NEDD9 Depletion Leads to MMP14 Inactivation by TIMP2 and Prevents Invasion and Metastasis
| Autor: | Polina Y. Kozyulina, Ryan J. Ice, Anuradha Rajulapati, Alexey V. Ivanov, Varvara K. Kozyreva, Scott A. Weed, Yuriy Loskutov, Mark Culp, Ryan H. Livengood, Sarah L. McLaughlin, Elena N. Pugacheva |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Lung Neoplasms MMP2 Transplantation Heterologous Breast Neoplasms Biology Article Metastasis Mice Circulating tumor cell Breast cancer Mice Inbred NOD Cell Line Tumor Matrix Metalloproteinase 14 medicine Animals Humans Neoplasm Invasiveness RNA Small Interfering Molecular Biology Adaptor Proteins Signal Transducing Tissue Inhibitor of Metalloproteinase-2 Carcinoma in situ Cancer Neoplastic Cells Circulating Phosphoproteins medicine.disease Matrix Metalloproteinase 9 Oncology Tissue Array Analysis Cancer cell MCF-7 Cells Cancer research Matrix Metalloproteinase 2 MMP14 Female RNA Interference Carcinoma in Situ Neoplasm Transplantation |
| Zdroj: | Molecular Cancer Research. 12:69-81 |
| ISSN: | 1557-3125 1541-7786 |
| DOI: | 10.1158/1541-7786.mcr-13-0300 |
| Popis: | The scaffolding protein NEDD9 is an established prometastatic marker in several cancers. Nevertheless, the molecular mechanisms of NEDD9-driven metastasis in cancers remain ill-defined. Here, using a comprehensive breast cancer tissue microarray, it was shown that increased levels of NEDD9 protein significantly correlated with the transition from carcinoma in situ to invasive carcinoma. Similarly, it was shown that NEDD9 overexpression is a hallmark of highly invasive breast cancer cells. Moreover, NEDD9 expression is crucial for the protease-dependent mesenchymal invasion of cancer cells at the primary site but not at the metastatic site. Depletion of NEDD9 is sufficient to suppress invasion of tumor cells in vitro and in vivo, leading to decreased circulating tumor cells and lung metastases in xenograft models. Mechanistically, NEDD9 localized to invasive pseudopods and was required for local matrix degradation. Depletion of NEDD9 impaired invasion of cancer cells through inactivation of membrane-bound matrix metalloproteinase MMP14 by excess TIMP2 on the cell surface. Inactivation of MMP14 is accompanied by reduced collagenolytic activity of soluble metalloproteinases MMP2 and MMP9. Reexpression of NEDD9 is sufficient to restore the activity of MMP14 and the invasive properties of breast cancer cells in vitro and in vivo. Collectively, these findings uncover critical steps in NEDD9-dependent invasion of breast cancer cells. Implications: This study provides a mechanistic basis for potential therapeutic interventions to prevent metastasis. Mol Cancer Res; 12(1); 69–81. ©2013 AACR. |
| Databáze: | OpenAIRE |
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