Metadherin Is a Prognostic Apoptosis Modulator in Mesothelioma Induced via NF-κB-Mediated Signaling
Therapies against malignant pleural mesothelioma (MPM) have yielded disappointing results, in part, because pathologic mechanisms remain obscure. In searching for rational molecular targets, we identified metadherin (MTDH), a multifunctional gene associated with several tumor types but previously un...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-06-01
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| Series: | Translational Oncology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S193652331930107X |
| _version_ | 1818137988511563776 |
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| author | Li Zhang Anand Singh Christopher Plaisier Nathanael Pruett R. Taylor Ripley David S. Schrump Chuong D. Hoang |
| author_facet | Li Zhang Anand Singh Christopher Plaisier Nathanael Pruett R. Taylor Ripley David S. Schrump Chuong D. Hoang |
| author_sort | Li Zhang |
| collection | DOAJ |
| description | Therapies against malignant pleural mesothelioma (MPM) have yielded disappointing results, in part, because pathologic mechanisms remain obscure. In searching for rational molecular targets, we identified metadherin (MTDH), a multifunctional gene associated with several tumor types but previously unrecognized in MPM. Cox proportional hazards regression analysis delineated associations between higher MTDH expression and lower patient survival from three independent MPM cohorts (n = 349 patients). Through in vitro assays with overexpression and downregulation constructs in MPM cells, we characterized the role of MTDH. We confirmed in vivo the phenotype of altered MTDH expression in a murine xenograft model. Transcriptional regulators of MTDH were identified by chromatin immunoprecipitation. Overexpression of both MTDH mRNA (12-fold increased) and protein levels was observed in tumor tissues. MTDH stable overexpression significantly augmented proliferation, invasiveness, colony formation, chemoresistance, and an antiapoptosis phenotype, while its suppression showed opposite effects in MPM cells. Interestingly, NF-κB and c-Myc (in a feed-forward loop motif) contributed to modulating MTDH expression. Knockdown of MTDH expression profoundly retarded xenograft tumor growth. Thus, our findings support the notion that MTDH integrates upstream signals from certain transcription factors and mediates pathogenic interactions contributing to MPM traits. MTDH represents a new MPM-associated gene that can contribute to insights of MPM biology and, as such, suggest other treatment strategies. |
| first_indexed | 2024-12-11T10:05:03Z |
| format | Article |
| id | doaj.art-3c940ff160d4425ca123e23db5f6596d |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-12-11T10:05:03Z |
| publishDate | 2019-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-3c940ff160d4425ca123e23db5f6596d2022-12-22T01:11:58ZengElsevierTranslational Oncology1936-52332019-06-01126859870Metadherin Is a Prognostic Apoptosis Modulator in Mesothelioma Induced via NF-κB-Mediated SignalingLi Zhang0Anand Singh1Christopher Plaisier2Nathanael Pruett3R. Taylor Ripley4David S. Schrump5Chuong D. Hoang6Thoracic Surgery Branch, NCI, National Institutes of Health, Bethesda, MD, USAThoracic Surgery Branch, NCI, National Institutes of Health, Bethesda, MD, USASchool of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, USAThoracic Surgery Branch, NCI, National Institutes of Health, Bethesda, MD, USADept. of Surgery, Baylor College of Medicine, Houston, TX, USAThoracic Surgery Branch, NCI, National Institutes of Health, Bethesda, MD, USAThoracic Surgery Branch, NCI, National Institutes of Health, Bethesda, MD, USA; Address all correspondence to: Chuong D. Hoang, MD, Thoracic Surgery Branch, National Cancer Institute – NIH, CCR and The Clinical Center, 10 Center Drive, Mail code 1201, Room 4-3940, Bethesda, MD 20892, USA.Therapies against malignant pleural mesothelioma (MPM) have yielded disappointing results, in part, because pathologic mechanisms remain obscure. In searching for rational molecular targets, we identified metadherin (MTDH), a multifunctional gene associated with several tumor types but previously unrecognized in MPM. Cox proportional hazards regression analysis delineated associations between higher MTDH expression and lower patient survival from three independent MPM cohorts (n = 349 patients). Through in vitro assays with overexpression and downregulation constructs in MPM cells, we characterized the role of MTDH. We confirmed in vivo the phenotype of altered MTDH expression in a murine xenograft model. Transcriptional regulators of MTDH were identified by chromatin immunoprecipitation. Overexpression of both MTDH mRNA (12-fold increased) and protein levels was observed in tumor tissues. MTDH stable overexpression significantly augmented proliferation, invasiveness, colony formation, chemoresistance, and an antiapoptosis phenotype, while its suppression showed opposite effects in MPM cells. Interestingly, NF-κB and c-Myc (in a feed-forward loop motif) contributed to modulating MTDH expression. Knockdown of MTDH expression profoundly retarded xenograft tumor growth. Thus, our findings support the notion that MTDH integrates upstream signals from certain transcription factors and mediates pathogenic interactions contributing to MPM traits. MTDH represents a new MPM-associated gene that can contribute to insights of MPM biology and, as such, suggest other treatment strategies.http://www.sciencedirect.com/science/article/pii/S193652331930107X |
| spellingShingle | Li Zhang Anand Singh Christopher Plaisier Nathanael Pruett R. Taylor Ripley David S. Schrump Chuong D. Hoang Metadherin Is a Prognostic Apoptosis Modulator in Mesothelioma Induced via NF-κB-Mediated Signaling Translational Oncology |
| title | Metadherin Is a Prognostic Apoptosis Modulator in Mesothelioma Induced via NF-κB-Mediated Signaling |
| title_full | Metadherin Is a Prognostic Apoptosis Modulator in Mesothelioma Induced via NF-κB-Mediated Signaling |
| title_fullStr | Metadherin Is a Prognostic Apoptosis Modulator in Mesothelioma Induced via NF-κB-Mediated Signaling |
| title_full_unstemmed | Metadherin Is a Prognostic Apoptosis Modulator in Mesothelioma Induced via NF-κB-Mediated Signaling |
| title_short | Metadherin Is a Prognostic Apoptosis Modulator in Mesothelioma Induced via NF-κB-Mediated Signaling |
| title_sort | metadherin is a prognostic apoptosis modulator in mesothelioma induced via nf κb mediated signaling |
| url | http://www.sciencedirect.com/science/article/pii/S193652331930107X |
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