Long form collapsin response mediator protein-1 (LCRMP-1) expression is associated with clinical outcome and lymph node metastasis in non-small cell lung cancer patients
ABSTRACT Collapsin response mediator protein (CRMP) family proteins are cytosolic phosphoproteins involved in semaphorin 3A-mediated neuronal cell growth cone collapse and cancer invasion. We identified a novel human isoform of CRMP family proteins named long form CRMP-1 (LCRMP-1), which was different from the known invasion suppressor, CRMP-1, in its molecular weight and the N-terminal exon-1. This study was aimed to elucidate the clinical significance of LCRMP-1 in non-small cell lung cancer (NSCLC) patients. Full-length human LCRMP-1 was cloned from lung adenocarcinoma based on the Expressed Sequence Tags (EST) database. We generated LCRMP-1 specific antibody and subsequent in vitro and in vivo invasion assays showed positive correlations between LCRMP-1 expression and lung cancer cell invasiveness. We further demonstrated that high LCRMP-1 mRNA expressions were associated with poor overall and disease-free survivals (P=0.004 and 0.006, respectively, log-rank test) in 72 NSCLC patients. The results were confirmed in an independent cohort of 54 NSCLC patients by immunohistochemistry (P=0.032, log-rank test). The metastatic lymph nodes showed higher LCRMP-1 expressions as compared with the paired primary lung tumors (P=0.012, McNemar's test). In conclusion, LCRMP-1 was a cancer invasion enhancer that could be a novel prognostic biomarker in NSCLC.
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ABSTRACT: The collapsin response mediator proteins (CRMPs) were originally identified as mediators of semaphorin 3A signaling and neuronal differentiation. The CRMP family consists of five homologous cytosolic proteins, CRMP1-5. Altered expression levels of CRMPs have been observed in several malignant tumors, including lung, breast, colorectal, prostate, pancreatic and neuroendocrine lung cancer. The aim of the current study was to review the recent progress achieved in understanding the association between the different levels of CRMP expression in tumors and their involvement in pathological functions, such as tumor metastasis, disease progression, subtype differentiation and clinical outcome, to address the potential value of CRMPs as biomarkers for the diagnosis and prognosis of cancer patients.Oncology letters 05/2014; 7(5):1333-1340. DOI:10.3892/ol.2014.1909 · 0.99 Impact Factor
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ABSTRACT: Myelin-associated inhibitors (MAIs) contribute to failed regeneration in the CNS. The intracellular signaling pathways through which MAIs block axonal repair remain largely unknown. Here, we report that the kinase GSK3beta is directly phosphorylated and inactivated by MAIs, consequently regulating protein-protein interactions that are critical for myelin-dependent inhibition. Inhibition of GSK3beta mimics the neurite outgrowth inhibitory effect of myelin. The inhibitory effects of GSK3beta inhibitors and myelin are not additive indicating that GSK3beta is a major effector of MAIs. Consistent with this, overexpression of GSK3beta attenuates myelin inhibition. MAI-dependent phosphorylation and inactivation of GSK3beta regulate phosphorylation of CRMP4, a cytosolic regulator of myelin inhibition, and its ability to complex with RhoA. Introduction of a CRMP4 antagonist attenuates the neurite outgrowth inhibitory properties of GSK3beta inhibitors. We describe the first example of GSK3beta inactivation in response to inhibitory ligands and link the neurite outgrowth inhibitory effects of GSK3beta inhibition directly to CRMP4. These findings raise the possibility that GSK3beta inhibition will not effectively promote long-distance CNS regeneration following trauma such as spinal cord injury.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2010; 30(16):5635-43. DOI:10.1523/JNEUROSCI.6154-09.2010 · 6.75 Impact Factor
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ABSTRACT: Collapsin response mediator protein-2 (CRMP-2) is the first described and most studied member of a family of proteins that mediate the addition of tubulin dimers to the growing microtubule. CRMPs have mainly been studied in the nervous system, but recently, they have been described in other tissues where they participate in vesicle transport, migration and mitosis. In this work, we aimed at studying the role of CRMP-2 in lung cancer cell division. We first explored the expression of CRMP-2 and phosphorylated (Thr 514) CRMP-2 in 91 samples obtained from patients with localized nonsmall cell lung cancer. We observed a significant correlation between high levels of nuclear phosphorylated CRMP-2 and poor prognosis in those patients. Interestingly, this association was only positive for untreated patients. To provide a mechanistic explanation to these findings, we used in vitro models to analyze the role of CRMP-2 and its phosphorylated forms in cell division. Thus, we observed by confocal microscopy and immunoprecipitation assays that CRMP-2 differentially colocalizes with the mitotic spindle during cell division. The use of phosphodefective or phosphomimetic mutants of CRMP-2 allowed us to prove that anomalies in the phosphorylation status of CRMP-2 result in changes in the mitotic tempo, and increments in the number of multinucleated cells. Finally, here we demonstrate that CRMP-2 phosphorylation impairment, or silencing induces p53 expression and promotes apoptosis through caspase 3 activation. These results pointed to CRMP-2 phosphorylation as a prognostic marker and potential new target to be explored in cancer therapy.International Journal of Cancer 05/2013; 132(9). DOI:10.1002/ijc.27881 · 5.01 Impact Factor