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Regulation of matrix metalloproteinases (MMPs) expression and secretion by LIM and SH3 protein (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 and thereby allowing metastasis. We investigated the effect of LASP1, a newly identified protein in invadopodia, on expression, secretion and activation of MMPs in invasive breast tumor cells. By analyzing and verifying microarray data sets and performing reporter assays, we demonstrate that LASP1 positively modulates the expression of c-Fos and AP-1 activity, and thereby up-regulates expression of MMP1, -3 and -9 in breast cancer cells. Furthermore, zymography assays and Western blot analysis revealed cytosolic LASP1 promotion of MMP vesicle secretion into the extracellular matrix, thus 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 observed in studies that investigated the upregulation of LASP1 in aggressive cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE77584 | GEO | 2017/02/03

SECONDARY ACCESSION(S): PRJNA310869

REPOSITORIES: GEO

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Homo sapiens

Project description:Regulation of matrix metalloproteinases (MMPs) expression and secretion by LIM and SH3 protein (LASP1)

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The invadopodial and cytoskeletal regulator glycine- and cysteine-rich protein 2 induces pro-metastatic matrix metalloproteinase expression in breast cancer cells

Project description:Actin cytoskeleton has multiple functions in cancer cell invasion and metastasis; yet how these functions are coordinated remains unclear. In the cytoplasm, actin is necessary for the formation of specialized membrane protrusions, termed invadopodia, that concentrate and secrete extracellular matrix-degrading enzymes, particularly the matrix metalloproteinases (MMPs), facilitating tumor cell invasion. We recently identified cysteine- and glycine-rich protein 2 (CRP2) as an actin-crosslinking protein whose activity is required for the assembly and elongation of the invadopodium actin backbone. Here, we report that CRP2 is also located in the nucleus of breast cancer cells to induce a complementary pro-metastasis gene expression program mostly related to breast cancer cell invasion and metastasis. We showed in this present study that CRP2 interacts with the transcription factors SRF and GATA3 to regulated the expression of MMP-9 and MMP-13 respectively. Overall, our data indicate that CRP2 act a key mediator of tumor cell invasion.

2023-04-26 | GSE199822 | GEO

Lasp1 gene disruption is linked to enhanced cell migration and tumor formation

Project description:Chronic loss of Lasp1 alters the expression of other genes associated with cell motility/attachment, and/or other cellular functions. Results provide new information showing that loss of Lasp1 leads to up- and down-regulation of genes involved in cell motility/attachment/growth. Keywords: Genotype comparison Total RNA isolated from Lasp1-/- MEFs compared to Lasp1+/+ MEFs.

2010-06-23 | E-GEOD-14800 | biostudies-arrayexpress

Inhibition of ß1 integrin induces its association with MT1-MMP and decreases MT1- MMP internalization and cellular invasiveness

Project description:Integrin signaling plays a fundamental role in the establishment of focal adhesions and the subsequent formation of invadopodia in malignant cancer cells. Invadopodia facilitate localized adhesion and degradation of the extracellular matrix (ECM), which promote tumour cell invasion and metastasis. Degradation of ECM components is often driven by membrane type-1 matrix metalloproteinase (MT1-MMP), and we have recently shown that regulation of enzyme internalization is dependent on signaling downstream of β1 integrin. Phosphorylation of the cytoplasmic tail of MT1-MMP is required for its internalization and delivery to Rab5-marked early endosomes, where it is then able to be recycled to new sites of invadopodia formation and promote invasion. Here we found that inhibition of β1 integrin, using the antibody AIIB2, inhibited the internalization and recycling of MT1-MMP that is necessary to support long-term cellular invasion. MT1-MMP and β1 integrin were sequestered at the cell surface when β1-integrin was inhibited, and their association under these conditions was detected using immunoprecipitation and mass spectrometry analysis. Sequestration of β1 integrin and MT1-MMP at the cell surface resulted in the formation of large invadopodia and local ECM degradation; however, the impaired internalization and recycling of MT1-MMP and β1 integrin ultimately led to a loss of invasive behaviour.

2022-12-22 | PXD024000 | Pride

Upregulation of Expression of Matrix Metalloproteinases in Alveolar Macrophages of HIV1+ Smokers with Early Emphysema

Project description:HIV1+ smokers develop emphysema at an earlier age and with a higher incidence than HIV1- smokers. Based on the knowledge that human alveolar macrophages (AM) are capable of producing proteases that degrade extracellular matrix components, we hypothesized that upregulation of AM matrix metalloproteinases may be associated with the emphysema of HIV1+ smokers. To test this hypothesis, microarray analysis was used to screen which MMP genes were expressed by AM isolated by bronchoalveolar lavage (BAL) of HIV1+ smokers with early emphysema. For each of the MMP genes observed to be expressed (MMP-1, -2, -7, -9, -10, -12 and -14), TaqMan PCR was used to quantify the relative expression in AM from 4 groups of individuals: HIV1 healthy nonsmokers, HIV1- healthy smokers, HIV1- smokers with early emphysema and HIV1+ smokers with early emphysema. Strikingly, while AM gene expression of MMPs was higher in HIV1- individuals with emphysema in comparison with HIV1- healthy smokers, for the majority of the MMPs (-1, -7, -9, -10, -12), AM expression from HIV1+ smokers with early emphysema was significantly higher than HIV1- smokers with early emphysema. Consistent with these observations, HIV1+ individuals with early emphysema had higher levels of epithelial lining fluid MMPs (-2, -7, -9,-12) than the 3 HIV1 groups. Interestingly, the active forms of MMP-2, -9 and -12 were detected in epithelial lining fluid from HIV1+ individuals with early emphysema, but not in any of the other groups. Considering that the substrate specificity of the upregulated AM MMPs includes collagenases, gelatinases, matrilysins and elastase, these data suggest that upregulated AM MMP genes and activation of MMP proteins may contribute to the emphysema of HIV1+ individuals who smoke. Keywords: expression study Asymptomatic HIV+ smokers with early emphysema

2016-03-24 | E-GEOD-10038 | biostudies-arrayexpress

Lasp1 gene deletion: Effect on gene expression in the gastric mucosa

Project description:Comparative analysis of gene expression in murine gastric fundic mucosa in wild-type and Lasp1-null littermates. The data provide a comprehensive overview of genes expressed in the mouse gastric mucosa and show that the expression of several known and unidentified genes is modified by disruption of the Lasp1 gene. Keywords: Genotypic comparison

2009-02-13 | GSE14813 | GEO

Active Site Specificity Profiling of the Matrix Metalloproteinase Family: Proteomic Identification of 4,300 Cleavage Sites by MMPs 1, 2, 3, 7, 8, 9, 12, 13, and 14.

Project description:Background: The active site of matrix metalloproteinases (MMPs) is highly conserved, complicating the rational design of specific substrates and inhibitors for individual family members. Results: Active site specificity profiles of 9 MMPs were determined using high throughput Proteomic Identification of protease Cleavage Sites (PICS). Conclusion: Subtle specificity divergences distinguish individual MMP family members. Significance: Understanding individual MMP cleavage site specificities will bolster the design of MMP specific activity assays and targeted inhibitory drugs.

2015-09-29 | PXD002265 | Pride

Lasp1 gene disruption is linked to enhanced cell migration and tumor formation

2009-02-12 | GSE14800 | GEO

Gene expression by LASP1 knocked down in PC3 cells

Project description:The aim of this research was to confirm the regulatory effect of LASP1 on gene expression in the development of prostate cancer.

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Transcriptome analysis of wild-type (WT) and CDH1 knockout (KO) human Gastric Organoids (hGOs)

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2023-03-10 | GSE146716 | GEO

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