibrogenic phenotype, including increased collagen and αSMA expression and migratory capacity. Incubation of activin-A treated KC conditioned medium with antibodies against TNFα and TGFβ1 partially blocks its capacity to activate HSCs. Only patients with alcoholic liver diseases and NASH cirrhosis have significantly higher activin-A levels and activin-A/follistatin ratio. CONCLUSIONS Activin-A may induce fibrosis in NASH and alcoholic cirrhosis via activation of KCs to express pro-inflammatory molecules that promote HSC-dependent fibrogenesis and could be a target for future anti-fibrotic therapies.
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21
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Donovan P, Dubey OA, Kallioinen S, Rogers KW, Muehlethaler K, Müller P, Rimoldi D, Constam DB. Paracrine Activin-A Signaling Promotes Melanoma Growth and Metastasis through Immune Evasion. J Invest Dermatol 2017; 137:2578-2587. [DOI: 10.1016/j.jid.2017.07.845] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 06/26/2017] [Accepted: 07/25/2017] [Indexed: 01/19/2023]
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22
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Zhang DY, Sun WL, Ma X, Zhang P, Wu W, Wu H, Zhou S, Lu Z. Up-regulated FSTL5 inhibits invasion of hepatocellular carcinoma through the Wnt/β-catenin/YAP pathway. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2017; 10:10325-10333. [PMID: 31966367 PMCID: PMC6965754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 09/18/2017] [Indexed: 06/10/2023]
Abstract
Patients with hepatocellular carcinoma (HCC) have a poor survival rate because of its high invasion ability. Therefore, it is necessary to elucidate the mechanisms of HCC migration and invasion. Our previous study showed that follistatin-like 5 (FSTL5), which was associated with the prognosis of HCC patients, acts as an inhibitor of HCC cell proliferation. It also promotes the transition of cell morphology from mesenchymal to epithelial, which is associated with the process of mesenchymal-to-epithelial transition. In this study, we used two HCC cell lines (SK-Hep1 and SMMC-7721) to explore the effect of FSTL5 on HCC invasion and migration. We found that up-regulated FSTL5 restrained HCC invasion and migration by transwell, wound healing, detachment, and attachment assays. Decreased expression of YAP was found upon over-expression of FSTL5, as well as inhibition of the Wnt/β-catenin signaling pathway. YAP is a downstream gene of the Wnt/β-catenin signaling pathway and plays an important role in HCC metastasis. Thus, we speculate that FSTL5 inhibits the invasion of HCC through the Wnt/β-catenin/YAP pathway. In conclusion, FSTL5 exerts an inhibitory effect on HCC metastasis and proliferation through the Wnt/β-catenin/YAP pathway and may be a target gene for anti-tumor therapy.
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Affiliation(s)
- Deng-Yong Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Bengbu Medical CollegeBengbu, Anhui, China
| | - Wan-Liang Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Bengbu Medical CollegeBengbu, Anhui, China
| | - Xiang Ma
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Bengbu Medical CollegeBengbu, Anhui, China
| | - Pei Zhang
- Department of Pharmacy, Bengbu Medical CollegeBengbu, Anhui, China
| | - Wei Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Bengbu Medical CollegeBengbu, Anhui, China
| | - Huan Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Bengbu Medical CollegeBengbu, Anhui, China
| | - Shuo Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Bengbu Medical CollegeBengbu, Anhui, China
| | - Zheng Lu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Bengbu Medical CollegeBengbu, Anhui, China
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Abstract
Testes-specific protease 50 (TSP50), a novelly identified oncogene, has the capacity to induce cell proliferation, cell invasion and tumor growth. Further studies indicated that CAGA-luc (an activin-responsive reporter construct) reporter activity could be significantly suppressed by TSP50 overexpression, implying that the activin signaling may participate in TSP50-mediated cell proliferation. Here, we reported that TSP50 had an inhibitory effect on activin signaling. Mechanistic studies revealed that TSP50 could interact with ActRIIA, inhibit activin typeIreceptor (ActRIB) phosphorylation, repress Smad2/3 nuclear accumulation and finally promote cell proliferation by reducing the expression of activin signal target gene p27. Additionally, we found that ActRIB activation could reverse TSP50-mediated cell proliferation and tumor growth. Furthermore, analysis of human breast cancer specimens by immunohistochemistry indicated that TSP50 expression was negatively related to p-Smad2/3 and p27 protein levels. Most importantly, breast cancer diagnosis-related indicators such as tumor size, tumor grade, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) levels, were correlated well with TSP50/p-Samd2/3 and TSP50/p27 expression status. Thus, our studies revealed a novel regulatory mechanism underlying TSP50-induced cell proliferation and provided a new favorable intervention target for the treatment of breast cancer.
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Gavriatopoulou M, Dimopoulos MA, Kastritis E, Terpos E. Emerging treatment approaches for myeloma-related bone disease. Expert Rev Hematol 2017; 10:217-228. [PMID: 28092987 DOI: 10.1080/17474086.2017.1283213] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Multiple myeloma is characterized by the presence of osteolytic lesions that leads to devastating skeletal-related events in the majority of patients. Myeloma bone disease is attributed to increased osteoclastic and suppressed osteoblastic activity. Areas covered: Bisphosphonates remain the main treatment option, however they have limitations on their own. Understanding the pathogenesis of myeloma bone disease may provide a roadmap for new therapeutic approaches. The pathway of RANKRANKLOPG pathway has revealed denosumab, a monoclonal antibody targeting RANKL as a novel emerging therapy for myeloma-related bone disease. Furthermore, the Wnt signaling inhibitors dicckopf-1 and sclerostin that are implicated in the pathogenesis of bone destruction of myeloma are now targeted by novel monoclonal antibodies. Activin-A is a TGF-beta superfamily member which increases osteoclast activity and inhibits osteoblast function in myeloma; sotatercept and other molecules targeting activin-A have entered into clinical development. Several other molecules and pathways that play an important role in the pathogenesis of bone destruction in myeloma, such as periostin, adiponectin, Notch and BTK signaling are also targeted in an attempt to develop novel therapies for myeloma-related bone disease. Expert commentary: We summarize the current advances in the biology of myeloma bone disease and the potential therapeutic targets.
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Affiliation(s)
- Maria Gavriatopoulou
- a Department of Clinical Therapeutics , National and Kapodistrian University of Athens School of Medicine , Athens , Greece
| | - Meletios A Dimopoulos
- a Department of Clinical Therapeutics , National and Kapodistrian University of Athens School of Medicine , Athens , Greece
| | - Efstathios Kastritis
- a Department of Clinical Therapeutics , National and Kapodistrian University of Athens School of Medicine , Athens , Greece
| | - Evangelos Terpos
- a Department of Clinical Therapeutics , National and Kapodistrian University of Athens School of Medicine , Athens , Greece
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Asgharpour A, Cazanave SC, Pacana T, Seneshaw M, Vincent R, Banini BA, Kumar DP, Daita K, Min HK, Mirshahi F, Bedossa P, Sun X, Hoshida Y, Koduru SV, Contaifer D, Warncke UO, Wijesinghe DS, Sanyal AJ. A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer. J Hepatol 2016; 65:579-88. [PMID: 27261415 PMCID: PMC5012902 DOI: 10.1016/j.jhep.2016.05.005] [Citation(s) in RCA: 380] [Impact Index Per Article: 42.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Revised: 03/30/2016] [Accepted: 05/06/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The lack of a preclinical model of progressive non-alcoholic steatohepatitis (NASH) that recapitulates human disease is a barrier to therapeutic development. METHODS A stable isogenic cross between C57BL/6J (B6) and 129S1/SvImJ (S129) mice were fed a high fat diet with ad libitum consumption of glucose and fructose in physiologically relevant concentrations and compared to mice fed a chow diet and also to both parent strains. RESULTS Following initiation of the obesogenic diet, B6/129 mice developed obesity, insulin resistance, hypertriglyceridemia and increased LDL-cholesterol. They sequentially also developed steatosis (4-8weeks), steatohepatitis (16-24weeks), progressive fibrosis (16weeks onwards) and spontaneous hepatocellular cancer (HCC). There was a strong concordance between the pattern of pathway activation at a transcriptomic level between humans and mice with similar histological phenotypes (FDR 0.02 for early and 0.08 for late time points). Lipogenic, inflammatory and apoptotic signaling pathways activated in human NASH were also activated in these mice. The HCC gene signature resembled the S1 and S2 human subclasses of HCC (FDR 0.01 for both). Only the B6/129 mouse but not the parent strains recapitulated all of these aspects of human NAFLD. CONCLUSIONS We here describe a diet-induced animal model of non-alcoholic fatty liver disease (DIAMOND) that recapitulates the key physiological, metabolic, histologic, transcriptomic and cell-signaling changes seen in humans with progressive NASH. LAY SUMMARY We have developed a diet-induced mouse model of non-alcoholic steatohepatitis (NASH) and hepatic cancers in a cross between two mouse strains (129S1/SvImJ and C57Bl/6J). This model mimics all the physiological, metabolic, histological, transcriptomic gene signature and clinical endpoints of human NASH and can facilitate preclinical development of therapeutic targets for NASH.
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Affiliation(s)
- Amon Asgharpour
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA
| | - Sophie C Cazanave
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA.
| | - Tommy Pacana
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA
| | - Mulugeta Seneshaw
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA
| | - Robert Vincent
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA
| | - Bubu A Banini
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA
| | - Divya Prasanna Kumar
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA
| | - Kalyani Daita
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA
| | - Hae-Ki Min
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA
| | - Faridoddin Mirshahi
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA
| | - Pierre Bedossa
- Department of Pathology, Hospital Beaujon, University Paris-Diderot, Paris, France
| | - Xiaochen Sun
- Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Yujin Hoshida
- Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | | | - Daniel Contaifer
- Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Urszula Osinska Warncke
- Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA; Department of Surgery, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Dayanjan S Wijesinghe
- Department of Pharmacotherapy and Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA; Department of Surgery, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0341, USA.
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Hardy JT, Buhimschi IA, McCarthy ME, Zhao G, Laky CA, Shook LL, Buhimschi CS. Imbalance of Amniotic Fluid Activin-A and Follistatin in Intraamniotic Infection, Inflammation, and Preterm Birth. J Clin Endocrinol Metab 2016; 101:2785-93. [PMID: 27159193 PMCID: PMC6287504 DOI: 10.1210/jc.2015-4147] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Microbial invasion of the amniotic fluid (AF) cavity stimulates an inflammatory response that involves activin-A, a pleiotropic mediator member of the TGFβ superfamily involved in connective tissue remodeling. The role of AF follistatin, a natural inhibitor of activin-A, in inflammation-induced preterm birth (PTB), has yet to be determined. OBJECTIVE The objective of the study was to investigate the relationships between AF activin-A and follistatin in physiological gestation and in pregnancies complicated by PTB and to evaluate a possible role played by the activin-A-follistatin balance in processes leading to PTB and preterm premature rupture of membranes (PPROM). STUDY DESIGN The AF levels of total activin-A and follistatin were immunoassayed in 168 women with a normal pregnancy outcome or PTB with and without intraamniotic inflammation or PPROM. The impact of the activin-A-follistatin imbalance on PTB terminal effector pathways (prostaglandins [prostaglandin E2, prostaglandin F2α] and matrix metalloproteinases [MMP-1, MMP-2, MMP-3, and MMP-9]) was investigated in an amniochorion explant system challenged with lipopolysaccharide (LPS) to mimic inflammation. RESULTS AF follistatin and the activin-A to follistatin ratio varied with gestational age, both decreasing toward term (P < .001). Activin-A was up-regulated in AF infection (>2-fold elevation in activin-A to follistatin ratio) correlating directly with severity of inflammation (both P < .001). Activin-A increased prostaglandins, MMP-1, and MMP-9 released by amniochorion (P < .05) to LPS-equivalent levels. Follistatin effectively blunted the prostaglandin response to activin-A and LPS and that of MMPs after activin-A but not after LPS challenge. CONCLUSION Activin-A and follistatin are part of the complex inflammatory response of the gestational sac to infection and modulate effector pathways leading to PTB. The activin-A to follistatin ratio may play a role in determining the clinical phenotype of PTB as preterm labor or PPROM.
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Affiliation(s)
- John T Hardy
- Department of Obstetrics/Gynecology and Reproductive Sciences (J.T.H., M.E.M., C.A.L., L.L.S.), Yale University School of Medicine, New Haven, Connecticut 06520; Center for Perinatal Research (I.A.B., G.Z.), The Research Institute at Nationwide Children's Hospital, and Department of Pediatrics (I.A.B.), The Ohio State University College of Medicine, Columbus, Ohio 43215; and Department of Obstetrics/Gynecology (I.A.B., C.S.B.), The Ohio State University College of Medicine, Columbus, Ohio 43210
| | - Irina A Buhimschi
- Department of Obstetrics/Gynecology and Reproductive Sciences (J.T.H., M.E.M., C.A.L., L.L.S.), Yale University School of Medicine, New Haven, Connecticut 06520; Center for Perinatal Research (I.A.B., G.Z.), The Research Institute at Nationwide Children's Hospital, and Department of Pediatrics (I.A.B.), The Ohio State University College of Medicine, Columbus, Ohio 43215; and Department of Obstetrics/Gynecology (I.A.B., C.S.B.), The Ohio State University College of Medicine, Columbus, Ohio 43210
| | - Megan E McCarthy
- Department of Obstetrics/Gynecology and Reproductive Sciences (J.T.H., M.E.M., C.A.L., L.L.S.), Yale University School of Medicine, New Haven, Connecticut 06520; Center for Perinatal Research (I.A.B., G.Z.), The Research Institute at Nationwide Children's Hospital, and Department of Pediatrics (I.A.B.), The Ohio State University College of Medicine, Columbus, Ohio 43215; and Department of Obstetrics/Gynecology (I.A.B., C.S.B.), The Ohio State University College of Medicine, Columbus, Ohio 43210
| | - Guomao Zhao
- Department of Obstetrics/Gynecology and Reproductive Sciences (J.T.H., M.E.M., C.A.L., L.L.S.), Yale University School of Medicine, New Haven, Connecticut 06520; Center for Perinatal Research (I.A.B., G.Z.), The Research Institute at Nationwide Children's Hospital, and Department of Pediatrics (I.A.B.), The Ohio State University College of Medicine, Columbus, Ohio 43215; and Department of Obstetrics/Gynecology (I.A.B., C.S.B.), The Ohio State University College of Medicine, Columbus, Ohio 43210
| | - Christine A Laky
- Department of Obstetrics/Gynecology and Reproductive Sciences (J.T.H., M.E.M., C.A.L., L.L.S.), Yale University School of Medicine, New Haven, Connecticut 06520; Center for Perinatal Research (I.A.B., G.Z.), The Research Institute at Nationwide Children's Hospital, and Department of Pediatrics (I.A.B.), The Ohio State University College of Medicine, Columbus, Ohio 43215; and Department of Obstetrics/Gynecology (I.A.B., C.S.B.), The Ohio State University College of Medicine, Columbus, Ohio 43210
| | - Lydia L Shook
- Department of Obstetrics/Gynecology and Reproductive Sciences (J.T.H., M.E.M., C.A.L., L.L.S.), Yale University School of Medicine, New Haven, Connecticut 06520; Center for Perinatal Research (I.A.B., G.Z.), The Research Institute at Nationwide Children's Hospital, and Department of Pediatrics (I.A.B.), The Ohio State University College of Medicine, Columbus, Ohio 43215; and Department of Obstetrics/Gynecology (I.A.B., C.S.B.), The Ohio State University College of Medicine, Columbus, Ohio 43210
| | - Catalin S Buhimschi
- Department of Obstetrics/Gynecology and Reproductive Sciences (J.T.H., M.E.M., C.A.L., L.L.S.), Yale University School of Medicine, New Haven, Connecticut 06520; Center for Perinatal Research (I.A.B., G.Z.), The Research Institute at Nationwide Children's Hospital, and Department of Pediatrics (I.A.B.), The Ohio State University College of Medicine, Columbus, Ohio 43215; and Department of Obstetrics/Gynecology (I.A.B., C.S.B.), The Ohio State University College of Medicine, Columbus, Ohio 43210
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Bufalino A, Cervigne NK, de Oliveira CE, Fonseca FP, Rodrigues PC, Macedo CCS, Sobral LM, Miguel MC, Lopes MA, Leme AFP, Lambert DW, Salo TA, Kowalski LP, Graner E, Coletta RD. Low miR-143/miR-145 Cluster Levels Induce Activin A Overexpression in Oral Squamous Cell Carcinomas, Which Contributes to Poor Prognosis. PLoS One 2015; 10:e0136599. [PMID: 26317418 PMCID: PMC4552554 DOI: 10.1371/journal.pone.0136599] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 08/06/2015] [Indexed: 11/18/2022] Open
Abstract
Deregulated expression of activin A is reported in several tumors, but its biological functions in oral squamous cell carcinoma (OSCC) are unknown. Here, we investigate whether activin A can play a causal role in OSCCs. Activin A expression was assessed by qPCR and immunohistochemistry in OSCC tissues. Low activin A-expressing cells were treated with recombinant activin A and assessed for apoptosis, proliferation, adhesion, migration, invasion and epithelial-mesenchymal transition (EMT). Those phenotypes were also evaluated in high activin A-expressing cells treated with follistatin (an activin A antagonist) or stably expressing shRNA targeting activin A. Transfections of microRNA mimics were performed to determine whether the overexpression of activin A is regulated by miR-143/miR-145 cluster. Activin A was overexpressed in OSCCs in comparison with normal oral mucosa, and high activin A levels were significantly associated with lymph node metastasis, tumor differentiation and poor survival. High activin A levels promoted multiple properties associated with malignant transformation, including decreased apoptosis and increased proliferation, migration, invasion and EMT. Both miR-143 and miR-145 were markedly downregulated in OSCC cell lines and in clinical specimens, and inversely correlated to activin A levels. Forced expression of miR-143 and miR-145 in OSCC cells significantly decreased the expression of activin A. Overexpression of activin A in OSCCs, which is controlled by downregulation of miR-143/miR-145 cluster, regulates apoptosis, proliferation and invasiveness, and it is clinically correlated with lymph node metastasis and poor survival.
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Affiliation(s)
- Andreia Bufalino
- Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil
| | - Nilva K. Cervigne
- Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil
| | | | - Felipe Paiva Fonseca
- Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil
| | | | | | - Lays Martin Sobral
- Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil
| | - Marcia Costa Miguel
- Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil
- Department of Dentistry, Federal University of Rio Grande do Norte, Natal-RN, Brazil
| | - Marcio Ajudarte Lopes
- Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil
| | | | - Daniel W. Lambert
- Integrated Biosciences, School of Clinical Dentistry and Sheffield Cancer Centre, University of Sheffield, Sheffield, United Kingdom
| | - Tuula A. Salo
- Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil
- Department of Diagnostics and Oral Medicine, Institute of Dentistry and Oulu University Hospital and Medical Research Center, University of Oulu, Oulu and Institute of Dentistry, University of Helsinki, Helsinki, Finland
| | - Luiz Paulo Kowalski
- Department of Head and Neck Surgery and Otorhinolaryngology, A. C. Camargo Cancer Center, São Paulo-SP, Brazil
| | - Edgard Graner
- Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil
| | - Ricardo D. Coletta
- Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba-SP, Brazil
- * E-mail:
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Bashir M, Damineni S, Mukherjee G, Kondaiah P. Activin-A signaling promotes epithelial-mesenchymal transition, invasion, and metastatic growth of breast cancer. NPJ Breast Cancer 2015; 1:15007. [PMID: 28721365 PMCID: PMC5515205 DOI: 10.1038/npjbcancer.2015.7] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 03/25/2015] [Accepted: 05/04/2015] [Indexed: 11/23/2022] Open
Abstract
Background: Activins belong to the transforming growth factor-β (TGF-β) superfamily of cytokines. Although the role of TGF-β in cancer progression has been highly advocated, the role of activin signaling in cancer is not well known. However, overexpression of activin-A has been observed in several cancers. Aims: The gene expression profile indicated higher expression of Activin-A in breast tumors. Hence the aim of this study was to evaluate the status and role of Activin signaling pathway in these tumors. Methods: Microarray analysis was performed to reveal gene expression changes in breast tumors. The results were validated by quantitative PCR and immunohistochemical analysis in two independent sets of normal and tumor samples. Further, correlation of activin expression with survival and distant metastasis was performed to evaluate its possible role in tumor progression. We used recombinant activin-A, inhibitors, overexpression, and knockdown strategies both in vitro and in vivo, to understand the mechanism underlying the protumorigenic role of this signaling pathway. Results: We report that activin-A signaling is hyperactivated in breast cancers as indicated by higher activin-A, phosphoSMAD2, and phosphoSMAD3 levels in advanced breast cancers. Bone morphogenetic proteins and molecules involved in this signaling pathway were downregulated, suggesting its suppression in breast cancers. Activin-A expression correlates inversely with survival and metastasis in advanced breast cancers. Further, activin-A promotes anchorage-independent growth, epithelial–mesenchymal transition, invasion, angiogenesis, and stemness of breast cancer cells. We show that activin-A-induced phenotype is mediated by SMAD signaling pathway. In addition, activin-A expression affects the tumor-forming ability and metastatic colonization of cancer cells in nude mice. Conclusions: These results suggest that activin-A has a critical role in breast cancer progression and, hence, targeting this pathway can be a valuable strategy in treating breast cancer patients.
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Affiliation(s)
- Mohsin Bashir
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
| | - Surekha Damineni
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
| | - Geetashree Mukherjee
- Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore, India
| | - Paturu Kondaiah
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
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Zhu J, Liu F, Wu Q, Liu X. Activin A regulates proliferation, invasion and migration in osteosarcoma cells. Mol Med Rep 2015; 11:4501-7. [PMID: 25634369 DOI: 10.3892/mmr.2015.3284] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2014] [Accepted: 01/02/2015] [Indexed: 11/06/2022] Open
Abstract
Activin A is a member of the TGF‑β superfamily. Previous studies have demonstrated that activin A exhibited pluripotent effects in several tumours. However, the roles of activin A signaling in osteosarcoma pathogenesis have not been previously investigated. Therefore, the present study aimed to investigate the effects of activin A on osteosarcoma cell proliferation, invasion and migration. Firstly, the expression of activin A in osteosarcoma cell lines (MG63, SaOS‑2 and U2OS) and a human osteoblastic cell line (hFOB1.19) was detected using reverse transcription quantitative polymerase chain reaction and western blotting. Activin A was upregulated in osteosarcoma cell lines compared with hFOB1.19 cells. To investigate the effects of activin A on osteosarcoma cell proliferation, invasion and migration, MG63 cells were generated in which activin A was either overexpressed or depleted. MTT staining, propidium iodide staining and a Transwell assay were used to analyze the cell cycle, proliferation, invasion and migration of MG63 cells, respectively. The results of the present study revealed that the abilities of proliferation, invasion and migration were suppressed in MG63 cells in which activin A was depleted, while they were enhanced in activin A-overexpressing cells. In conclusion, the results of the present study suggested that activin A may facilitate proliferation, invasion and migration of osteosarcoma cells, and it may therefore be a potential target for the treatment of osteosarcoma.
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Affiliation(s)
- Jianwei Zhu
- Department of Orthopedics, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Fan Liu
- Department of Orthopedics, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Quanming Wu
- Department of Orthopedics, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Xiancheng Liu
- Department of Oncology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
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L. Hopper J, Begum N, Smith L, A. Hughes T. The role of PSMD9 in human disease: future clinical and therapeutic implications. AIMS MOLECULAR SCIENCE 2015. [DOI: 10.3934/molsci.2015.4.476] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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Activin A is anti-lymphangiogenic in a melanoma mouse model. J Invest Dermatol 2014; 135:212-221. [PMID: 25084052 DOI: 10.1038/jid.2014.328] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Revised: 07/22/2014] [Accepted: 07/23/2014] [Indexed: 02/07/2023]
Abstract
Melanoma spreads primarily to the sentinel lymph nodes, and its risk correlates with lymphangiogenesis, which is mainly driven by vascular endothelial growth factor (VEGF)-C. However, anti-lymphangiogenic factors are poorly characterized. We have shown in a melanoma model that Wnt1 reduces lymphangiogenesis by reducing VEGF-C expression. Screening this model for additional potentially anti-lymphangiogenic factors identified increased activin A expression and reduced expression of the antagonist, follistatin (FST), in Wnt1(+) cells. Activin A is known to reduce blood vessel formation, but the effects on lymphangiogenesis are unknown. Here we show that human primary melanoma expresses significantly higher levels of activin A and lower levels of FST compared with nevi and melanoma metastasis. Using our mouse model with melanoma cells overexpressing Wnt1, FST, Wnt1/FST, or the inhibin βA subunit (INHBA, resulting in activin A expression), we found both activin A and Wnt1 to reduce lymphangiogenesis. Whereas Wnt1 also reduced metastasis, this was not seen with activin A. In vitro, activin A phosphorylated SMAD2 in both melanoma and lymphatic endothelium but, although it reduced sprouting of lymphatic endothelium, it enhanced the migration of melanoma cells. In conclusion, activin A is an anti-lymphangiogenic factor, but because of its pleiotropic effects on cell mobility it appears not suitable as a pharmacological target.
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32
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Webb SL, Edwards CM. Novel therapeutic targets in myeloma bone disease. Br J Pharmacol 2014; 171:3765-76. [PMID: 24750110 PMCID: PMC4128042 DOI: 10.1111/bph.12742] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 04/02/2014] [Accepted: 04/15/2014] [Indexed: 12/21/2022] Open
Abstract
Multiple myeloma is a neoplastic disorder of plasma cells characterized by clonal proliferation within the bone marrow. One of the major clinical features of multiple myeloma is the destructive osteolytic bone disease that occurs in the majority of patients. Myeloma bone disease is associated with increased osteoclast activity and suppression of osteoblastogenesis. Bisphosphonates have been the mainstay of treatment for many years; however, their use is limited by their inability to repair existing bone loss. Therefore, research into novel approaches for the treatment of myeloma bone disease is of the utmost importance. This review will discuss the current advances in our understanding of osteoclast stimulation and osteoblast suppression mechanisms in myeloma bone disease and the treatments that are under development to target this destructive and debilitating feature of myeloma.
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Affiliation(s)
- S L Webb
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
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Paganelli M, Nyabi O, Sid B, Evraerts J, El Malmi I, Heremans Y, Dollé L, Benton C, Calderon PB, van Grunsven L, Heimberg H, Campard D, Sokal E, Najimi M. Downregulation of Sox9 Expression Associates with Hepatogenic Differentiation of Human Liver Mesenchymal Stem/Progenitor Cells. Stem Cells Dev 2014; 23:1377-91. [DOI: 10.1089/scd.2013.0169] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Affiliation(s)
- Massimiliano Paganelli
- Laboratory of Pediatric Hepatology and Cell Therapy, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium
| | - Omar Nyabi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium
| | - Brice Sid
- Toxicology and Cancer Biology Research Group, PMNT Unit, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Jonathan Evraerts
- Laboratory of Pediatric Hepatology and Cell Therapy, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium
| | - Imane El Malmi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium
| | - Yves Heremans
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - Laurent Dollé
- Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels, Belgium
| | - Carley Benton
- Laboratory of Pediatric Hepatology and Cell Therapy, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium
| | - Pedro-Buc Calderon
- Toxicology and Cancer Biology Research Group, PMNT Unit, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Leo van Grunsven
- Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels, Belgium
| | - Harry Heimberg
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - David Campard
- Laboratory of Pediatric Hepatology and Cell Therapy, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium
| | - Etienne Sokal
- Laboratory of Pediatric Hepatology and Cell Therapy, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium
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Brüning A, Brem GJ, Vogel M, Mylonas I. Tetracyclines cause cell stress-dependent ATF4 activation and mTOR inhibition. Exp Cell Res 2013; 320:281-9. [PMID: 24280420 DOI: 10.1016/j.yexcr.2013.11.012] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Revised: 11/13/2013] [Accepted: 11/15/2013] [Indexed: 12/20/2022]
Abstract
Tetracyclines have long been used as valuable broad-spectrum antibiotics. The high antibacterial activity of tetracyclines, combined with their good tolerability, has led to their widespread use in treating various infectious diseases. However, similar to other antibiotics, tetracyclines are also known for their adverse effects on different human tissues, including hepatic steatosis. We observed that tetracyclines, including doxycycline and minocycline, caused enhanced expression of the liver chalone inhibin βE in HepG2 cells, mediated by the cell stress-regulated transcription factor ATF4. ATF4 and its target genes ATF3, CHOP, and inhibin βE are involved in cell cycle control, cell survival, cell metabolism, and modulation of cytokine expression. Furthermore, we observed that long term tetracycline incubation also caused inhibition of the mTOR complex, a central regulator of cell metabolism, further contributing to the observed cell-cycle arrest and autophagy in doxycycline- and minocycline-treated cell lines. ATF4 activation and mTOR inhibition link two crucial regulators of the cellular stress response and cell metabolism to the effects of tetracyclines on eukaryotic cell metabolism, and may help to understand the antibiotic-independent influence of these drugs on human tissues. Since the observed effects of tetracyclines on human cells were also found to be dependent on the magnesium ion concentrations supplied, the data further indicate the importance of magnesium supplementation to reduce or prevent side effects of long term treatment with tetracyclines.
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Affiliation(s)
- Ansgar Brüning
- Department of Obstetrics and Gynecology, Ludwig-Maximilians-University, Munich, Germany.
| | - German J Brem
- Department of Obstetrics and Gynecology, Ludwig-Maximilians-University, Munich, Germany
| | - Marianne Vogel
- Department of Obstetrics and Gynecology, Ludwig-Maximilians-University, Munich, Germany
| | - Ioannis Mylonas
- Department of Obstetrics and Gynecology, Ludwig-Maximilians-University, Munich, Germany
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Fox JL, Dews M, Minn AJ, Thomas-Tikhonenko A. Targeting of TGFβ signature and its essential component CTGF by miR-18 correlates with improved survival in glioblastoma. RNA (NEW YORK, N.Y.) 2013; 19:177-190. [PMID: 23249750 PMCID: PMC3543081 DOI: 10.1261/rna.036467.112] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Accepted: 11/12/2012] [Indexed: 06/01/2023]
Abstract
The miR-17∼92 cluster is thought to be an oncogene, yet its expression is low in glioblastoma multiforme (GBM) cell lines. This could allow unfettered expression of miR-17∼92 target genes such as connective tissue growth factor (CTGF; or CCN2), which is known to contribute to GBM pathogenesis. Indeed, microRNA-18a (but not other miR-17∼92 members) has a functional site in the CTGF 3' UTR, and its forced reexpression sharply reduces CTGF protein and mRNA levels. Interestingly, it also reduces the levels of CTGF primary transcript. The unexpected effects of miR-18a on CTGF transcription are mediated in part by direct targeting of Smad3 and ensuing weakening of TGFβ signaling. Having defined the TGFβ signature in GBM cells, we demonstrate a significant anti-correlation between miR-18 and TGFβ signaling in primary GBM samples from The Cancer Genome Atlas. Most importantly, high levels of miR-18 combined with low levels of the TGFβ metagene correlate with prolonged patient survival. Thus, low expression of the miR-17∼92 cluster, and specifically miR-18a, could significantly contribute to GBM pathogenesis.
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Affiliation(s)
- Jamie L. Fox
- Division of Cancer Pathobiology, Department of Pathology & Laboratory Medicine, Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
- Cancer Biology Graduate Program, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Michael Dews
- Division of Cancer Pathobiology, Department of Pathology & Laboratory Medicine, Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
| | - Andy J. Minn
- Cancer Biology Graduate Program, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Abramson Family Cancer Research Institute and Department of Radiation Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Andrei Thomas-Tikhonenko
- Division of Cancer Pathobiology, Department of Pathology & Laboratory Medicine, Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
- Cancer Biology Graduate Program, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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Brüning A, Matsingou C, Brem GJ, Rahmeh M, Mylonas I. Inhibin beta E is upregulated by drug-induced endoplasmic reticulum stress as a transcriptional target gene of ATF4. Toxicol Appl Pharmacol 2012; 264:300-4. [PMID: 22935518 DOI: 10.1016/j.taap.2012.08.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Revised: 08/02/2012] [Accepted: 08/06/2012] [Indexed: 01/13/2023]
Abstract
Inhibins and activins are gonadal peptide hormones of the transforming growth factor-β super family with important functions in the reproductive system. By contrast, the recently identified inhibin βE subunit, primarily expressed in liver cells, appears to exert functions unrelated to the reproductive system. Previously shown downregulation of inhibin βE in hepatoma cells and anti-proliferative effects of ectopic inhibin βE overexpression indicated growth-regulatory effects of inhibin βE. We observed a selective re-expression of the inhibin βE subunit in HepG2 hepatoblastoma cells, MCF7 breast cancer cells, and HeLa cervical cancer cells under endoplasmic reticulum stress conditions induced by tunicamycin, thapsigargin, and nelfinavir. Analysis of XPB1 splicing and ATF4 activation revealed that inhibin βE re-expression was associated with induction of the endoplasmic reticulum stress reaction by these drugs. Transfection of an ATF4 expression plasmid specifically induced inhibin βE expression in HeLa cells and indicates inhibin βE as a hitherto unidentified target gene of ATF4, a key transcription factor of the endoplasmic reticulum stress response. Therefore, the inhibin βE subunit defines not only a new player but also a possible new marker for drug-induced endoplasmic reticulum stress.
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Affiliation(s)
- Ansgar Brüning
- Department of Obstetrics and Gynecology, Ludwig-Maximilians-University Munich, Munich, Germany.
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Ottley E, Gold E. Insensitivity to the growth inhibitory effects of activin A: An acquired capability in prostate cancer progression. Cytokine Growth Factor Rev 2012; 23:119-25. [DOI: 10.1016/j.cytogfr.2012.04.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2012] [Accepted: 04/16/2012] [Indexed: 11/29/2022]
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Genetic variation in human muscle strength--opportunities for therapeutic interventions? Curr Opin Pharmacol 2012; 12:355-62. [PMID: 22445284 DOI: 10.1016/j.coph.2012.03.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2011] [Revised: 03/02/2012] [Accepted: 03/02/2012] [Indexed: 11/22/2022]
Abstract
Inter-individual variation in muscle mass and muscular fitness is broad; being at the upper tail of the distribution not only contributes to improve elite sport performance, but is also associated with longer independent living and higher quality-of-life in the aging population. Heritability estimates of muscle phenotypes are substantial and warrant the search for genetic components underlying this individual variability. The 'kinesiogenomics' field is young, but genetic associations with muscle strength-related phenotypes have been reported already for more than 40 candidate genes, and genome-wide scans revealed several additional regions of interest in the genome. Although genetic findings may reveal attractive targets for novel muscle atrophy therapy, the benefit of exercise as a major stimulus for natural muscle mass enhancement or maintenance cannot be underestimated.
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Sengupta B, Siddiqi S. Hepatocellular carcinoma: important biomarkers and their significance in molecular diagnostics and therapy. Curr Med Chem 2012; 19:3722-9. [PMID: 22680921 PMCID: PMC11447867 DOI: 10.2174/092986712801661059] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2011] [Revised: 02/06/2012] [Accepted: 02/28/2012] [Indexed: 11/22/2022]
Abstract
The increasing incidence of hepatocellular carcinoma (HCC) is of great concern not only in the United States but throughout the world because of two major reasons: firstly, HCC is one of the most lethal form of malignancies with less than 10% survival rate and secondly, a lack of prudent diagnostics makes early detection of HCC nearly impossible. The poor prognosis of HCC accentuates the need to develop new diagnostic markers and therapeutic approaches. In this review we discuss recent advances made in the discovery of molecular biomarkers and their significance in the detection of HCC. We focus on three major classes of biomarkers: serological, tumor, peri-tumoral tissue and cancer stem cell markers. Considerable progress has been made recently in our understanding of HCC at the molecular level increasing the potential of molecular targeted therapy. A number of molecular targets have been identified that have been showing promising results. Of particular interest is Sorafenib, a multi-tyrosine kinase inhibitor that has been approved for the HCC treatment. Inhibitors of other molecular targets such as VEGF, EGFR, mTOR etc. are emerging as plausible therapeutic agents for the treatment of HCC and are discussed in this review.
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Affiliation(s)
- B. Sengupta
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
| | - S.A. Siddiqi
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
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Neuroprotective effects of exogenous activin A on oxygen-glucose deprivation in PC12 cells. Molecules 2011; 17:315-27. [PMID: 22210170 PMCID: PMC6290572 DOI: 10.3390/molecules17010315] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2011] [Revised: 12/19/2011] [Accepted: 12/22/2011] [Indexed: 02/07/2023] Open
Abstract
Ischemic cerebrovascular disease is one of the most common causes of death in the World. Exogenous activin A (ActA) protects neurons against toxicity and plays a central role in regulating the brain's response to injury. In the present study, we investigated the mechanisms involved in the neuroprotective effects of ActA in a model of hypoxic-ischemic brain disease. We found that ActA could effectively increase the survival rate of PC12 cells and relieve oxygen-glucose deprivation (OGD) damage. To clarify the neuroprotective mechanisms of ActA, the effects of ActA on the ActA/Smad pathway and on the up-regulation of inducible nitric oxide synthase (NOS) and superoxide dismutase (SOD) were investigated using OGD in PC12 cells. The results showed that ActA could increase the expression of activin receptor IIA (ActRIIA), Smad3 and Smad4 and that 50 ng/mL and 100 ng/mL of ActA could reduce NO levels and increase SOD activity by 78.9% and 79.9%, respectively. These results suggested that the neuroprotective effects of ActA in ischemia could be related to the activation of the ActA/Smad signaling pathway and to its anti-oxidant activities.
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Breuhahn K, Schirmacher P. Signaling networks in human hepatocarcinogenesis--novel aspects and therapeutic options. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2011; 97:251-77. [PMID: 21074736 DOI: 10.1016/b978-0-12-385233-5.00009-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) represents one of the most common human malignancies with poor prognosis. Because therapeutic strategies are insufficient for most HCC patients, there is a great need to determine the central molecular mechanisms and pathways in order to derive novel targets for systemic therapy. There is vast evidence that not only the dysregulation of distinct signaling cascades, but also their interactions at different levels, affect tumor cell function. Through these interactions, the effects of pathways can be increased, and even new tumor-supporting qualities acquired that further facilitate HCC progression. Although several approaches for the modulation of these relevant pathways are under development, future therapeutic strategies should take into account that oncogenic stimuli cannot be understood in a monodimensional manner. In order to avoid escape mechanisms during therapy, strategies based on comprehensive knowledge of the interactive regulatory network in hepatocarcinogenesis are necessary.
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Affiliation(s)
- K Breuhahn
- Institute of Pathology, University Hospital, Heidelberg, Germany
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Dunphy KA, Schneyer AL, Hagen MJ, Jerry DJ. The role of activin in mammary gland development and oncogenesis. J Mammary Gland Biol Neoplasia 2011; 16:117-26. [PMID: 21475961 DOI: 10.1007/s10911-011-9214-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Accepted: 03/16/2011] [Indexed: 10/18/2022] Open
Abstract
TGFβ contributes to mammary gland development and has paradoxical roles in breast cancer because it has both tumor suppressor and tumor promoter activity. Another member of the TGFβ superfamily, activin, also has roles in the developing mammary gland, but these functions, and the role of activin in breast cancer, are not well characterized. TGFβ and activin share the same intracellular signaling pathways, but divergence in their signaling pathways are suggested. The purpose of this review is to compare the spatial and temporal expression of TGFβ and activin during mammary gland development, with consideration given to their functions during each developmental period. We also review the contributions of TGFβ and activin to breast cancer resistance and susceptibility. Finally, we consider the systemic contributions of activin in regulating obesity and diabetes; and the impact this regulation has on breast cancer. Elevated levels of activin in serum during pregnancy and its influence on pregnancy associated breast cancer are also considered. We conclude that evidence demonstrates that activin has tumor suppressing potential, without definitive indication of tumor promoting activity in the mammary gland, making it a good target for development of therapeutics.
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Affiliation(s)
- Karen A Dunphy
- Department of Veterinary and Animal Science, University of Massachusetts-Amherst, Amherst, MA, USA.
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Inhibin/activin expression in human and rodent liver: subunits α and βB as new players in human hepatocellular carcinoma? Br J Cancer 2011; 104:1303-12. [PMID: 21407220 PMCID: PMC3078591 DOI: 10.1038/bjc.2011.53] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Background: Activins and inhibins belong to the TGFβ-superfamily, which controls cell proliferation and differentiation in many organs. Activin A, the dimer of inhibin βA subunit, acts strongly anti-proliferative in hepatocytes. Little is known on the other activin/inhibin subunits in human liver and hepatocellular carcinoma (HCC). Methods: We studied the expression of the complete inhibin family α, βA, βB, βC, βE in normal liver, tumour-adjacent and HCC tissue, 12 additional organs and rodent liver. A total of 16 HCC and 10 disease-free livers were analysed. Expression of inhibin subunits was determined by qRT–PCR, normalised to RNA input and by geNorm algorithm, and confirmed by immunohistochemistry. Results: Remarkably, βA expression was not decreased in HCC. Similarly, βC and βE exhibited no major changes. In contrast, inhibin α, barely detectable in normal liver, was strongly increased in tumour-adjacent liver and dramatically enhanced in HCC. βB was strongly enhanced in some HCC. At variance with human liver, rodent liver showed higher inhibin α and βC expression, but βA was somewhat, and βB dramatically lower. Conclusions: Upregulation of inhibin α – and possibly of βB – may shield HCC cells from anti-proliferative effects of activin A. Dramatic variations between humans and rodents may reflect different functions of some inhibins/activins.
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Shi Y, Bao YL, Wu Y, Yu CL, Huang YX, Sun Y, Zheng LH, Li YX. Alantolactone Inhibits Cell Proliferation by Interrupting the Interaction between Cripto-1 and Activin Receptor Type II A in Activin Signaling Pathway. ACTA ACUST UNITED AC 2011; 16:525-35. [DOI: 10.1177/1087057111398486] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
It has been suggested that deregulation of activin signaling contributes to tumor formation. Activin signaling is blocked in cancer cells due to the complex formed by Cripto-1, activin, and activin receptor type II (ActRII). In this study, the authors used a mammalian two-hybrid system to construct a drug screening model to obtain a small molecular inhibitor capable of interrupting the interaction between Cripto-1 and ActRII. They screened 300 natural components and identified alantolactone. Data suggested that alantolactone induced activin/SMAD3 signaling in human colon adenocarcinoma HCT-8 cells. The authors also found that alantolactone exhibited antiproliferative function specific to tumor cells, with almost no toxicity to normal cells at a concentration of 5 µg/mL. Furthermore, they proved that the antiproliferative function of alantolactone was activin/SMAD3 dependent. These results suggest that alantolactone performs its antitumor effect by interrupting the interaction between Cripto-1 and the activin receptor type IIA in the activin signaling pathway. Moreover, screening for inhibitors of Cripto-1/ActRII is a potentially beneficial approach to aid in discovering novel cancer treatment.
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Affiliation(s)
- Ying Shi
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130024, China, Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, Changchun, 130024, China
| | - Yong Li Bao
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130024, China, Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, Changchun, 130024, China
| | - Yin Wu
- Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, Changchun, 130024, China
| | - Chun Lei Yu
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130024, China, Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, Changchun, 130024, China
| | - Yan Xin Huang
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130024, China
| | - Ying Sun
- Institute of Genetics and Cytology, Northeast Normal University, Changchun, 130024, China
| | - Li Hua Zheng
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, 130024, China, Institute of Genetics and Cytology, Northeast Normal University, Changchun, 130024, China
| | - Yu Xin Li
- Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, Changchun, 130024, China, Institute of Genetics and Cytology, Northeast Normal University, Changchun, 130024, China
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Ye H, He B, Wang J. Evaluation of the effects of somatostatin on portal hemodynamics in rabbits after hepatectomy by color Doppler ultrasound. Shijie Huaren Xiaohua Zazhi 2010; 18:2901-2904. [DOI: 10.11569/wcjd.v18.i27.2901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the value of color Doppler ultrasound in evaluating the effects of somatostatin on portal hemodynamics in rabbits after hepatectomy.
METHODS: Thirty-two rabbits were randomly divided into three groups: control group (n = 6), normal saline group (n = 13), somatostatin group (n = 13). The normal saline group and somatostatin group underwent 50% hepatectomy, while the control group underwent a sham operation. Color Doppler ultrasound was then used to measure and compare various portal vein hemodynamic parameters, including flow direction, diameter, hemokinetic velocity, average flow rate, and blood flow volume, among each group.
RESULTS: There were no significant differences in portal diameter and hemokinetic velocity among all the three groups before and after the surgery (all P > 0.05). However, the average flow rate and blood flow volume were significant lower in the somatostatin group than in the control group and normal saline group (all P < 0.05).
CONCLUSION: Application of somatostatin early after hepatectomy may reduce the flow rate and blood flow volume in the portal vein, which may be the cause that somatostatin reduces elevated portal pressure. Color Doppler ultrasound is effective in evaluating the effects of somatostatin on portal hemodynamics in rabbits after hepatectomy.
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Ventura-Holman T, Mamoon A, Subauste MC, Subauste JS. The effect of oncoprotein v-erbA on thyroid hormone-regulated genes in hepatocytes and their potential role in hepatocellular carcinoma. Mol Biol Rep 2010; 38:1137-44. [DOI: 10.1007/s11033-010-0211-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2010] [Accepted: 06/11/2010] [Indexed: 12/29/2022]
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Lotinun S, Pearsall RS, Davies MV, Marvell TH, Monnell TE, Ucran J, Fajardo RJ, Kumar R, Underwood KW, Seehra J, Bouxsein ML, Baron R. A soluble activin receptor Type IIA fusion protein (ACE-011) increases bone mass via a dual anabolic-antiresorptive effect in Cynomolgus monkeys. Bone 2010; 46:1082-8. [PMID: 20080223 DOI: 10.1016/j.bone.2010.01.370] [Citation(s) in RCA: 109] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2009] [Revised: 12/16/2009] [Accepted: 01/09/2010] [Indexed: 01/10/2023]
Abstract
Activin A belongs to the TGF-beta superfamily and plays an important role in bone metabolism. It was reported that a soluble form of extracellular domain of the activin receptor type IIA (ActRIIA) fused to the Fc domain of murine IgG, an activin antagonist, has an anabolic effect on bone in intact and ovariectomized mice. The present study was designed to examine the skeletal effect of human ActRIIA-IgG1-Fc (ACE-011) in non-human primates. Young adult female Cynomolgus monkeys were given a biweekly subcutaneous injection of either 10mg/kg ACE-011 or vehicle (VEH) for 3months. Treatment effects were evaluated by histomorphometric analysis of the distal femur, femoral midshaft, femoral neck and 12th thoracic vertebrae, by muCT analysis of femoral neck and by biomarkers of bone turnover. Compared to VEH, at the distal femur ACE-011-treated monkeys had significantly increased cancellous bone volume (+93%), bone formation rate per bone surface (+166%) and osteoblast surface (+196%) indicating an anabolic action. Monkeys treated with ACE-011 also had decreased osteoclast surface and number. No differences were observed in parameters of cortical bone at the midshaft of the femur. Similar to distal femur, ACE-011-treated monkeys had significantly greater cancellous bone volume, bone formation rate and osteoblast surface at the femoral neck relative to VEH. A significant increase in bone formation rate and osteoblast surface with a decrease in osteoclast surface was observed in thoracic vertebrae. muCT analysis of femoral neck indicated more plate-like structure in ACE-011-treated monkeys. Monkeys treated with ACE-011 had no effect on serum bone-specific alkaline phosphatase and CTX at the end of the study. These observations demonstrate that ACE-011 is a dual anabolic-antiresorptive compound, improving cancellous bone volume by promoting bone formation and inhibiting bone resorption in non-human primates. Thus, soluble ActRIIA fusion protein may be useful in the prevention and/or treatment of osteoporosis and other diseases involving accelerated bone loss.
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Affiliation(s)
- Sutada Lotinun
- Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02115, USA.
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