The Notch1 gene may control cell chemoresistance in esophageal squamous cell cancer

Abstract

Background: In our previous study, missense mutations in the Notch1 gene were found in chemotherapyresistant 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.

Notch signaling pathway in cancer: from mechanistic insights to targeted therapies

“… 85 The missense mutation site in the Notch1 gene was found to be located in the region where Notch1 binds to DLL4, enhancing the Notch1-DLL4 interaction. 86 This may lead to resistance to neoadjuvant chemotherapy in patients with ESCC by promoting the activation of the Notch1 signaling pathway. Additionally, both mRNA and protein levels of Notch2 were significantly increased in ESCC tissues, serving as an independent predictor of poor OS and PFS.…”