Cargando…

High DKK3 expression related to immunosuppression was associated with poor prognosis in glioblastoma: machine learning approach

BACKGROUND: Glioblastoma multiforme (GBM) is an aggressive malignant primary brain tumor. Wnt/β-catenin is known to be related to GBM stemness. Cancer stem cells induce immunosuppressive and treatment resistance in GBM. We hypothesized that Wnt/β-catenin-related genes with immunosuppression could be...

Descripción completa

Detalles Bibliográficos
Autores principales: Han, Myung-Hoon, Min, Kyueng-Whan, Noh, Yung-Kyun, Kim, Jae Min, Cheong, Jin Hwan, Ryu, Je Il, Won, Yu Deok, Koh, Seong-Ho, Myung, Jae Kyung, Park, Ji Young, Kwon, Mi Jung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9588473/
https://www.ncbi.nlm.nih.gov/pubmed/35599254
http://dx.doi.org/10.1007/s00262-022-03222-4
_version_ 1784814136904908800
author Han, Myung-Hoon
Min, Kyueng-Whan
Noh, Yung-Kyun
Kim, Jae Min
Cheong, Jin Hwan
Ryu, Je Il
Won, Yu Deok
Koh, Seong-Ho
Myung, Jae Kyung
Park, Ji Young
Kwon, Mi Jung
author_facet Han, Myung-Hoon
Min, Kyueng-Whan
Noh, Yung-Kyun
Kim, Jae Min
Cheong, Jin Hwan
Ryu, Je Il
Won, Yu Deok
Koh, Seong-Ho
Myung, Jae Kyung
Park, Ji Young
Kwon, Mi Jung
author_sort Han, Myung-Hoon
collection PubMed
description BACKGROUND: Glioblastoma multiforme (GBM) is an aggressive malignant primary brain tumor. Wnt/β-catenin is known to be related to GBM stemness. Cancer stem cells induce immunosuppressive and treatment resistance in GBM. We hypothesized that Wnt/β-catenin-related genes with immunosuppression could be related to the prognosis in patients with GBM. METHODS: We obtained the clinicopathological data of 525 patients with GBM from the brain cancer gene database. The fraction of tumor-infiltrating immune cells was evaluated using in silico flow cytometry. Among gene sets of Wnt/β-catenin pathway, Dickkopf-3 (DKK3) gene related to the immunosuppressive response was found using machine learning. We performed gene set enrichment analysis (GSEA), network-based analysis, survival analysis and in vitro drug screening assays based on Dickkopf-3 (DKK3) expression. RESULTS: In analyses of 31 genes related to Wnt/β-catenin signaling, high DKK3 expression was negatively correlated with increased antitumoral immunity, especially CD8 + and CD4 + T cells, in patients with GBM. High DKK3 expression was correlated with poor survival and disease progression in patients with GBM. In pathway-based network analysis, DKK3 was directly linked to the THY1 gene, a tumor suppressor gene. Through in vitro drug screening, we identified navitoclax as an agent with potent activity against GBM cell lines with high DKK3 expression. CONCLUSIONS: These results suggest that high DKK3 expression could be a therapeutic target in GBM. The results of the present study could contribute to the design of future experimental research and drug development programs for GBM. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00262-022-03222-4.
format Online
Article
Text
id pubmed-9588473
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Springer Berlin Heidelberg
record_format MEDLINE/PubMed
spelling pubmed-95884732022-10-25 High DKK3 expression related to immunosuppression was associated with poor prognosis in glioblastoma: machine learning approach Han, Myung-Hoon Min, Kyueng-Whan Noh, Yung-Kyun Kim, Jae Min Cheong, Jin Hwan Ryu, Je Il Won, Yu Deok Koh, Seong-Ho Myung, Jae Kyung Park, Ji Young Kwon, Mi Jung Cancer Immunol Immunother Original Article BACKGROUND: Glioblastoma multiforme (GBM) is an aggressive malignant primary brain tumor. Wnt/β-catenin is known to be related to GBM stemness. Cancer stem cells induce immunosuppressive and treatment resistance in GBM. We hypothesized that Wnt/β-catenin-related genes with immunosuppression could be related to the prognosis in patients with GBM. METHODS: We obtained the clinicopathological data of 525 patients with GBM from the brain cancer gene database. The fraction of tumor-infiltrating immune cells was evaluated using in silico flow cytometry. Among gene sets of Wnt/β-catenin pathway, Dickkopf-3 (DKK3) gene related to the immunosuppressive response was found using machine learning. We performed gene set enrichment analysis (GSEA), network-based analysis, survival analysis and in vitro drug screening assays based on Dickkopf-3 (DKK3) expression. RESULTS: In analyses of 31 genes related to Wnt/β-catenin signaling, high DKK3 expression was negatively correlated with increased antitumoral immunity, especially CD8 + and CD4 + T cells, in patients with GBM. High DKK3 expression was correlated with poor survival and disease progression in patients with GBM. In pathway-based network analysis, DKK3 was directly linked to the THY1 gene, a tumor suppressor gene. Through in vitro drug screening, we identified navitoclax as an agent with potent activity against GBM cell lines with high DKK3 expression. CONCLUSIONS: These results suggest that high DKK3 expression could be a therapeutic target in GBM. The results of the present study could contribute to the design of future experimental research and drug development programs for GBM. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00262-022-03222-4. Springer Berlin Heidelberg 2022-05-23 2022 /pmc/articles/PMC9588473/ /pubmed/35599254 http://dx.doi.org/10.1007/s00262-022-03222-4 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/) .
spellingShingle Original Article
Han, Myung-Hoon
Min, Kyueng-Whan
Noh, Yung-Kyun
Kim, Jae Min
Cheong, Jin Hwan
Ryu, Je Il
Won, Yu Deok
Koh, Seong-Ho
Myung, Jae Kyung
Park, Ji Young
Kwon, Mi Jung
High DKK3 expression related to immunosuppression was associated with poor prognosis in glioblastoma: machine learning approach
title High DKK3 expression related to immunosuppression was associated with poor prognosis in glioblastoma: machine learning approach
title_full High DKK3 expression related to immunosuppression was associated with poor prognosis in glioblastoma: machine learning approach
title_fullStr High DKK3 expression related to immunosuppression was associated with poor prognosis in glioblastoma: machine learning approach
title_full_unstemmed High DKK3 expression related to immunosuppression was associated with poor prognosis in glioblastoma: machine learning approach
title_short High DKK3 expression related to immunosuppression was associated with poor prognosis in glioblastoma: machine learning approach
title_sort high dkk3 expression related to immunosuppression was associated with poor prognosis in glioblastoma: machine learning approach
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9588473/
https://www.ncbi.nlm.nih.gov/pubmed/35599254
http://dx.doi.org/10.1007/s00262-022-03222-4
work_keys_str_mv AT hanmyunghoon highdkk3expressionrelatedtoimmunosuppressionwasassociatedwithpoorprognosisinglioblastomamachinelearningapproach
AT minkyuengwhan highdkk3expressionrelatedtoimmunosuppressionwasassociatedwithpoorprognosisinglioblastomamachinelearningapproach
AT nohyungkyun highdkk3expressionrelatedtoimmunosuppressionwasassociatedwithpoorprognosisinglioblastomamachinelearningapproach
AT kimjaemin highdkk3expressionrelatedtoimmunosuppressionwasassociatedwithpoorprognosisinglioblastomamachinelearningapproach
AT cheongjinhwan highdkk3expressionrelatedtoimmunosuppressionwasassociatedwithpoorprognosisinglioblastomamachinelearningapproach
AT ryujeil highdkk3expressionrelatedtoimmunosuppressionwasassociatedwithpoorprognosisinglioblastomamachinelearningapproach
AT wonyudeok highdkk3expressionrelatedtoimmunosuppressionwasassociatedwithpoorprognosisinglioblastomamachinelearningapproach
AT kohseongho highdkk3expressionrelatedtoimmunosuppressionwasassociatedwithpoorprognosisinglioblastomamachinelearningapproach
AT myungjaekyung highdkk3expressionrelatedtoimmunosuppressionwasassociatedwithpoorprognosisinglioblastomamachinelearningapproach
AT parkjiyoung highdkk3expressionrelatedtoimmunosuppressionwasassociatedwithpoorprognosisinglioblastomamachinelearningapproach
AT kwonmijung highdkk3expressionrelatedtoimmunosuppressionwasassociatedwithpoorprognosisinglioblastomamachinelearningapproach