Trimeric Tn antigen on syndecan 1 produced by ppGalNAc-T13 enhances cancer metastasis via a complex formation with integrin α5β1 and matrix metalloproteinase 9.

Abstract

We demonstrated previously that ppGalNAc-T13 (T13), identified as an up-regulated gene with increased metastasis in a DNA microarray, generated trimeric Tn (tTn) antigen (GalNAcα1-Ser/Thr)3 on Syndecan 1 in highly metastatic sublines of Lewis lung cancer. However, it is not known how tTn antigen regulates cancer metastasis. Here, we analyzed the roles of tTn antigen in cancer properties. tTn antigen on Syndecan 1 increased cell adhesion to fibronectin in an integrin-dependent manner. Furthermore, cell adhesion to fibronectin induced phosphorylation of focal adhesion kinase and paxillin in T13-transfectant cells. In the search of Syndecan 1-interacting molecules, it was demonstrated that tTn antigen-carrying Syndecan 1 interacted with integrin α5β1 and matrix metalloproteinase 9 and that these molecules shifted to a glycolipid-enriched microdomain/rafts along with increased metastatic potential in T13-transfectant cells. We also identified a tTn substitution site on Syndecan 1, demonstrating that tTn on Syndecan 1 is essential for the interaction with integrin α5β1 as well as for the reaction with mAb MLS128. These data suggest that high expression of the ppGalNAc-T13 gene generates tTn antigen on Syndecan 1 under reduced expression of GM1, leading to enhanced invasion and metastasis via the formation of a molecular complex consisting of integrin α5β1, Syndecan 1, and MMP-9 in the glycolipid-enriched microdomain/rafts.

• Authors: Yasuyuki Matsumoto, Qing Zhang, Kaoru Akita, Hiroshi Nakada, Kazunori Hamamura, Akiko Tsuchida, Tetsuya Okajima, Keiko Furukawa, Takeshi Urano, Koichi Furukawa
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 33 Pg. 24264-76 (Aug 16 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 23814067 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Tumor-Associated, Carbohydrate
• Fibronectins
• Integrin alpha5beta1
• Paxillin
• Syndecan-1
• Tn antigen
• Phosphotyrosine
• N-Acetylgalactosaminyltransferases
• polypeptide N-acetylgalactosaminyltransferase
• Focal Adhesion Protein-Tyrosine Kinases
• Matrix Metalloproteinase 9

Topics

• Animals
• Antigens, Tumor-Associated, Carbohydrate (chemistry, genetics, metabolism)
• Base Sequence
• Carcinoma, Lewis Lung (enzymology, pathology)
• Cell Adhesion (drug effects)
• Fibronectins (pharmacology)
• Focal Adhesion Protein-Tyrosine Kinases (metabolism)
• Gene Knockdown Techniques
• Integrin alpha5beta1 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Membrane Microdomains (drug effects, metabolism)
• Mice
• Models, Biological
• Molecular Sequence Data
• N-Acetylgalactosaminyltransferases (metabolism)
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Paxillin (metabolism)
• Phosphotyrosine (metabolism)
• Protein Multimerization (drug effects)
• Signal Transduction (drug effects)
• Syndecan-1 (metabolism)