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Updated: Oct 4, 2025
Modeling Oral-Esophageal Squamous Cell Carcinoma in 3D Organoids
Published on: December 23, 2022
The Notch1 gene may control cell chemoresistance in esophageal squamous cell cancer
Kun Gao1, Wenqun Xing1, Xianben Liu1
1Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
Background:
In our previous study, missense mutations in the Notch1 gene were found in chemotherapy-resistant esophageal squamous cell cancer (ESCC) patients. In this study, we explored changes in the interaction between Notch1 and DLL4 resulting from missense mutations.
Methods:
Bioinformatics analysis was performed to assess and compare the different biological structures and functions of wild type (WT) and mutation type (MT) sequences of Notch1. A genetic information search was performed, and the results were analyzed using in silico modeling. Homology modeling of the Notch1 protein was carried out using Swiss-Model software, and modeling of site-directed mutations was carried out using PyMOL software to observe the protein structure. The Notch1-DLL4 ligand-receptor complex protein model was constructed, Wincoot software was used to determine site-directed mutations, and a protein-ligand interaction profiler (PLIP) was used to calculate the noncovalent interactions in the complex.
Results:
The mutation site was located in the region where Notch1 binds to DLL4. A careful examination of the in silico structural model revealed that the mutation caused an alteration in the surface charge, and the water-bridge bonds of the interaction between Notch1-DLL4 increased in number from 5 to 7.
Conclusions:
Notch1 gene missense mutation leads to an increase in the number of water-bridge bonds, thus enhancing the Notch1-DLL4 interaction, which may lead to tighter Notch1-DLL4 binding, either making the pathway easier to activate or increasing the length of time it is active.
Insights
Missense mutations in the Notch1 gene enhance Notch1-DLL4 interactions by increasing water-bridge bonds. This may increase pathway activation in chemotherapy-resistant esophageal squamous cell cancer (ESCC).
Area of Science:
- Molecular biology
- Cancer research
- Bioinformatics
Background:
- Previous studies identified missense mutations in the Notch1 gene in chemotherapy-resistant esophageal squamous cell cancer (ESCC).
- This study investigates how these missense mutations alter the interaction between Notch1 and its ligand DLL4.
Purpose of the Study:
- To explore the structural and functional consequences of Notch1 missense mutations on Notch1-DLL4 interactions.
- To understand the potential impact of these altered interactions on pathway activation in ESCC.
Main Methods:
- Utilized bioinformatics and in silico modeling, including homology modeling (Swiss-Model) and site-directed mutation analysis (PyMOL).
- Constructed Notch1-DLL4 ligand-receptor complex models and analyzed noncovalent interactions using PLIP.
- Assessed structural and functional changes between wild-type (WT) and mutation-type (MT) Notch1 sequences.
Main Results:
- The mutation site was identified within the Notch1-DLL4 binding region.
- In silico modeling revealed that mutations alter surface charge and increase water-bridge bonds between Notch1 and DLL4 from 5 to 7.
- These changes suggest an enhanced interaction between Notch1 and DLL4.
Conclusions:
- Notch1 missense mutations increase water-bridge bonds, strengthening the Notch1-DLL4 interaction.
- Enhanced binding may lead to increased or prolonged activation of the Notch signaling pathway.
- This mechanism could contribute to chemotherapy resistance in ESCC.
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