The ability of LCRMP-1 to promote cancer invasion by enhancing filopodia formation is antagonized by CRMP-1

Szu Hua Pan, Yu Chih Chao, Pei Fang Hung, Hsuan Yu Chen, Shuenn Chen Yang, Yih Leong Chang, Chen Tu Wu, Cheng Chi Chang, Wen Lung Wang, Wing Kai Chan, Yi Ying Wu, Ting Fang Che, Lu Kai Wang, Chien Yu Lin, Yung Chie Lee, Min Liang Kuo, Chau Hwang Lee, Jeremy J.W. Chen, Tse Ming Hong, Pan Chyr Yang

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Abstract

Metastasis is a predominant cause of death in patients with cancer. It is a complex multistep process that needs to be better understood if we are to develop new approaches to managing tumor metastasis. Tumor cell invasion of the local stroma is suppressed by collapsin response mediator protein-1 (CRMP-1). Recently, we identified a long isoform of CRMP-1 (LCRMP-1), expression of which correlates with cancer cell invasiveness and poor clinical outcome in patients with non-small-cell lung cancer (NSCLC). Here, we report that LCRMP-1 overexpression in noninvasive human cell lines enhanced filopodia formation, cancer cell migration, and invasion via stabilization of actin. This effect required a highly conserved N-terminal region of LCRMP-1 as well as the WASP family verprolin-homologous protein-1/actin nucleation pathway (WAVE-1/actin nucleation pathway). Furthermore, LCRMP-1 appeared to act downstream of Cdc42, a Rho family protein known to be involved in actin rearrangement. In addition, LCRMP-1 associated with CRMP-1, which downregulated cancer cell metastasis by interrupting the association of LCRMP-1 and WAVE-1. Finally, we found that high-level expression of LCRMP-1 and low-level expression of CRMP-1 were associated with lymph node metastasis and poor survival in patients with NSCLC. In sum, we show that LCRMP-1 and CRMP-1 have opposing functions in regulating cancer cell invasion and metastasis and propose that this pathway may serve as a potential anticancer target.

Original languageEnglish
Pages (from-to)3189-3205
Number of pages17
JournalJournal of Clinical Investigation
Volume121
Issue number8
DOIs
Publication statusPublished - 2011 Aug 1

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Pan, S. H., Chao, Y. C., Hung, P. F., Chen, H. Y., Yang, S. C., Chang, Y. L., Wu, C. T., Chang, C. C., Wang, W. L., Chan, W. K., Wu, Y. Y., Che, T. F., Wang, L. K., Lin, C. Y., Lee, Y. C., Kuo, M. L., Lee, C. H., Chen, J. J. W., Hong, T. M., & Yang, P. C. (2011). The ability of LCRMP-1 to promote cancer invasion by enhancing filopodia formation is antagonized by CRMP-1. Journal of Clinical Investigation, 121(8), 3189-3205. https://doi.org/10.1172/JCI42975