Molecular mechanism underlying the increased risk of colorectal cancer metastasis caused by single nucleotide polymorphisms in LI-cadherin gene
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...
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Nature Portfolio
2023-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-32444-4 |
| _version_ | 1797841091448274944 |
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| author | Anna Yui Daisuke Kuroda Takahiro Maruno Makoto Nakakido Satoru Nagatoishi Susumu Uchiyama Kouhei Tsumoto |
| author_facet | Anna Yui Daisuke Kuroda Takahiro Maruno Makoto Nakakido Satoru Nagatoishi Susumu Uchiyama Kouhei Tsumoto |
| author_sort | Anna Yui |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T16:25:25Z |
| format | Article |
| id | doaj.art-9d45ec937d9c402697d5ac00b689738e |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-09T16:25:25Z |
| publishDate | 2023-04-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj.art-9d45ec937d9c402697d5ac00b689738e2023-04-23T11:15:18ZengNature PortfolioScientific Reports2045-23222023-04-0113111110.1038/s41598-023-32444-4Molecular mechanism underlying the increased risk of colorectal cancer metastasis caused by single nucleotide polymorphisms in LI-cadherin geneAnna Yui0Daisuke Kuroda1Takahiro Maruno2Makoto Nakakido3Satoru Nagatoishi4Susumu Uchiyama5Kouhei Tsumoto6Department of Bioengineering, School of Engineering, The University of TokyoMedical Device Development and Regulation Research Center, School of Engineering, The University of TokyoDepartment of Biotechnology, Graduate School of Engineering, Osaka UniversityDepartment of Bioengineering, School of Engineering, The University of TokyoInstitute of Medical Science, The University of TokyoDepartment of Biotechnology, Graduate School of Engineering, Osaka UniversityDepartment of Bioengineering, School of Engineering, The University of TokyoAbstract 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.https://doi.org/10.1038/s41598-023-32444-4 |
| spellingShingle | Anna Yui Daisuke Kuroda Takahiro Maruno Makoto Nakakido Satoru Nagatoishi Susumu Uchiyama Kouhei Tsumoto Molecular mechanism underlying the increased risk of colorectal cancer metastasis caused by single nucleotide polymorphisms in LI-cadherin gene Scientific Reports |
| title | Molecular mechanism underlying the increased risk of colorectal cancer metastasis caused by single nucleotide polymorphisms in LI-cadherin gene |
| title_full | Molecular mechanism underlying the increased risk of colorectal cancer metastasis caused by single nucleotide polymorphisms in LI-cadherin gene |
| title_fullStr | Molecular mechanism underlying the increased risk of colorectal cancer metastasis caused by single nucleotide polymorphisms in LI-cadherin gene |
| title_full_unstemmed | Molecular mechanism underlying the increased risk of colorectal cancer metastasis caused by single nucleotide polymorphisms in LI-cadherin gene |
| title_short | Molecular mechanism underlying the increased risk of colorectal cancer metastasis caused by single nucleotide polymorphisms in LI-cadherin gene |
| title_sort | molecular mechanism underlying the increased risk of colorectal cancer metastasis caused by single nucleotide polymorphisms in li cadherin gene |
| url | https://doi.org/10.1038/s41598-023-32444-4 |
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