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Lymphocyte antigen 6G6D-mediated modulation through p38α MAPK and DNA methylation in colorectal cancer

In addition to being novel biomarkers for poor cancer prognosis, members of Lymphocyte antigen-6 (Ly6) gene family also play a crucial role in avoiding immune responses to tumors. However, it has not been possible to identify the underlying mechanism of how Ly6 gene regulation operates in human canc...

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Autores principales: Caruso, Francesca Pia, D’Andrea, Mario Rosario, Coppola, Luigi, Landriscina, Matteo, Condelli, Valentina, Cerulo, Luigi, Giordano, Guido, Porras, Almudena, Pancione, Massimo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9373545/
https://www.ncbi.nlm.nih.gov/pubmed/35953834
http://dx.doi.org/10.1186/s12935-022-02672-1
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author Caruso, Francesca Pia
D’Andrea, Mario Rosario
Coppola, Luigi
Landriscina, Matteo
Condelli, Valentina
Cerulo, Luigi
Giordano, Guido
Porras, Almudena
Pancione, Massimo
author_facet Caruso, Francesca Pia
D’Andrea, Mario Rosario
Coppola, Luigi
Landriscina, Matteo
Condelli, Valentina
Cerulo, Luigi
Giordano, Guido
Porras, Almudena
Pancione, Massimo
author_sort Caruso, Francesca Pia
collection PubMed
description In addition to being novel biomarkers for poor cancer prognosis, members of Lymphocyte antigen-6 (Ly6) gene family also play a crucial role in avoiding immune responses to tumors. However, it has not been possible to identify the underlying mechanism of how Ly6 gene regulation operates in human cancers. Transcriptome, epigenome and proteomic data from independent cancer databases were analyzed in silico and validated independently in 334 colorectal cancer tissues (CRC). RNA mediated gene silencing of regulatory genes, and treatment with MEK and p38 MAPK inhibitors were also tested in vitro. We report here that the Lymphocyte antigen 6G6D is universally downregulated in mucinous CRC, while its activation progresses through the classical adenoma-carcinoma sequence. The DNA methylation changes in LY6G6D promoter are intimately related to its transcript regulation, epigenomic and histological subtypes. Depletion of DNA methyltransferase 1 (DNMT1), which maintains DNA methylation, results in the derepression of LY6G6D expression. RNA-mediated gene silencing of p38α MAPK or its selective chemical inhibition, however, reduces LY6G6D expression, reducing trametinib’s anti-inflammatory effects. Patients treated with FOLFOX-based first-line therapy experienced decreased survival due to hypermethylation of the LY6G6D promoter and decreased p38α MAPK signaling. We found that cancer-specific immunodominant epitopes are controlled by p38α MAPKs signaling and suppressed by DNA methylation in histological variants with Mucinous differentiation. This work provides a promising prospective for clinical application in diagnosis and personalized therapeutic strategies of colorectal cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-022-02672-1.
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spelling pubmed-93735452022-08-13 Lymphocyte antigen 6G6D-mediated modulation through p38α MAPK and DNA methylation in colorectal cancer Caruso, Francesca Pia D’Andrea, Mario Rosario Coppola, Luigi Landriscina, Matteo Condelli, Valentina Cerulo, Luigi Giordano, Guido Porras, Almudena Pancione, Massimo Cancer Cell Int Research In addition to being novel biomarkers for poor cancer prognosis, members of Lymphocyte antigen-6 (Ly6) gene family also play a crucial role in avoiding immune responses to tumors. However, it has not been possible to identify the underlying mechanism of how Ly6 gene regulation operates in human cancers. Transcriptome, epigenome and proteomic data from independent cancer databases were analyzed in silico and validated independently in 334 colorectal cancer tissues (CRC). RNA mediated gene silencing of regulatory genes, and treatment with MEK and p38 MAPK inhibitors were also tested in vitro. We report here that the Lymphocyte antigen 6G6D is universally downregulated in mucinous CRC, while its activation progresses through the classical adenoma-carcinoma sequence. The DNA methylation changes in LY6G6D promoter are intimately related to its transcript regulation, epigenomic and histological subtypes. Depletion of DNA methyltransferase 1 (DNMT1), which maintains DNA methylation, results in the derepression of LY6G6D expression. RNA-mediated gene silencing of p38α MAPK or its selective chemical inhibition, however, reduces LY6G6D expression, reducing trametinib’s anti-inflammatory effects. Patients treated with FOLFOX-based first-line therapy experienced decreased survival due to hypermethylation of the LY6G6D promoter and decreased p38α MAPK signaling. We found that cancer-specific immunodominant epitopes are controlled by p38α MAPKs signaling and suppressed by DNA methylation in histological variants with Mucinous differentiation. This work provides a promising prospective for clinical application in diagnosis and personalized therapeutic strategies of colorectal cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-022-02672-1. BioMed Central 2022-08-11 /pmc/articles/PMC9373545/ /pubmed/35953834 http://dx.doi.org/10.1186/s12935-022-02672-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Caruso, Francesca Pia
D’Andrea, Mario Rosario
Coppola, Luigi
Landriscina, Matteo
Condelli, Valentina
Cerulo, Luigi
Giordano, Guido
Porras, Almudena
Pancione, Massimo
Lymphocyte antigen 6G6D-mediated modulation through p38α MAPK and DNA methylation in colorectal cancer
title Lymphocyte antigen 6G6D-mediated modulation through p38α MAPK and DNA methylation in colorectal cancer
title_full Lymphocyte antigen 6G6D-mediated modulation through p38α MAPK and DNA methylation in colorectal cancer
title_fullStr Lymphocyte antigen 6G6D-mediated modulation through p38α MAPK and DNA methylation in colorectal cancer
title_full_unstemmed Lymphocyte antigen 6G6D-mediated modulation through p38α MAPK and DNA methylation in colorectal cancer
title_short Lymphocyte antigen 6G6D-mediated modulation through p38α MAPK and DNA methylation in colorectal cancer
title_sort lymphocyte antigen 6g6d-mediated modulation through p38α mapk and dna methylation in colorectal cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9373545/
https://www.ncbi.nlm.nih.gov/pubmed/35953834
http://dx.doi.org/10.1186/s12935-022-02672-1
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