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2016 ; 7
(39
): 64244-64259
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Regulation of matrix metalloproteinases (MMPs) expression and secretion in
MDA-MB-231 breast cancer cells by LIM and SH3 protein 1 (LASP1)
#MMPMID27588391
Endres M
; Kneitz S
; Orth MF
; Perera RK
; Zernecke A
; Butt E
Oncotarget
2016[Sep]; 7
(39
): 64244-64259
PMID27588391
show ga
The process of tumor invasion requires degradation of extracellular matrix by
proteolytic enzymes. Cancer cells form protrusive invadopodia, which produce and
release matrix metalloproteinases (MMPs) to degrade the basement membrane thereby
enabling metastasis. We investigated the effect of LASP1, a newly identified
protein in invadopodia, on expression, secretion and activation of MMPs in
invasive breast tumor cell lines.By analyzing microarray data of in-house
generated control and LASP1-depleted MDA-MB-231 breast cancer cells, we observed
downregulation of MMP1, -3 and -9 upon LASP1 depletion. This was confirmed by
Western blot analysis. Conversely, rescue experiments restored in part MMP
expression and secretion. The regulatory effect of LASP1 on MMP expression was
also observed in BT-20 breast cancer cells as well as in prostate and bladder
cancer cell lines.In line with bioinformatic FunRich analysis of our data, which
mapped a high regulation of transcription factors by LASP1, public microarray
data analysis detected a correlation between high LASP1 expression and enhanced
c-Fos levels, a protein that is part of the transcription factor AP-1 and known
to regulate MMP expression. Compatibly, in luciferase reporter assays, AP-1
showed a decreased transcriptional activity after LASP1 knockdown.Zymography
assays and Western blot analysis revealed an additional promotion of MMP
secretion into the extracellular matrix by LASP1, thus, most likely, altering the
microenvironment during cancer progression.The newly identified role of LASP1 in
regulating matrix degradation by affecting MMP transcription and secretion
elucidated the migratory potential of LASP1 overexpressing aggressive tumor cells
in earlier studies.
|Adaptor Proteins, Signal Transducing/genetics/*metabolism
[MESH]