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Overexpression of MMP-9 and HIF-1α in Breast Cancer Cells under Hypoxic Conditions
PURPOSE: Hypoxia, which is a loss of oxygen in tissues, is a common condition in solid tumors due to the tumor outgrowing existing vasculature. Under hypoxic conditions, hypoxia-inducible factor (HIF)-1α rapidly accumulates and transactivates hundreds of genes, such as matrix metalloproteinases (MMP...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Korean Breast Cancer Society
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148536/ https://www.ncbi.nlm.nih.gov/pubmed/21847402 http://dx.doi.org/10.4048/jbc.2011.14.2.88 |
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author | Choi, Jae Young Jang, Yeon Soo Min, Sun Young Song, Jeong Yoon |
author_facet | Choi, Jae Young Jang, Yeon Soo Min, Sun Young Song, Jeong Yoon |
author_sort | Choi, Jae Young |
collection | PubMed |
description | PURPOSE: Hypoxia, which is a loss of oxygen in tissues, is a common condition in solid tumors due to the tumor outgrowing existing vasculature. Under hypoxic conditions, hypoxia-inducible factor (HIF)-1α rapidly accumulates and transactivates hundreds of genes, such as matrix metalloproteinases (MMPs). MMPs contribute to invasion and metastasis of tumor cells by degrading the surrounding basement membrane and extracellular matrix barriers, which enables the easy migration and spread of cancer cells. We examined whether hypoxia increases tumor cell invasion, and whether increased invasiveness was due to HIF-1α and MMP-9 expression. METHODS: Transwell invasion assays were performed to demonstrate whether hypoxia enhance tumor invasion by use of MDA-MB-231 breast cancer cells. An immunofluorescence assay was used to demonstrate expression of HIF-1α and MMP-9 under hypoxic conditions. Luciferase and ChiP assays were performed to demonstrate that MMP-9 promoter activity was regulated by HIF-1α. RESULTS: HIF-1α was stabilized under hypoxic conditions and stimulated MMP-9 expression, which affected the tumor invasiveness of breast cancer cells. HIF-1α transactivated the MMP-9 promoter by forming a transcriptional unit with p300, thus increasing expression of MMP-9 transcripts. Zymography indicated that MMP-9 had more gelatinase activity under hypoxic conditions than normoxic conditions. Furthermore, the small GTPase Ras was also activated in response to hypoxia, which then aids stabilization of HIF-1α, and in turn upregulates MMP-9 expression. We also demonstrate that MMP-9 is upregulated concurrently with HIF-1α in tumor tissues from patients with breast cancer. CONCLUSION: These results suggest that HIF-1α promotes cell invasion through a MMP-9-dependent mechanism and that future antitumor agents could be used to target HIF-1α and MMP-9. |
format | Online Article Text |
id | pubmed-3148536 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Korean Breast Cancer Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-31485362011-08-16 Overexpression of MMP-9 and HIF-1α in Breast Cancer Cells under Hypoxic Conditions Choi, Jae Young Jang, Yeon Soo Min, Sun Young Song, Jeong Yoon J Breast Cancer Original Article PURPOSE: Hypoxia, which is a loss of oxygen in tissues, is a common condition in solid tumors due to the tumor outgrowing existing vasculature. Under hypoxic conditions, hypoxia-inducible factor (HIF)-1α rapidly accumulates and transactivates hundreds of genes, such as matrix metalloproteinases (MMPs). MMPs contribute to invasion and metastasis of tumor cells by degrading the surrounding basement membrane and extracellular matrix barriers, which enables the easy migration and spread of cancer cells. We examined whether hypoxia increases tumor cell invasion, and whether increased invasiveness was due to HIF-1α and MMP-9 expression. METHODS: Transwell invasion assays were performed to demonstrate whether hypoxia enhance tumor invasion by use of MDA-MB-231 breast cancer cells. An immunofluorescence assay was used to demonstrate expression of HIF-1α and MMP-9 under hypoxic conditions. Luciferase and ChiP assays were performed to demonstrate that MMP-9 promoter activity was regulated by HIF-1α. RESULTS: HIF-1α was stabilized under hypoxic conditions and stimulated MMP-9 expression, which affected the tumor invasiveness of breast cancer cells. HIF-1α transactivated the MMP-9 promoter by forming a transcriptional unit with p300, thus increasing expression of MMP-9 transcripts. Zymography indicated that MMP-9 had more gelatinase activity under hypoxic conditions than normoxic conditions. Furthermore, the small GTPase Ras was also activated in response to hypoxia, which then aids stabilization of HIF-1α, and in turn upregulates MMP-9 expression. We also demonstrate that MMP-9 is upregulated concurrently with HIF-1α in tumor tissues from patients with breast cancer. CONCLUSION: These results suggest that HIF-1α promotes cell invasion through a MMP-9-dependent mechanism and that future antitumor agents could be used to target HIF-1α and MMP-9. Korean Breast Cancer Society 2011-06 2011-06-18 /pmc/articles/PMC3148536/ /pubmed/21847402 http://dx.doi.org/10.4048/jbc.2011.14.2.88 Text en © 2011 Korean Breast Cancer Society http://creativecommons.org/licenses/by-nc/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Choi, Jae Young Jang, Yeon Soo Min, Sun Young Song, Jeong Yoon Overexpression of MMP-9 and HIF-1α in Breast Cancer Cells under Hypoxic Conditions |
title | Overexpression of MMP-9 and HIF-1α in Breast Cancer Cells under Hypoxic Conditions |
title_full | Overexpression of MMP-9 and HIF-1α in Breast Cancer Cells under Hypoxic Conditions |
title_fullStr | Overexpression of MMP-9 and HIF-1α in Breast Cancer Cells under Hypoxic Conditions |
title_full_unstemmed | Overexpression of MMP-9 and HIF-1α in Breast Cancer Cells under Hypoxic Conditions |
title_short | Overexpression of MMP-9 and HIF-1α in Breast Cancer Cells under Hypoxic Conditions |
title_sort | overexpression of mmp-9 and hif-1α in breast cancer cells under hypoxic conditions |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148536/ https://www.ncbi.nlm.nih.gov/pubmed/21847402 http://dx.doi.org/10.4048/jbc.2011.14.2.88 |
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