Oncotarget 6:2434 (2015)

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

Xu B1,2, Jin X1,3, Min L4, Li Q1,3, Deng L1,5, Wu H3, Lin G3, Chen L6, Zhang H6, Li C3, Wang L6, Zhu J1,3, Wang W1,3, Chu F1,3, Shen J1,2, Li H3, Mao J1,3.


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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