Role of LIM and SH3 Protein 1 (LASP1) in the Metastatic Dissemination of Medulloblastoma

Institute of Clinical Biochemistry and Pathobiochemistry, University of Wuerzburg, Wuerzburg, Germany.
Cancer Research (Impact Factor: 9.33). 10/2010; 70(20):8003-14. DOI: 10.1158/0008-5472.CAN-10-0592
Source: PubMed


Medulloblastoma is the most common malignant pediatric brain tumor and is one of the leading causes of cancer-related mortality in children. Treatment failure mainly occurs in children harboring metastatic tumors, which typically carry an isochromosome 17 or gain of 17q, a common hallmark of intermediate and high-risk medulloblastoma. Through mRNA expression profiling, we identified LIM and SH3 protein 1 (LASP1) as one of the most upregulated genes on chromosome 17q in tumors with 17q gain. In an independent validation cohort of 101 medulloblastoma samples, the abundance of LASP1 mRNA was significantly associated with 17q gain, metastatic dissemination, and unfavorable outcome. LASP1 protein expression was analyzed by immunohistochemistry in a large cohort of patients (n = 207), and high protein expression levels were found to be strongly correlated with 17q gain, metastatic dissemination, and inferior overall and progression-free survival. In vitro experiments in medulloblastoma cell lines showed a strong reduction of cell migration, increased adhesion, and decreased proliferation upon LASP1 knockdown by small interfering RNA-mediated silencing, further indicating a functional role for LASP1 in the progression and metastatic dissemination of medulloblastoma.

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    • "Recent studies have shown that LASP-1 is transcriptionally upregulated in response to the morphogen Sonic Hedgehog [22]. Disruption of the Hedgehog signaling cascade leads to a number of developmental disorders and plays a key role in the formation of a range of human cancers. "
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    ABSTRACT: Background LIM and SH3 protein 1 (LASP-1) is a specific focal adhesion protein that is known to be involved in numerous biological and pathological processes. LASP-1 overexpression has been described in several types of cancers, but its expression and role in clear cell renal cell cancer (ccRCC) remains unknown. Methods Using immunohistochemistry, we analyzed LASP-1 protein expression in 216 clinicopathologically characterized ccRCC cases. We also examined LASP-1 expression in 20 paired ccRCC tissues and in 2 cell lines by real-time PCR and Western blot. Using RNA interference, we investigated the effects of LASP-1 depletion on tumor cell behavior in vitro. Statistical analyses were used to determine the associations between LASP-1 levels, tumor features and patient outcomes. Results LASP-1 overexpression was observed in ccRCC tissues (P<0.0001) compared to adjuvant nontumorous tissues, and its expression levels were closely correlated with overall survival and recurrence-free survival (P = 0.044 and 0.006, respectively) in patients with ccRCC. RNA interference-mediated silencing of the LASP-1 gene in 786–0 ccRCC cells significantly inhibited cell migration. Conclusions The results of the present study indicate that LASP-1 may serve as a prognostic biomarker for ccRCC patients and may be a promising target for the treatment of ccRCC.
    PLoS ONE 06/2014; 9(6):e100557. DOI:10.1371/journal.pone.0100557 · 3.23 Impact Factor
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    • "The LASP1 protein includes three domains: an N-terminal LIM domain, a nebulin repeat domain and a C-terminal SH3 domain [27]. LASP1 is expressed at low basal levels in all normal human tissues, but is over-expressed in metastatic human breast cancer [28], ovarian cancer [29] and medulloblastoma [30]. Increased LASP1 expression could lead to a more aggressive breast carcinoma phenotype, and knocking down LASP1 may reduce the migratory capacity of breast cancer cells, possibly by influencing the localization of zyxin [29]. "
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    ABSTRACT: This study was performed to investigate the effect of microRNA-203 (miR-203) on cell proliferation and migration in triple-negative breast cancer (TNBC). Real-time PCR was performed to detect the expression of miR-203 in TNBC cell lines. miR-203 precursor and control microRNA (miRNA) were transfected into triple-negative breast cancer (TNBC) cell lines and the effects of miR-203 up-regulation on the proliferation and migration of cells were investigated. Meanwhile, the mRNA and protein levels of baculoviral IAP repeat-containing protein 5 (BIRC5) and Lim and SH3 domain protein 1 (LASP1) were measured. Luciferase assays were also performed to validate BIRC5 and LASP1 as miR-203 targets. Both miR-203 and BIRC5 siRNA signicantly inhibited cell proliferation in TNBC cells. Both miR-203 and LASP1 siRNA signicantly inhibited cell migration in TNBC cells, also. Moreover, up-regulated of BIRC5 and LASP1 was able to abrogate the effects induced by transfection with the miR-203 precursor. These data suggest that miR-203 may function as a tumor suppressor in TNBC cells. Thus, miR-203 could be a potential therapeutic target for this disease.
    Journal of Experimental & Clinical Cancer Research 06/2012; 31(1):58. DOI:10.1186/1756-9966-31-58 · 4.43 Impact Factor
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    • "However, since then the major obstacles to identify, purify and to distinguish TSC from their differentiated derivatives mostly arise from the lack of robust markers [25]. Using resources such as array comparative genomic hybridization, expression sequence tags and microarrays [96-98], researchers may possibly identify novel factors that induce functional compartmentalization of individual tumor cells. The genomics era will succeed to scrutinize genetically complex patterns of functional traits controlled by multiple genes [99]. "
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    ABSTRACT: Compelling evidence broadens our understanding of tumors as highly heterogeneous populations derived from one common progenitor. In this review we portray various stages of tumorigenesis, tumor progression, self-seeding and metastasis in analogy to the superorganisms of insect societies to exemplify the highly complex architecture of a neoplasm as a system of functional "castes." Accordingly, we propose a model in which clonal expansion and cumulative acquisition of genetic alterations produce tumor compartments each equipped with distinct traits and thus distinct functions that cooperate to establish clinically apparent tumors. This functional compartment model also suggests mechanisms for the self-construction of tumor stem cell niches. Thus, thinking of a tumor as a superorganism will provide systemic insight into its functional compartmentalization and may even have clinical implications.
    Journal of Translational Medicine 05/2011; 9(1):79. DOI:10.1186/1479-5876-9-79 · 3.93 Impact Factor
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