Oncotarget

Research Papers:

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

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

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Oncotarget. 2015; 6:2434-2450. https://doi.org/10.18632/oncotarget.2966

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Abstract

Bin Xu1,4,*, Xiaobao Jin1,2,*, Ling Min5,*, Qin Li1,2, Lulu Deng1,6, Hui Wu2, Guixian Lin2, Lixin Chen3, Haifeng Zhang3, Chunmei Li2, Liwei Wang3, Jiayong Zhu1,2, Weizhang Wang1,2, Fujiang Chu1,2, Juan Shen1,4, Hongzhi Li2 and Jianwen Mao1,2

1 Guangdong Key Laboratory for Bioactive Drugs Research, Guangdong Pharmaceutical University, Guangzhou, China

2 School of Basic Medicine, Guangdong Pharmaceutical University, Guangzhou, China

3 Department of Pharmacology and Department of Physiology, Medical College, Jinan University, Guangzhou, China

4 School of Biosciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China

5 Cancer Center of Guangzhou Medical University, Guangzhou, China

6 Department of Pharmacology, Guangdong Pharmaceutical University, Guangzhou, China

* These authors contributed equally to this work

Correspondence:

Jianwen Mao, email:

Lixin Chen, email:

Keywords: chloride channel-3, tumor metastasis, membrane ruffling, cell migration

Received: September 10, 2014 Accepted: December 10, 2014 Published: December 11, 2014

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.


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