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The human ion channel TRPM2 modulates migration and invasion in neuroblastoma through regulation of integrin expression

Transient receptor potential channel TRPM2 is highly expressed in many cancers and involved in regulation of key physiological processes including mitochondrial function, bioenergetics, and oxidative stress. In Stage 4 non-MYCN amplified neuroblastoma patients, high TRPM2 expression is associated wi...

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Autores principales: Bao, Lei, Festa, Fernanda, Hirschler-Laszkiewicz, Iwona, Keefer, Kerry, Wang, Hong-Gang, Cheung, Joseph Y., Miller, Barbara A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9709080/
https://www.ncbi.nlm.nih.gov/pubmed/36446940
http://dx.doi.org/10.1038/s41598-022-25138-w
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author Bao, Lei
Festa, Fernanda
Hirschler-Laszkiewicz, Iwona
Keefer, Kerry
Wang, Hong-Gang
Cheung, Joseph Y.
Miller, Barbara A.
author_facet Bao, Lei
Festa, Fernanda
Hirschler-Laszkiewicz, Iwona
Keefer, Kerry
Wang, Hong-Gang
Cheung, Joseph Y.
Miller, Barbara A.
author_sort Bao, Lei
collection PubMed
description Transient receptor potential channel TRPM2 is highly expressed in many cancers and involved in regulation of key physiological processes including mitochondrial function, bioenergetics, and oxidative stress. In Stage 4 non-MYCN amplified neuroblastoma patients, high TRPM2 expression is associated with worse outcome. Here, neuroblastoma cells with high TRPM2 expression demonstrated increased migration and invasion capability. RNA sequencing, RT-qPCR, and Western blotting demonstrated that the mechanism involved significantly greater expression of integrins α1, αv, β1, and β5 in cells with high TRPM2 expression. Transcription factors HIF-1α, E2F1, and FOXM1, which bind promoter/enhancer regions of these integrins, were increased in cells with high TRPM2 expression. Subcellular fractionation confirmed high levels of α1, αv, and β1 membrane localization and co-immunoprecipitation confirmed the presence of α1β1, αvβ1, and αvβ5 complexes. Inhibitors of α1β1, αvβ1, and αvβ5 complexes significantly reduced migration and invasion in cells highly expressing TRPM2, confirming their functional role. Increased pAkt(Ser473) and pERK(Thr202/Tyr204), which promote migration through mechanisms including integrin activation, were found in cells highly expressing TRPM2. TRPM2 promotes migration and invasion in neuroblastoma cells with high TRPM2 expression through modulation of integrins together with enhancing cell survival, negatively affecting patient outcome and providing rationale for TRPM2 inhibition in anti-neoplastic therapy.
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spelling pubmed-97090802022-12-01 The human ion channel TRPM2 modulates migration and invasion in neuroblastoma through regulation of integrin expression Bao, Lei Festa, Fernanda Hirschler-Laszkiewicz, Iwona Keefer, Kerry Wang, Hong-Gang Cheung, Joseph Y. Miller, Barbara A. Sci Rep Article Transient receptor potential channel TRPM2 is highly expressed in many cancers and involved in regulation of key physiological processes including mitochondrial function, bioenergetics, and oxidative stress. In Stage 4 non-MYCN amplified neuroblastoma patients, high TRPM2 expression is associated with worse outcome. Here, neuroblastoma cells with high TRPM2 expression demonstrated increased migration and invasion capability. RNA sequencing, RT-qPCR, and Western blotting demonstrated that the mechanism involved significantly greater expression of integrins α1, αv, β1, and β5 in cells with high TRPM2 expression. Transcription factors HIF-1α, E2F1, and FOXM1, which bind promoter/enhancer regions of these integrins, were increased in cells with high TRPM2 expression. Subcellular fractionation confirmed high levels of α1, αv, and β1 membrane localization and co-immunoprecipitation confirmed the presence of α1β1, αvβ1, and αvβ5 complexes. Inhibitors of α1β1, αvβ1, and αvβ5 complexes significantly reduced migration and invasion in cells highly expressing TRPM2, confirming their functional role. Increased pAkt(Ser473) and pERK(Thr202/Tyr204), which promote migration through mechanisms including integrin activation, were found in cells highly expressing TRPM2. TRPM2 promotes migration and invasion in neuroblastoma cells with high TRPM2 expression through modulation of integrins together with enhancing cell survival, negatively affecting patient outcome and providing rationale for TRPM2 inhibition in anti-neoplastic therapy. Nature Publishing Group UK 2022-11-29 /pmc/articles/PMC9709080/ /pubmed/36446940 http://dx.doi.org/10.1038/s41598-022-25138-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Bao, Lei
Festa, Fernanda
Hirschler-Laszkiewicz, Iwona
Keefer, Kerry
Wang, Hong-Gang
Cheung, Joseph Y.
Miller, Barbara A.
The human ion channel TRPM2 modulates migration and invasion in neuroblastoma through regulation of integrin expression
title The human ion channel TRPM2 modulates migration and invasion in neuroblastoma through regulation of integrin expression
title_full The human ion channel TRPM2 modulates migration and invasion in neuroblastoma through regulation of integrin expression
title_fullStr The human ion channel TRPM2 modulates migration and invasion in neuroblastoma through regulation of integrin expression
title_full_unstemmed The human ion channel TRPM2 modulates migration and invasion in neuroblastoma through regulation of integrin expression
title_short The human ion channel TRPM2 modulates migration and invasion in neuroblastoma through regulation of integrin expression
title_sort human ion channel trpm2 modulates migration and invasion in neuroblastoma through regulation of integrin expression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9709080/
https://www.ncbi.nlm.nih.gov/pubmed/36446940
http://dx.doi.org/10.1038/s41598-022-25138-w
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