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First published online 28 July 2009
doi: 10.1242/jcs.050468

Journal of Cell Science 122, 2906-2913 (2009)
Published by The Company of Biologists 2009
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Research Article

The ADAMTS12 metalloprotease gene is epigenetically silenced in tumor cells and transcriptionally activated in the stroma during progression of colon cancer

Angela Moncada-Pazos1, Alvaro J. Obaya2, Mario F. Fraga3, Cristina G. Viloria1, Gabriel Capellá4, Mireia Gausachs4, Manel Esteller3, Carlos López-Otín1 and Santiago Cal1,*

1 Departamento de Bioquímica y Biología Molecular, Area de Fisiología, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain
2 Biología Funcional, Area de Fisiología, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain
3 Cancer Epigenetic Laboratory, Spanish National Cancer Centre (CNIO), 28029 Madrid, Spain
4 Laboratori de Recerca Translacional, IDIBELL, Institut Català d'Oncologia, L'Hospitalet de Llobregat, 08907 Barcelona, Spain

* Author for correspondence (santical{at}uniovi.es)

Accepted 5 June 2009

Proteases have long been associated with tumor progression, given their ability to degrade extracellular matrix components and facilitate invasion and metastasis. However, recent findings indicate that different proteases can also act as tumor-suppressor enzymes. We have recently reported that lung carcinoma cells expressing the ADAMTS-12 metalloprotease show a remarkable impairment of growth in immunodeficient mice as compared with parental cells. Here, we show that ADAMTS12 promoter is hypermethylated in cancer cell lines and tumor tissues. Interestingly, ADAMTS12 expression in the stromal cells surrounding epithelial malignant cells is higher than in the paired normal tissues. Moreover, the expression of this metalloprotease in colon fibroblasts co-cultured with colon cancer cell lines is higher than in those cultured alone. Furthermore, the expression of ADAMTS-12 by these fibroblasts is linked with an anti-proliferative effect on tumor cells. Based on these findings, we hypothesize that ADAMTS-12 is a novel anti-tumor protease that can reduce the proliferative properties of tumor cells. This function is lost by epigenetic silencing in tumor cells, but concurrently induced in stromal cells, probably as part of a response of the normal tissue aimed at controlling the progression of cancer.

Key words: Metalloprotease, Thrombospondin, Methylation, Degradome


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