ADAM23 negatively modulates alpha(v)beta(3) integrin activation during metastasis.
The ADAM23 gene is frequently silenced in different types of tumors, and, in breast tumors, silencing is correlated with tumor progression, suggesting that it might be associated with the acquisition of a metastatic phenotype. ADAM23 exerts its function mainly through the disintegrin domain, because its metalloprotease domain is inactive. Analysis of ADAM23 binding to integrins has revealed a specific interaction with alpha(v)beta(3) integrin mediated by the disintegrin domain. Altered expression of alpha(v)beta(3) integrin has been observed in different types of tumors, and expression of this integrin in the activated form has been shown to promote metastasis formation. Here, we investigated the possibility that interaction between ADAM23 and alpha(v)beta(3) integrin might negatively modulate alpha(v)beta(3) activation during metastatic progression. ADAM23 expression was knocked down using short hairpin RNA in the MDA-MB-435 cell line, which has been extensively used as a model for alpha(v)beta(3) integrin activation. Ablation of ADAM23 enhanced alpha(v)beta(3) integrin activation by at least 2- to 4-fold and ADAM23 knockdown cells showed enhanced migration and adhesion to classic alpha(v)beta(3) integrin ligands. Ablation of ADAM23 expression also enhanced pulmonary tumor cell arrest in immunodeficient mice. To complement our findings with clinical evidence, we showed that silencing of ADAM23 gene by DNA promoter hypermethylation in a collection of 94 primary breast tumors was significantly associated with lower distant metastases-free and disease-specific survivals and was an independent prognostic factor for poor disease outcome. Our results strongly support a functional role of ADAM23 during metastatic progression by negatively modulating alpha(v)beta(3) integrin activation.
Verbisck
Newton V
NV
Laboratory of Molecular Biology and Genomics, Ludwig Institute for Cancer Research, São Paulo SP, Brazil.
Costa
Erico T
ET
Costa
Fabrício F
FF
Cavalher
Felícia P
FP
Costa
Michele D M
MD
Muras
Angelita
A
Paixão
Valéria A
VA
Moura
Ricardo
R
Granato
Mariana F
MF
Ierardi
Daniela F
DF
Machado
Tamara
T
Melo
Fabiana
F
Ribeiro
Karina B
KB
Cunha
Isabela W
IW
Lima
Vladmir C C
VC
Maciel
Maria do Socorro
Mdo S
Carvalho
André L
AL
Soares
Fernando F
FF
Zanata
Silvio
S
Sogayar
Mari C
MC
Chammas
Roger
R
Camargo
Anamaria A
AA
D051722:ADAM Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics* / Q000502:physiology; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D016337:RNA, Catalytic / Q000235:genetics
D004273:DNA, Neoplasm; D039302:Integrin alphaVbeta3; D016337:RNA, Catalytic; C418481:hairpin ribozyme; D051722:ADAM Proteins; C114633:ADAM23 protein, human