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Abstract
LI-cadherin is a member of the cadherin superfamily. LI-cadherin mediates Ca2+-dependent cell–cell adhesion through homodimerization. A previous study reported two single nucleotide polymorphisms (SNPs) in the LI-cadherin-coding gene (CDH17). These SNPs correspond to the amino acid changes of Lys115 to Glu and Glu739 to Ala. Patients with colorectal cancer carrying these SNPs are reported to have a higher risk of lymph node metastasis than patients without the SNPs. Although proteins associated with metastasis have been identified, the molecular mechanisms underlying the functions of these proteins remain unclear, making it difficult to develop effective strategies to prevent metastasis. In this study, we employed biochemical assays and molecular dynamics (MD) simulations to elucidate the molecular mechanisms by which the amino acid changes caused by the SNPs in the LI-cadherin-coding gene increase the risk of metastasis. Cell aggregation assays showed that the amino acid changes weakened the LI-cadherin-dependent cell–cell adhesion. In vitro assays demonstrated a decrease in homodimerization tendency and MD simulations suggested an alteration in the intramolecular hydrogen bond network by the mutation of Lys115. Taken together, our results indicate that the increased risk of lymph node metastasis is due to weakened cell–cell adhesion caused by the decrease in homodimerization tendency.
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1 The University of Tokyo, Department of Bioengineering, School of Engineering, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X)
2 The University of Tokyo, Medical Device Development and Regulation Research Center, School of Engineering, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X); National Institute of Infectious Diseases, Research Center for Drug and Vaccine Development, Tokyo, Japan (GRID:grid.410795.e) (ISNI:0000 0001 2220 1880)
3 Osaka University, Department of Biotechnology, Graduate School of Engineering, Osaka, Japan (GRID:grid.136593.b) (ISNI:0000 0004 0373 3971); U-Medico Inc., Osaka, Japan (GRID:grid.136593.b)
4 The University of Tokyo, Institute of Medical Science, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X)
5 Osaka University, Department of Biotechnology, Graduate School of Engineering, Osaka, Japan (GRID:grid.136593.b) (ISNI:0000 0004 0373 3971)
6 The University of Tokyo, Department of Bioengineering, School of Engineering, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X); The University of Tokyo, Institute of Medical Science, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X); The University of Tokyo, Department of Chemistry and Biotechnology, School of Engineering, Tokyo, Japan (GRID:grid.26999.3d) (ISNI:0000 0001 2151 536X)