Matrix Metalloproteinase Mmp-1a Is Dispensable for Normal Growth and Fertility in Mice and Promotes Lung Cancer Progression by Modulating Inflammatory Responses
| Autor: | Antonio Fueyo, Miriam Fanjul-Fernández, Carlos López-Otín, José M.P. Freije, M. Soledad Fernández-García, Steven D. Shapiro, Alicia R. Folgueras, Milagros Balbín, María F. Suárez |
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| Rok vydání: | 2013 |
| Předmět: |
Lung Neoplasms
MMP1 Biology medicine.disease_cause Urethane Biochemistry Gene Expression Regulation Enzymologic Metastasis Mice Prostate cancer In vivo medicine Animals Neoplasm Metastasis Lung cancer Molecular Biology Cell Proliferation Inflammation Mice Knockout Carcinoma Cancer Molecular Bases of Disease Cell Biology Prognosis medicine.disease Mice Inbred C57BL Tumor progression Immunology Disease Progression Cancer research Additions and Corrections Matrix Metalloproteinase 1 Carcinogenesis Peptide Hydrolases |
| Zdroj: | Journal of Biological Chemistry. 288:14647-14656 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m112.439893 |
| Popis: | Human MMP-1 is a matrix metalloproteinase repeatedly associated with many pathological conditions, including cancer. Thus, MMP1 overexpression is a poor prognosis marker in a variety of advanced cancers, including colorectal, breast, and lung carcinomas. Moreover, MMP-1 plays a key role in the metastatic behavior of melanoma, breast, and prostate cancer cells. However, functional and mechanistic studies on the relevance of MMP-1 in cancer have been hampered by the absence of an in vivo model. In this work, we have generated mice deficient in Mmp1a, the murine ortholog of human MMP1. Mmp1a(-/-) mice are viable and fertile and do not exhibit obvious abnormalities, which has facilitated studies of cancer susceptibility. These studies have shown a decreased susceptibility to develop lung carcinomas induced by chemical carcinogens in Mmp1a(-/-) mice. Histopathological analysis indicated that tumors generated in Mmp1a(-/-) mice are smaller than those of wild-type mice, consistently with the idea that the absence of Mmp-1a hampers tumor progression. Proteomic analysis revealed decreased levels of chitinase-3-like 3 and accumulation of the receptor for advanced glycation end-products and its ligand S100A8 in lung samples from Mmp1a(-/-) mice compared with those from wild-type. These findings suggest that Mmp-1a could play a role in tumor progression by modulating the polarization of a Th1/Th2 inflammatory response to chemical carcinogens. On the basis of these results, we propose that Mmp1a knock-out mice provide an excellent in vivo model for the functional analysis of human MMP-1 in both physiological and pathological conditions. |
| Databáze: | OpenAIRE |
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