title: The ADAMTS12 metalloprotease gene is epigenetically silenced in tumor cells and transcriptionally activated in the stroma during progression of colon cancer.
abstract: 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.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Area de Fisiología, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Angela
authors.initials: A
authors.lastname: Moncada-Pazos
authors.forename: Alvaro J
authors.initials: AJ
authors.lastname: Obaya
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
authors.forename: Cristina G
authors.initials: CG
authors.lastname: Viloria
authors.forename: Gabriel
authors.initials: G
authors.lastname: Capellá
authors.forename: Mireia
authors.initials: M
authors.lastname: Gausachs
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.forename: Santiago
authors.initials: S
authors.lastname: Cal
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis / Q000235:genetics*; D000071096:ADAMTS Proteins; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D018450:Disease Progression; D004790:Enzyme Induction; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics; D017154:Stromal Cells / Q000201:enzymology* / Q000473:pathology; D015533:Transcriptional Activation / Q000235:genetics*
chemical_list: D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C496252:ADAMTS12 protein, human