Genetic inactivation of ADAMTS15 metalloprotease in human colorectal cancer.
Matrix metalloproteinases have been traditionally linked to cancer dissemination through their ability to degrade most extracellular matrix components, thus facilitating invasion and metastasis of tumor cells. However, recent functional studies have revealed that some metalloproteases, including several members of the ADAMTS family, also exhibit tumor suppressor properties. In particular, ADAMTS1, ADAMTS9, and ADAMTS18 have been found to be epigenetically silenced in malignant tumors of different sources, suggesting that they may function as tumor suppressor genes. Herein, we show that ADAMTS15 is genetically inactivated in colon cancer. We have performed a mutational analysis of the ADAMTS15 gene in human colorectal carcinomas, with the finding of four mutations in 50 primary tumors and 6 colorectal cancer cell lines. Moreover, functional in vitro and in vivo studies using HCT-116 and SW-620 colorectal cancer cells and severe combined immunodeficient mice have revealed that ADAMTS15 restrains tumor growth and invasion. Furthermore, the presence of ADAMTS15 in human colorectal cancer samples showed a negative correlation with the histopathologic differentiation grade of the corresponding tumors. Collectively, these results provide evidence that extracellular proteases, including ADAMTS15, may be targets of inactivating mutations in human cancer and further validate the concept that secreted metalloproteases may show tumor suppressor properties.
Viloria
Cristina G
CG
Departamento de Bioquímica y Biología Molecular and Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Servicio de Anatomía Patológica, Hospital Central de Asturias, Oviedo, Spain.
Obaya
Alvaro J
AJ
Moncada-Pazos
Angela
A
Llamazares
María
M
Astudillo
Aurora
A
Capellá
Gabriel
G
Cal
Santiago
S
López-Otín
Carlos
C
D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000071096:ADAMTS Proteins; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D018938:Caco-2 Cells; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D020868:Gene Silencing / Q000502:physiology*; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D017385:Sequence Homology; D014407:Tumor Cells, Cultured
D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C500267:ADAMTS15 protein, human