The ability of LCRMP-1 to promote cancer invasion by enhancing filopodia formation is antagonized by CRMP-1
Szu-Hua Pan, … , Tse-Ming Hong, Pan-Chyr Yang
Szu-Hua Pan, … , Tse-Ming Hong, Pan-Chyr Yang
Published July 11, 2011
Citation Information: J Clin Invest. 2011;121(8):3189-3205. https://doi.org/10.1172/JCI42975.
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Research Article Oncology

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

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.

Authors

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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Figure 3

Effects of LCRMP-1 on actin dynamics.

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Effects of LCRMP-1 on actin dynamics. (A) Expressions of G-actin and F-a...
(A) Expressions of G-actin and F-actin in indicated CL1-0 stable cells (vector control, LCRMP-1, and LCRMP-1 R29AK31A mutant), analyzed by immunofluorescence staining with FITC-conjugated DNase I (G-actin, green) and rhodamine-conjugated phalloidin (F-actin, red). For ratio-merge panel, blue and red indicate F-actin and G-actin, respectively. The level of F-actin relative to that of total actin was quantified (n = 100 cells per group; original magnification, ×400). (B) Expressions of G-actin and F-actin in indicated CL1-0 stable cells analyzed by immunoblotting. The protein level of F-actin relative to that of constant G-actin was quantified (n = 3 experiments). (C) F-actin reorganization examined by Dynamic NIWOP tomography in CL1-0/vector (line 2A10) and CL1-0/LCRMP-1 (lines 1003 and 1015) cells. Arrows indicate filopodia. Filopodia were counted every 5 minutes, and the averages over a 25-minute period were calculated from 8 random cells in each group (n = 2 experiments; original magnification, ×1,000). Error bars indicate mean ± SEM, and P values were calculated by 2-sided Student’s t test.