CSE1L, a Novel Microvesicle Membrane Protein, Mediates Ras-Triggered Microvesicle Generation and Metastasis of Tumor Cells

Ching-Fong Liao,Shing-Chuan Shen,Cheng-Jeng Tai,Jeng-Fong Chiou,Shu-Hui Lin,Ming-Chung Jiang,Tsu-Han Hsu,Woan-Ruoh Lee,Hung-Chang Chen,Chung-Min Yeh,Li-Tzu Li,Chun-Chao Chang,Kun-Tu Yeh,Ying-Chun Chen,Shue-Fen Luo

doi:10.2119/molmed.2012.00205

Abstract

Tumor-derived microvesicles are rich in metastasis-related proteases and play a role in the interactions between tumor cells and tumor microenvironment in tumor metastasis. Because shed microvesicles may remain in the extracellular environment around tumor cells, the microvesicle membrane protein may be the potential target for cancer therapy. Here we report that chromosome segregation 1-like (CSE1L) protein is a microvesicle membrane protein and is a potential target for cancer therapy. v-H-Ras expression induced extracellular signal-regulated kinase (ERK)-dependent CSE1L phosphorylation and microvesicle biogenesis in various cancer cells. CSE1L overexpression also triggered microvesicle generation, and CSE1L knockdown diminished v-H-Ras-induced microvesicle generation, matrix metalloproteinase (MMP)-2 and MMP-9 secretion and metastasis of B16F10 melanoma cells. CSE1L was preferentially accumulated in microvesicles and was located in the microvesicle membrane. Furthermore, anti-CSE1L antibody-conjugated quantum dots could target tumors in animal models. Our findings highlight a novel role of Ras-ERK signaling in tumor progression and suggest that CSE1L may be involved in the "early" and "late" metastasis of tumor cells in tumorigenesis. Furthermore, the novel microvesicle membrane protein, CSE1L, may have clinical utility in cancer diagnosis and targeted cancer therapy.

Highlights

Microvesicles are plasma membrane–derived particles that are released from cells by the outward budding and fission of the plasma membrane [1]
Tumor-derived microvesicles are rich in metastasis-related proteases such as matrix metalloproteinase (MMP)-2 and MMP-9, which are involved in the degradation of extracellular matrix in the tumor microenvironment, thereby promoting tumor metastasis [12]
We investigated whether chromosome segregation 1–like (CSE1L) was involved in microvesicle biogenesis and MMP-2 secretion induced by Ras

Summary

INTRODUCTION

Microvesicles (microparticles) are plasma membrane–derived particles that are released from cells by the outward budding and fission of the plasma membrane [1]. Tumor cells constitutionally release microvesicles by the way they transmit their membrane growth factor receptors, metastasis-related proteases and other bioactive molecules to other tumor cells, nontumor cells and other tissue components in the tumor microenvironment, thereby promoting tumor progression [8, 9]. CSE1L REGULATES MICROVESICLE BIOGENESIS microvesicle shedding is a major secretory pathway for cathepsin B, a metastasis-related protease, releasing from tumor cells [10]. ERK has been shown to mediate the shedding of microvesicles during tumor invasion through the modulation of myosin lightchain kinase (MLCK) activation [18]. The cellular mechanism that regulates microvesicle biogenesis, promoting tumor metastasis, is not fully understood. Our results suggest that CSE1L may be a potential target for targeted cancer therapy

MATERIALS AND METHODS

RESULTS

DISCUSSION

Findings

CONCLUSION