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PSEN1 is associated with colon cancer development via potential influences on PD-L1 nuclear translocation and tumor-immune interactions

Presenilin 1 (PSEN1), as a catalytical core of the γ-secretase complex, plays multiple actions through mediating transmembrane domain shedding of the substrates. Unlike extensive studies performed on investigating the functions of γ-secretase substrates or the effects of γ-secretase inhibitors, our...

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Autores principales: Wei, Wangzhi, Zhang, Yu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9428321/
https://www.ncbi.nlm.nih.gov/pubmed/36059511
http://dx.doi.org/10.3389/fimmu.2022.927474
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author Wei, Wangzhi
Zhang, Yu
author_facet Wei, Wangzhi
Zhang, Yu
author_sort Wei, Wangzhi
collection PubMed
description Presenilin 1 (PSEN1), as a catalytical core of the γ-secretase complex, plays multiple actions through mediating transmembrane domain shedding of the substrates. Unlike extensive studies performed on investigating the functions of γ-secretase substrates or the effects of γ-secretase inhibitors, our findings uncover a potential action of PSEN1 on PD-L1 alternative truncation and nuclear translocation, broadening our understanding on how the γ-secretase contributes to colon cancer development as well as suggesting a potential strategy to improve the efficacy of PD-1/PD-L1 blockade. Immunohistochemical data showed loss of PD-L1 protein expression in all the primary colon adenocarcioma (COAD) cases in the HPA collection, while PSEN1 was scored to be highly expressed, indicating their converse expression patterns (p<0.001). Meanwhile a strongly positive gene correlation was explored by TIMER2 and GEPIA (p<0.001). Up-regulated PSEN1 expression in COAD might facilitate liberating a C-terminal PD-L1 truncation via proteolytic processing. Then following an established regulatory pathway of PD-L1 nuclear translocation, we found that PSEN1 showed significant correlations with multiple components in HDAC2-mediated deacetylation, clathrin-dependent endocytosis, vimentin-associated nucleocytoplasmic shuttling and importin family-mediated nuclear import. Moreover, connections of PSEN1 to the immune response genes transactivated by nuclear PD-L1 were tested. Additionally, contributions of PSEN1 to the tumor invasiveness (p<0.05) and the tumor infiltrating cell enrichments (p<0.001) were investigated by cBioportal and the ESTIMATE algorithm. Levels of PSEN1 were negatively correlated with infiltrating CD8+ T (p<0.05) and CD4+ T helper (Th) 1 cells (p<0.001), while positively correlated with regulatory T cells (Tregs) (p<0.001) and cancer associated fibroblasts (CAFs) (p<0.001). It also displayed significant associations with diverse immune metagenes characteristic of T cell exhaustion, Tregs and CAFs, indicating possible actions in immune escape. Despite still a preliminary stage of this study, we anticipate to deciphering a novel function of PSEN1, and supporting more researchers toward the elucidations of the mechanisms linking the γ-secretase to cancers, which has yet to be fully addressed.
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spelling pubmed-94283212022-09-01 PSEN1 is associated with colon cancer development via potential influences on PD-L1 nuclear translocation and tumor-immune interactions Wei, Wangzhi Zhang, Yu Front Immunol Immunology Presenilin 1 (PSEN1), as a catalytical core of the γ-secretase complex, plays multiple actions through mediating transmembrane domain shedding of the substrates. Unlike extensive studies performed on investigating the functions of γ-secretase substrates or the effects of γ-secretase inhibitors, our findings uncover a potential action of PSEN1 on PD-L1 alternative truncation and nuclear translocation, broadening our understanding on how the γ-secretase contributes to colon cancer development as well as suggesting a potential strategy to improve the efficacy of PD-1/PD-L1 blockade. Immunohistochemical data showed loss of PD-L1 protein expression in all the primary colon adenocarcioma (COAD) cases in the HPA collection, while PSEN1 was scored to be highly expressed, indicating their converse expression patterns (p<0.001). Meanwhile a strongly positive gene correlation was explored by TIMER2 and GEPIA (p<0.001). Up-regulated PSEN1 expression in COAD might facilitate liberating a C-terminal PD-L1 truncation via proteolytic processing. Then following an established regulatory pathway of PD-L1 nuclear translocation, we found that PSEN1 showed significant correlations with multiple components in HDAC2-mediated deacetylation, clathrin-dependent endocytosis, vimentin-associated nucleocytoplasmic shuttling and importin family-mediated nuclear import. Moreover, connections of PSEN1 to the immune response genes transactivated by nuclear PD-L1 were tested. Additionally, contributions of PSEN1 to the tumor invasiveness (p<0.05) and the tumor infiltrating cell enrichments (p<0.001) were investigated by cBioportal and the ESTIMATE algorithm. Levels of PSEN1 were negatively correlated with infiltrating CD8+ T (p<0.05) and CD4+ T helper (Th) 1 cells (p<0.001), while positively correlated with regulatory T cells (Tregs) (p<0.001) and cancer associated fibroblasts (CAFs) (p<0.001). It also displayed significant associations with diverse immune metagenes characteristic of T cell exhaustion, Tregs and CAFs, indicating possible actions in immune escape. Despite still a preliminary stage of this study, we anticipate to deciphering a novel function of PSEN1, and supporting more researchers toward the elucidations of the mechanisms linking the γ-secretase to cancers, which has yet to be fully addressed. Frontiers Media S.A. 2022-08-17 /pmc/articles/PMC9428321/ /pubmed/36059511 http://dx.doi.org/10.3389/fimmu.2022.927474 Text en Copyright © 2022 Wei and Zhang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Wei, Wangzhi
Zhang, Yu
PSEN1 is associated with colon cancer development via potential influences on PD-L1 nuclear translocation and tumor-immune interactions
title PSEN1 is associated with colon cancer development via potential influences on PD-L1 nuclear translocation and tumor-immune interactions
title_full PSEN1 is associated with colon cancer development via potential influences on PD-L1 nuclear translocation and tumor-immune interactions
title_fullStr PSEN1 is associated with colon cancer development via potential influences on PD-L1 nuclear translocation and tumor-immune interactions
title_full_unstemmed PSEN1 is associated with colon cancer development via potential influences on PD-L1 nuclear translocation and tumor-immune interactions
title_short PSEN1 is associated with colon cancer development via potential influences on PD-L1 nuclear translocation and tumor-immune interactions
title_sort psen1 is associated with colon cancer development via potential influences on pd-l1 nuclear translocation and tumor-immune interactions
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9428321/
https://www.ncbi.nlm.nih.gov/pubmed/36059511
http://dx.doi.org/10.3389/fimmu.2022.927474
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