title: Regulation of matrix metalloproteinases (MMPs) expression and secretion in MDA-MB-231 breast cancer cells by LIM and SH3 protein 1 (LASP1).
abstract: 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.
authors: Institute of Experimental Biomedicine II, University Medical Clinic of Wuerzburg, Wuerzburg, Germany.
authors: Marcel
authors: M
authors: Endres
authors: Physiological Chemistry, Biozentrum, University of Wuerzburg, Am Hubland, Wuerzburg, Germany.
authors: Susanne
authors: S
authors: Kneitz
authors: Institute of Experimental Biomedicine II, University Medical Clinic of Wuerzburg, Wuerzburg, Germany.
authors: Martin F
authors: MF
authors: Orth
authors: Institute of Experimental Biomedicine II, University Medical Clinic of Wuerzburg, Wuerzburg, Germany.
authors: Ruwan K
authors: RK
authors: Perera
authors: Institute of Experimental Biomedicine II, University Medical Clinic of Wuerzburg, Wuerzburg, Germany.
authors: Alma
authors: A
authors: Zernecke
authors: Institute of Experimental Biomedicine II, University Medical Clinic of Wuerzburg, Wuerzburg, Germany.
authors: Elke
authors: E
authors: Butt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019295:Computational Biology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D030541:Databases, Genetic; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D000069261:Podosomes / Q000201:enzymology / Q000473:pathology; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C096353:LASP1 protein, human; D060588:LIM Domain Proteins; D018808:Transcription Factor AP-1; D053505:Matrix Metalloproteinases, Secreted; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: AP-1; LASP1; c-Fos; extracellular matrix; matrix metalloproteinases