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Lithium inhibits tumor lymphangiogenesis and metastasis through the inhibition of TGFBIp expression in cancer cells

 Yong-Sun Maeng  ;  Rina Lee  ;  Boram Lee  ;  Seung-ilChoi  ;  Eung Kweon Kim 
 SCIENTIFIC REPORTS, Vol.9(6) : 20739, 2016 
Journal Title
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Animals ; Cell Line, Tumor ; Colonic Neoplasms/drug therapy* ; Colonic Neoplasms/metabolism ; Colonic Neoplasms/pathology ; Extracellular Matrix Proteins/biosynthesis* ; Gene Expression Regulation, Neoplastic/drug effects* ; Glycogen Synthase Kinase 3 beta/metabolism ; Lithium/pharmacology* ; Lymphangiogenesis/drug effects* ; Mice ; Neoplasm Metastasis ; Neoplasm Proteins/metabolism* ; Phosphorylation/drug effects ; Smad3 Protein/metabolism ; Transforming Growth Factor beta/biosynthesis*
Metastasis is the main cause of mortality in cancer patients. Although there are many anti-cancer drugs targeting tumor growth, anti-metastatic agents are rarely developed. Angiogenesis and lymphangiogenesis are crucial for cancer progression; in particular, lymphangiogenesis is pivotal for metastasis in cancer. Here we report that lithium inhibits colon cancer metastasis by blocking lymphangiogenesis. Lithium reduces the expression of transforming growth factor-β-induced protein (TGFBIp) in colon cancer cells by inhibiting Smad3 phosphorylation via GSK3β inactivation. Moreover, lithium inhibits lymphatic endothelial cell migration, which is increased upon TGFBIp expression in tumor cells. Lithium had no significant effect on SW620 tumor growth in vitro and in vivo; however, it inhibited lymphangiogenesis in tumors. In tumor xenografts model, lithium was found to prevent metastasis to the lungs, liver, and lymph nodes by inhibiting TGFBIp-induced tumor lymphangiogenesis. Collectively, our findings demonstrate a novel role of lithium in the inhibition of colon cancer metastasis by blocking TGFBIp expression, and thereby TGFBIp-induced lymphangiogenesis, in primary tumors.
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1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
5. Research Institutes (연구소) > Corneal Dystrophy Research Institute (각막이상증연구소) > 1. Journal Papers
Yonsei Authors
Kim, Eung Kweon(김응권) ORCID logo https://orcid.org/0000-0002-1453-8042
Maeng, Yong Sun(맹용선) ORCID logo https://orcid.org/0000-0003-1694-8405
Choi, Seung Il(최승일) ORCID logo https://orcid.org/0000-0001-7168-8795
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