scholarly journals The Neurokinin-1 Receptor Is a Target in Pediatric Rhabdoid Tumors

2021 ◽  
Vol 29 (1) ◽  
pp. 94-110
Author(s):  
Julian Kolorz ◽  
Salih Demir ◽  
Adrian Gottschlich ◽  
Iris Beirith ◽  
Matthias Ilmer ◽  
...  
Keyword(s):  
Cancer Genomics ◽  
In Silico Analysis ◽  
Cancer Therapies ◽  
Tissue Samples ◽  
Neurokinin 1 Receptor ◽  
Promising Target ◽  
Apoptotic Effect ◽  
Late Adverse Effects ◽  
Neurokinin 1 ◽  
Rhabdoid Tumors

Rhabdoid tumors (RT) are among the most aggressive tumors in early childhood. Overall survival remains poor, and treatment only effectively occurs at the cost of high toxicity and late adverse effects. It has been reported that the neurokinin-1 receptor/ substance P complex plays an important role in cancer and proved to be a promising target. However, its role in RT has not yet been described. This study aims to determine whether the neurokinin-1 receptor is expressed in RT and whether neurokinin-1 receptor (NK1R) antagonists can serve as a novel therapeutic approach in treating RTs. By in silico analysis using the cBio Cancer Genomics Portal we found that RTs highly express neurokinin-1 receptor. We confirmed these results by RT-PCR in both tumor cell lines and in human tissue samples of various affected organs. We demonstrated a growth inhibitory and apoptotic effect of aprepitant in viability assays and flow cytometry. Furthermore, this effect proved to remain when used in combination with the cytostatic cisplatin. Western blot analysis showed an upregulation of apoptotic signaling pathways in rhabdoid tumors when treated with aprepitant. Overall, our findings suggest that NK1R may be a promising target for the treatment of RT in combination with other anti-cancer therapies and can be targeted with the NK1R antagonist aprepitant.

scholarly journals Computational Analysis of the Neurokinin-1 Receptor Interactions with Antagonists

2021 ◽  
Vol 120 (3) ◽  
pp. 123a
Author(s):  
Marcelo Cardoso dos ◽  
Reis Melo ◽  
Cesar de ◽  
la Fuente-Nunez
Keyword(s):  
Computational Analysis ◽  
Neurokinin 1 Receptor ◽  
Receptor Interactions ◽  
Neurokinin 1

scholarly journals Interaction of glutamine 165 in the fourth transmembrane segment of the human neurokinin-1 receptor with quinuclidine antagonists.

1994 ◽  
Vol 269 (21) ◽  
pp. 14957-14961
Author(s):  
T.M. Fong ◽  
H. Yu ◽  
M.A. Cascieri ◽  
D. Underwood ◽  
C.J. Swain ◽  
...  
Keyword(s):  
Transmembrane Segment ◽  
Neurokinin 1 Receptor ◽  
Neurokinin 1

scholarly journals The glycosyltransferase ST3GAL2 is regulated by miR-615-3p in the intestinal tract of Campylobacter jejuni infected mice

Gut Pathogens ◽  
2021 ◽  
Vol 13 (1) ◽  
Author(s):  
De Xi ◽  
Lukas Hofmann ◽  
Thomas Alter ◽  
Ralf Einspanier ◽  
Stefan Bereswill ◽  
...  
Keyword(s):  
Campylobacter Jejuni ◽  
Regulatory Networks ◽  
In Silico Analysis ◽  
Luciferase Reporter ◽  
Colonic Tissue ◽  
Tissue Samples ◽  
Vitro Model ◽  
Pathway Analyses

Abstract Background Campylobacter jejuni (C. jejuni) infections are of increasing importance worldwide. As a typical mucosal pathogen, the interaction of C. jejuni with mucins is a prominent step in the colonisation of mucosal surfaces. Despite recent advances in understanding the interaction between bacterial pathogens and host mucins, the mechanisms of mucin glycosylation during intestinal C. jejuni infection remain largely unclear. This prompted us to identify relevant regulatory networks that are concerted by miRNAs and could play a role in the mucin modification and interaction. Results We firstly used a human intestinal in vitro model, in which we observed altered transcription of MUC2 and TFF3 upon C. jejuni NCTC 11168 infection. Using a combined approach consisting of in silico analysis together with in vitro expression analysis, we identified the conserved miRNAs miR-125a-5p and miR-615-3p associated with MUC2 and TFF3. Further pathway analyses showed that both miRNAs appear to regulate glycosyltransferases, which are related to the KEGG pathway ‘Mucin type O-glycan biosynthesis’. To validate the proposed interactions, we applied an in vivo approach utilising a well-established secondary abiotic IL-10−/− mouse model for infection with C. jejuni 81-176. In colonic tissue samples, we confirmed infection-dependent aberrant transcription of MUC2 and TFF3. Moreover, two predicted glycosyltransferases, the sialyltransferases ST3GAL1 and ST3GAL2, exhibited inversely correlated transcriptional levels compared to the expression of the identified miRNAs miR-125a-5p and miR-615-3p, respectively. In this study, we mainly focused on the interaction between miR-615-3p and ST3GAL2 and were able to demonstrate their molecular interaction using luciferase reporter assays and RNAi. Detection of ST3GAL2 in murine colonic tissue by immunofluorescence demonstrated reduced intensity after C. jejuni 81-176 infection and was thus consistent with the observations made above. Conclusions We report here for the first time the regulation of glycosyltransferases by miRNAs during murine infection with C. jejuni 81-176. Our data suggest that mucin type O-glycan biosynthesis is concerted by the interplay of miRNAs and glycosyltransferases, which could determine the shape of intestinal glycosylated proteins during infection.

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