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First published online 25 September 2007
doi: 10.1242/jcs.005751

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The ADAMTS12 metalloproteinase exhibits anti-tumorigenic properties through modulation of the Ras-dependent ERK signalling pathway

María Llamazares^1,*, Alvaro J. Obaya², Angela Moncada-Pazos¹, Ritva Heljasvaara^1,, Jesús Espada¹, Carlos López-Otín¹ and Santiago Cal^1,

¹ Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncologia, Universidad de Oviedo, 33006-Oviedo, Asturias, Spain
² Departamento de Biología Funcional (Fisiología), Instituto Universitario de Oncologia, Universidad de Oviedo, 33006-Oviedo, Asturias, Spain

Author for correspondence (e-mail: santical{at}uniovi.es)

Accepted 15 July 2007

Members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of proteolytic enzymes are implicated in a variety of physiological processes, such as collagen maturation, organogenesis, angiogenesis, reproduction and inflammation. Moreover, deficiency or overexpression of certain ADAMTS proteins is directly involved in serious human diseases, including cancer. However, the functional roles of other family members, such as ADAMTS12, remain unknown. Here, by using different in vitro and in vivo approaches, we have evaluated the possible role of ADAMTS12 in the development and progression of cancer. First, we show that expression of ADAMTS12 in Madin-Darby canine kidney (MDCK) cells prevents the tumorigenic effects of hepatocyte growth factor (HGF) by blocking the activation of the Ras-MAPK signalling pathway and that this regulation involves the thrombospondin domains of the metalloproteinase. We also show that addition of recombinant human ADAMTS12 to bovine aortic endothelial cells (BAE-1 cells) abolishes their ability to form tubules upon stimulation with vascular endothelial growth factor (VEGF). Additionally, tumours induced in immunodeficient SCID mice injected with A549 cells overexpressing ADAMTS12 show a remarkable growth deficiency in comparison with tumours formed in animals injected with parental A549 cells. Overall, our data suggest that ADAMTS12 confers tumour-protective functions upon cells that produce this proteolytic enzyme.

Key words: Cell-cell adhesion, Hepatocyte growth factor, Cell migration, E-cadherin

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