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