title: Galectin 3 regulates HCC cell invasion by RhoA and MLCK activation.
abstract: Hepatocellular carcinoma (HCC) carries a poor prognosis with no effective treatment available other than liver transplantation for selected patients. Vascular invasion of HCC is one of the most important negative predictor of survival. As the regulation of invasion of HCC cells is not well understood, our aim was to study the mechanisms by which galectin 3, a β-galactosidase-binding lectin mediates HCC cell migration. HCC was induced by N-diethylnitrosamine in wild-type and galectin 3(-/-) mice, and tumor formation, histology, and tumor cell invasion were assessed. The galectin 3(-/-) mice developed significantly smaller tumor burden with a less invasive phenotype than the wild-type animals. Galectin 3 was upregulated in the wild-type HCC tumor tissue, but not in the surrounding parenchyma. Galectin 3 expression in HCC was induced by NF-κB transactivation as determined by chromatin immunoprecipitation assays. In vitro studies assessed the pro-migratory effects of galectin 3. The migration of hepatoma cells was significantly decreased after transfection by the galectin 3 siRNA and also after using the Rho kinase inhibitor Y-27632. The reorganization of the actin cytoskeleton, RhoA GTPase activity and the phosphorylation of MLC2 (myosin light chain 2) were decreased in the galectin 3 siRNA-transfected cells. In addition, in vitro and in vivo evidence showed that galectin 3 deficiency reduced hepatoma cell proliferation and increased their apoptosis rate. In conclusion, galectin 3 is an important lectin that is induced in HCC cells, and promotes hepatoma cell motility and invasion by an autocrine pathway. Targeting galectin 3 therefore could be an important novel treatment strategy to halt disease progression.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, UC Davis Medical Center, Sacramento, CA, USA.
authors.forename: Nobuko
authors.initials: N
authors.lastname: Serizawa
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, UC Davis Medical Center, Sacramento, CA, USA.|State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-environmental Sciences, Chinese Academy of Sciences, Beijing, China.
authors.forename: Jijing
authors.initials: J
authors.lastname: Tian
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, UC Davis Medical Center, Sacramento, CA, USA.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Fukada
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, UC Davis Medical Center, Sacramento, CA, USA.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Baghy
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, UC Davis Medical Center, Sacramento, CA, USA.
authors.forename: Fiona
authors.initials: F
authors.lastname: Scott
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, UC Davis Medical Center, Sacramento, CA, USA.
authors.forename: Xiangling
authors.initials: X
authors.lastname: Chen
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, UC Davis Medical Center, Sacramento, CA, USA.
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Kiss
authors.affiliation: Department of Pathology, UC Davis Medical Center, Sacramento, CA, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Olson
authors.affiliation: Department of Dermatology, UC Davis Medical Center, Sacramento, CA, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Hsu
authors.affiliation: Department of Dermatology, UC Davis Medical Center, Sacramento, CA, USA.
authors.forename: Fu-Tong
authors.initials: FT
authors.lastname: Liu
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, UC Davis Medical Center, Sacramento, CA, USA.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Török
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-environmental Sciences, Chinese Academy of Sciences, Beijing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, UC Davis Medical Center, Sacramento, CA, USA.
authors.forename: Joy X
authors.initials: JX
authors.lastname: Jiang
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D024722:Cardiac Myosins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D037502:Galectin 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018994:Myosin Light Chains / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D037502:Galectin 3; C485095:Lgals3 protein, mouse; D018994:Myosin Light Chains; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; C107184:myosin light chain 2; D054460:rho-Associated Kinases; D009219:Myosin-Light-Chain Kinase; D024722:Cardiac Myosins; D020742:rhoA GTP-Binding Protein