Chloride channel-3 promotes tumor metastasis by regulating membrane ruffling and is associated with poor survival.

Bin Xu,Chunmei Li,Liwei Wang,Xiaobao Jin,Haifeng Zhang,Weizhang Wang,Lixin Chen,Guixian Lin,Hongzhi Li,Qin Li,Jianwen Mao,Ling Min,Jiayong Zhu,Juan Shen,Hui Wu,Lulu Deng,Fujiang Chu

doi:10.18632/oncotarget.2966

Bin Xu, Chunmei Li + Show 15 more

Open Access

https://doi.org/10.18632/oncotarget.2966

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Abstract

The chloride channel-3 (ClC-3) protein is known to be a component of Cl- channels involved in cell volume regulation or acidification of intracellular vesicles. Here, we report that ClC-3 was highly expressed in the cytoplasm of metastatic carcinomatous cells and accelerated cell migration in vitro and tumor metastasis in vivo. High-grade expression of cytoplasmic ClC-3 predicted poor survival in cancer patients. We found that independent of its volume-activated Cl- channel properties, ClC-3 was able to promote cell membrane ruffling, required for tumor metastasis. ClC-3 mediated membrane ruffling by regulating keratin 18 phosphorylation to control β1 Integrin recycling. Therefore, cytoplasmic ClC-3 plays an active and key role in tumor metastasis and may be a valuable prognostic biomarker and a therapeutic target to prevent tumor spread.

Highlights

The initial step in tumor metastasis is the invasion of cancer cells into surrounding tissue and the vasculature
We observed that ClC-3, a member of the ClC chloride channel gene family, accumulated at membrane ruffles in the leading edge of lamellipodia of migrating cells and on the dorsal surface of cells treated with epidermal growth factor (EGF)
These results show that ClC-3 is necessary to promote membrane ruffle formation

Summary

Introduction

The initial step in tumor metastasis is the invasion of cancer cells into surrounding tissue and the vasculature. This requires chemotactic migration of cancer cells, steered by protrusive activity of the cell membrane [1]. Membrane ruffles are often seen at the leading edge and on the dorsal surface of a migratory cell [5], and their structure, molecular composition, and the mechanisms leading to their formation remain largely unclear [6]. Actin remodeling is initially induced by cytokines to form membrane ruffles [7].

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