Long form collapsin response mediator protein-1(LCRMP-1) is a novel invasion enhancer: Yin-Yang regulation of cancer cell invasion by LCRMP-1 and CRMP-1

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Tumor metastasis is the major contributor of mortality in cancer patients. The underlying mechanisms are complicated and not fully characterized. By using cDNA microarray and invasion/metastasis cell line model, we previously identified a novel invasion suppressor collapsin response mediator protein-1 (CRMP-1) that can predict outcomes and metastasis in lung cancer patients. CRMP-1 is a 66 kDa cytosolic protein and is the downstream signaling molecule of semaphorin 3A. Through filamentous (F)-actin depolymerization, CRMP-1 can suppress cancer cell invasion. This study by immunoprecipitation, we identified a new isoform of CRMP-1 with molecular size about 76 kDa, we named it as LCRMP-1. The sequence alignment showed that C-terminals of LCRMP-1 and CRMP-1were identical and the N-terminal regions were encoded by different exon-1. The LCRMP-1 proteins form a filamentous structure in cytoplasm of the cells and are co-localized with CRMP-1, tubulin and actin. Further characterization revealed that LCRMP-1 is functionally antagonized with CRMP-1. The LCRMP-1 can enhance cancer cell migration and invasion, and increased in LCRMP-1/CRMP-1 expression ratio is associated with the increase of invasion ability. The LCRMP-1 could interact with actin and overexpression of LCRMP-1 enhanced filopodia formation. The LCRMP-1 could reverse the cdc42 dominant negative mutant induced filopodia regression and confirm that LCRMP-1 is the downstream of cdc42. Serial deletion of LCRMP-1 N-terminal region revealed that 22 to 72 amino acids is the key domain that responsible for the filopodia formation. The LCRMP-1 induced nucleation for actin polymerization is mediated through WAVE-1 instead of the traditional N-WASP pathway. Silencing of WAVE-1 by siRNA abolished the LCRMP-1 induced actin polymerization and filopodia formation further led to suppression of cell invasion. Our results suggest that LCRMP-1 is a novel invasion enhancer and functionally antagonized with CRMP-1. The Yin Yang regulation of LCRMP-1 and CRMP-1 expressions may modulate cancer cell migration and invasion ability. The LCRMP-1/ CRMP-1 are useful targets to design new therapeutic strategy to suppress cancer metastasis.