Transgenic Overexpression of the Proprotein Convertase Furin Enhances Skin Tumor Growth
Furin, one of the members of the family of proprotein convertases (PCs), ubiquitously expressed as a type I membrane-bound proteinase, activates several proteins that contribute to tumor progression. In vitro studies using cancer cell lines and clinical specimens demonstrated that furin processes im...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2012-04-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558612800650 |
| _version_ | 1818664890894647296 |
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| author | Jian Fu Daniel E. Bassi Jirong Zhang Tianyu Li Emmanuelle Nicolas Andres J.P. Klein-Szanto |
| author_facet | Jian Fu Daniel E. Bassi Jirong Zhang Tianyu Li Emmanuelle Nicolas Andres J.P. Klein-Szanto |
| author_sort | Jian Fu |
| collection | DOAJ |
| description | Furin, one of the members of the family of proprotein convertases (PCs), ubiquitously expressed as a type I membrane-bound proteinase, activates several proteins that contribute to tumor progression. In vitro studies using cancer cell lines and clinical specimens demonstrated that furin processes important substrates such as insulin-like growth factor 1 receptor (IGF-1R) and transforming growth factor β, leading to increased tumor growth and progression. Despite the numerous studies associating furin with tumor development, its effects in preclinical models has not been comprehensively studied. In this study, we sought to determine the protumorigenic role of furin in vivo after a two-stage chemical carcinogenesis protocol in transgenic mice in which furin expression was targeted to the epidermal basal layer. We found that processing of the PC substrate IGF-1R and the proliferation rate of mouse epidermis was enhanced in transgenic mice when compared with their WT counterparts. Histopathologic diagnoses of the tumors demonstrated that furin transgenic mice (line F47) developed twice as many squamous carcinomas as the control, WT mice (P < .002). Similarly, tumors cells from transgenic mice were able to process PC substrates more efficiently than tumor cells from WT mice. Furthermore, furin expression resulted in a higher SCC volume in transgenic mice as well as an increase in the percentage of high-grade SCC, including poorly differentiated and spindle cell carcinomas. In conclusion, expression of furin in the basal layer of the epidermis increased tumor development and enhanced tumor growth, supporting the consideration of furin as a potential target for cancer treatment. |
| first_indexed | 2024-12-17T05:39:56Z |
| format | Article |
| id | doaj.art-08d5cfb5e8ef49778f1808ef1f3987f2 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-17T05:39:56Z |
| publishDate | 2012-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-08d5cfb5e8ef49778f1808ef1f3987f22022-12-21T22:01:28ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022012-04-0114427128210.1593/neo.12166Transgenic Overexpression of the Proprotein Convertase Furin Enhances Skin Tumor GrowthJian Fu0Daniel E. Bassi1Jirong Zhang2Tianyu Li3Emmanuelle Nicolas4Andres J.P. Klein-Szanto5Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USADepartment of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USADepartment of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USABioinformatics and Biostatistics Facility, Fox Chase Cancer Center, Philadelphia, PA, USAGenomics Facility, Fox Chase Cancer Center, Philadelphia, PA, USADepartment of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USAFurin, one of the members of the family of proprotein convertases (PCs), ubiquitously expressed as a type I membrane-bound proteinase, activates several proteins that contribute to tumor progression. In vitro studies using cancer cell lines and clinical specimens demonstrated that furin processes important substrates such as insulin-like growth factor 1 receptor (IGF-1R) and transforming growth factor β, leading to increased tumor growth and progression. Despite the numerous studies associating furin with tumor development, its effects in preclinical models has not been comprehensively studied. In this study, we sought to determine the protumorigenic role of furin in vivo after a two-stage chemical carcinogenesis protocol in transgenic mice in which furin expression was targeted to the epidermal basal layer. We found that processing of the PC substrate IGF-1R and the proliferation rate of mouse epidermis was enhanced in transgenic mice when compared with their WT counterparts. Histopathologic diagnoses of the tumors demonstrated that furin transgenic mice (line F47) developed twice as many squamous carcinomas as the control, WT mice (P < .002). Similarly, tumors cells from transgenic mice were able to process PC substrates more efficiently than tumor cells from WT mice. Furthermore, furin expression resulted in a higher SCC volume in transgenic mice as well as an increase in the percentage of high-grade SCC, including poorly differentiated and spindle cell carcinomas. In conclusion, expression of furin in the basal layer of the epidermis increased tumor development and enhanced tumor growth, supporting the consideration of furin as a potential target for cancer treatment.http://www.sciencedirect.com/science/article/pii/S1476558612800650 |
| spellingShingle | Jian Fu Daniel E. Bassi Jirong Zhang Tianyu Li Emmanuelle Nicolas Andres J.P. Klein-Szanto Transgenic Overexpression of the Proprotein Convertase Furin Enhances Skin Tumor Growth Neoplasia: An International Journal for Oncology Research |
| title | Transgenic Overexpression of the Proprotein Convertase Furin Enhances Skin Tumor Growth |
| title_full | Transgenic Overexpression of the Proprotein Convertase Furin Enhances Skin Tumor Growth |
| title_fullStr | Transgenic Overexpression of the Proprotein Convertase Furin Enhances Skin Tumor Growth |
| title_full_unstemmed | Transgenic Overexpression of the Proprotein Convertase Furin Enhances Skin Tumor Growth |
| title_short | Transgenic Overexpression of the Proprotein Convertase Furin Enhances Skin Tumor Growth |
| title_sort | transgenic overexpression of the proprotein convertase furin enhances skin tumor growth |
| url | http://www.sciencedirect.com/science/article/pii/S1476558612800650 |
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