title: Expression of N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase involved in chondroitin sulfate synthesis is responsible for pulmonary metastasis.
abstract: Chondroitin sulfate (CS) containing E-disaccharide units, glucuronic acid-N-acetylgalactosamine(4, 6-O-disulfate), at surfaces of tumor cells plays a key role in tumor metastasis. However, the molecular mechanism of the metastasis involving the CS chain-containing E-units is not fully understood. In this study, to clarify the role of E-units in the metastasis and to search for potential molecular targets for anticancer drugs, the isolation and characterization of Lewis lung carcinoma (LLC) cells stably downregulated by the knockdown for the gene encoding N-acetylgalactosamine 4-O-sulfate 6-O-sulfotransferase (GalNAc4S-6ST), which is responsible for the formation of E-units in CS chains, were performed. Knockdown of GalNAc4S-6ST in LLC cells resulted in a reduction in the proportion of E-units, in adhesiveness to extracellular matrix adhesion molecules and in proliferation in vitro. Furthermore, the stable downregulation of GalNAc4S-6ST expression in LLC cells markedly inhibited the colonization of the lungs by inoculated LLC cells and invasive capacity of LLC cells. These results provide clear evidence that CS chain-containing E-units and/or GalNAc4S-6ST play a crucial role in pulmonary metastasis at least through the increased adhesion and the invasive capacity of LLC cells and also provides insights into future drug targets for anticancer treatment.
authors.affiliation: Laboratory of Proteoglycan Signaling and Therapeutics, Frontier Research Center for Post-Genomic Science and Technology, Graduate School of Life Science Hokkaido University, West-11, North-21, Kita-ku, Sapporo, Hokkaido 001-0021, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Mizumoto
authors.forename: Moto
authors.initials: M
authors.lastname: Watanabe
authors.forename: Shuhei
authors.initials: S
authors.lastname: Yamada
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugahara
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002809:Chondroitin Sulfates / Q000096:biosynthesis*; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000556:secondary*; D051379:Mice; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D015238:Sulfotransferases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D002809:Chondroitin Sulfates; C416670:N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase; D015238:Sulfotransferases
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