3927

LASP1

LIM and SH3 protein 1;LASP1;LIM and SH3 protein 1

LIM and SH3 domain protein 1|metastatic lymph node gene 50 protein

17q11-q21.3

protein-coding

BACKGROUND: LIM and SH3 protein 1 (LASP-1), initially identified from a cDNA library of metastatic axillary lymph nodes of breast cancer patients, is a specific focal adhesion protein involved in numerous biological and pathological processes. The overexpression of LASP-1 has been described in several types of cancers, but the role of LASP-1 in colorectal cancer (CRC) is unknown. In a previous study, comparative proteomic analysis was performed and LASP-1 was identified as a CRC-associated protein in those patients with CRC. METHODS: Using immunohistochemistry, we analysed LASP-1 protein expression in 126 clinicopathologically characterised CRC cases. Using gene transfection and RNA interference, we investigated the effects of LASP-1 overexpression and depletion on tumor cellular behavior in vitro and in vivo. Using 2-D DIGE, we analysed the effect of the presence and absence of LASP-1 gene on protein expression profiles of CRC cells. RESULTS: Overexpression of LASP-1 was found in metastatic CRC tissues (p=0.002), and its expression level was closely correlated with overall survival of patients with CRC (p=0.002). RNA interference-mediated silencing of the LASP-1 gene in SW620 CRC cells inhibited cell proliferation and migration significantly. However, gene transfection-mediated overexpression of LASP-1 in SW480 CRC cells resulted in aggressive phenotypes of cancer cells and promoted cancer growth and metastasis. Furthermore, both overexpression and silencing of the LASP-1 gene caused a very similar protein expression pattern in different CRC cell lines. The identified LASP-1-modulated proteins, including some key cellular molecules, were involved in various biological processes. CONCLUSIONS: The results show that LASP-1 might be a promising target in the treatment of patients with CRC with growth and metastasis of CRC.

To better understand the mechanism underlying colorectal carcinoma (CRC) genesis or metastasis, and to search for potential markers for CRC prognosis, a comparative proteomic analysis was performed on CRC tissue. Proteins were extracted from normal colorectal mucosa, non-metastatic CRC (nmCRC) and metastatic CRC (mCRC) tissue samples. Protein profiling of each sample was performed by two-dimensional electrophoresis coupled with MALDI-TOF MS, followed by confirmation by Western blotting. Thirty-one proteins were found to be differentially expressed between normal mucosa, nmCRC and mCRC tissue. In 126 paraffin-embedded CRC samples, three differentially expressed proteins, identified as LASP-1, S100A9 and RhoGDI by proteomic analysis, were detected by immunohistochemical staining to determine the clinicopathological characteristics of these proteins in CRC. Increased expression levels of these proteins were found in CRC, especially mCRC, compared with normal mucosa. The results provide the basis for searching for potential markers for CRC genesis and metastasis, and also provide clues for elucidating the mechanism of CRC progression. The pattern changes identified have the potential to be used for the design of marker panels for assistance in diagnostic and therapeutic strategies in CRC.

PURPOSE: The LIM and SH3 protein 1 (LASP-1) is a focal adhesion protein, and its expression has been reported to be increased in many malignant tumors. However, the role of LASP-1 in gastric cancer is still unknown. The aim of this study was to determine the relationship of LASP-1 expression with the progression and prognosis of gastric cancer. METHODS: expression of LASP-1 was evaluated in gastric cancer tissues and cell lines by immunohistochemistry and Western blot analysis. The relationship between LASP-1 expression and clinicopathological characteristics was analyzed. Using RNA interference, the effects of LASP-1 on cell proliferation, migration and invasion were investigated in gastric cancer cell lines both in vitro and in vivo. RESULTS: The LASP-1 was overexpressed in gastric cancer tissues and cell lines. LASP-1 expression was significantly associated with tumor size, invasive depth, TNM stage, lymph node metastasis and p53 expression (all P < 0.05). Multivariate survival analysis showed that LASP-1 expression was recognized as an independent prognostic factor of patient's survival. Knockdown of LASP-1 inhibited cell proliferation, migration and invasion in vitro as well as tumorigenesis and metastasis in vivo. CONCLUSIONS: Our study showed that LASP-1, overexpressed in gastric cancer and associated with poor prognosis, plays an important role in the growth and metastasis of gastric cancer.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide with poor prognosis associated with tumor invasion and metastasis. The tumor suppressor p53 plays critical roles in tumor development, but there is increasing evidence for its involvement in tumor metastasis with the underlying mechanisms largely unexplored. METHODS: Using combinatorial analysis of a p53 binding database with HCC microarray expression profile, we identified a novel metastasis-related gene Lasp1 as a potential p53 target. RESULTS: In this study, we demonstrate that Lasp1 is indeed a bona fide p53 target by validating the functional repression effect of p53 on Lasp1 via a p53 response element. Transient transfection of wild-type p53 but not the mutant form suppressed Lasp1 in Hep3B (p53-/-) cells, while p53 siRNA up-regulated its expression in HepG2 (p53+/+) cells. p53 mutations at key residues involved in DNA binding abrogates the p53-mediated suppression of Lasp1 expression. In addition, Lasp1 regulates HCC cell growth as well as cell migration and invasion ability. CONCLUSIONS: p53 transcriptionally represses Lasp1, which is a partner protein in affecting HCC cell motility. This suggests that p53 may play a role in influencing tumor metastasis through Lasp1.

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.