title: Chloride channel-3 promotes tumor metastasis by regulating membrane ruffling and is associated with poor survival.
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.
authors.affiliation: Guangdong Key Laboratory for Bioactive Drugs Research, Guangdong Pharmaceutical University, Guangzhou, China.|School of Biosciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: Guangdong Key Laboratory for Bioactive Drugs Research, Guangdong Pharmaceutical University, Guangzhou, China.|School of Basic Medicine, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Xiaobao
authors.initials: X
authors.lastname: Jin
authors.affiliation: Cancer Center of Guangzhou Medical University, Guangzhou, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Min
authors.affiliation: Guangdong Key Laboratory for Bioactive Drugs Research, Guangdong Pharmaceutical University, Guangzhou, China.|School of Basic Medicine, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Guangdong Key Laboratory for Bioactive Drugs Research, Guangdong Pharmaceutical University, Guangzhou, China.|Department of Pharmacology, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Deng
authors.affiliation: School of Basic Medicine, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wu
authors.affiliation: School of Basic Medicine, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Guixian
authors.initials: G
authors.lastname: Lin
authors.affiliation: Department of Pharmacology and Department of Physiology, Medical College, Jinan University, Guangzhou, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Department of Physiology, Medical College, Jinan University, Guangzhou, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: School of Basic Medicine, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Department of Physiology, Medical College, Jinan University, Guangzhou, China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Guangdong Key Laboratory for Bioactive Drugs Research, Guangdong Pharmaceutical University, Guangzhou, China.|School of Basic Medicine, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Jiayong
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Guangdong Key Laboratory for Bioactive Drugs Research, Guangdong Pharmaceutical University, Guangzhou, China.|School of Basic Medicine, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Weizhang
authors.initials: W
authors.lastname: Wang
authors.affiliation: Guangdong Key Laboratory for Bioactive Drugs Research, Guangdong Pharmaceutical University, Guangzhou, China.|School of Basic Medicine, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Fujiang
authors.initials: F
authors.lastname: Chu
authors.affiliation: Guangdong Key Laboratory for Bioactive Drugs Research, Guangdong Pharmaceutical University, Guangzhou, China.|School of Biosciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Shen
authors.affiliation: School of Basic Medicine, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Li
authors.affiliation: Guangdong Key Laboratory for Bioactive Drugs Research, Guangdong Pharmaceutical University, Guangzhou, China.|School of Basic Medicine, Guangdong Pharmaceutical University, Guangzhou, China.
authors.forename: Jianwen
authors.initials: J
authors.lastname: Mao
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D019012:Integrin beta1 / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D053538:Keratin-18 / Q000235:genetics / Q000378:metabolism; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011379:Prognosis; D034622:RNA Interference; D014183:Transplantation, Heterologous
chemical_list: D014408:Biomarkers, Tumor; D018118:Chloride Channels; C115376:ClC-3 channel; D019012:Integrin beta1; D053538:Keratin-18