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Identification of Differentially Expressed Genes in Different Glioblastoma Regions and Their Association with Cancer Stem Cell Development and Temozolomide Response

The molecular heterogeneity of gene expression profiles of glioblastoma multiforme (GBM) are the most important prognostic factors for tumor recurrence and drug resistance. Thus, the aim of this study was to identify potential target genes related to temozolomide (TMZ) resistance and GBM recurrence....

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Autores principales: Hsu, Justin Bo-Kai, Lee, Tzong-Yi, Cheng, Sho-Jen, Lee, Gilbert Aaron, Chen, Yung-Chieh, Le, Nguyen Quoc Khanh, Huang, Shiu-Wen, Kuo, Duen-Pang, Li, Yi-Tien, Chang, Tzu-Hao, Chen, Cheng-Yu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625522/
https://www.ncbi.nlm.nih.gov/pubmed/34834399
http://dx.doi.org/10.3390/jpm11111047
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author Hsu, Justin Bo-Kai
Lee, Tzong-Yi
Cheng, Sho-Jen
Lee, Gilbert Aaron
Chen, Yung-Chieh
Le, Nguyen Quoc Khanh
Huang, Shiu-Wen
Kuo, Duen-Pang
Li, Yi-Tien
Chang, Tzu-Hao
Chen, Cheng-Yu
author_facet Hsu, Justin Bo-Kai
Lee, Tzong-Yi
Cheng, Sho-Jen
Lee, Gilbert Aaron
Chen, Yung-Chieh
Le, Nguyen Quoc Khanh
Huang, Shiu-Wen
Kuo, Duen-Pang
Li, Yi-Tien
Chang, Tzu-Hao
Chen, Cheng-Yu
author_sort Hsu, Justin Bo-Kai
collection PubMed
description The molecular heterogeneity of gene expression profiles of glioblastoma multiforme (GBM) are the most important prognostic factors for tumor recurrence and drug resistance. Thus, the aim of this study was to identify potential target genes related to temozolomide (TMZ) resistance and GBM recurrence. The genomic data of patients with GBM from The Cancer Genome Atlas (TCGA; 154 primary and 13 recurrent tumors) and a local cohort (29 primary and 4 recurrent tumors), samples from different tumor regions from a local cohort (29 tumor and 25 peritumoral regions), and Gene Expression Omnibus data (GSE84465, single-cell RNA sequencing; 3589 cells) were included in this study. Critical gene signatures were identified based an analysis of differentially expressed genes (DEGs). DEGs were further used to evaluate gene enrichment levels among primary and recurrent GBMs and different tumor regions through gene set enrichment analysis. Protein–protein interactions (PPIs) were incorporated into gene regulatory networks to identify the affected metabolic pathways. The enrichment levels of 135 genes were identified in the peritumoral regions as being risk signatures for tumor recurrence. Fourteen genes (DVL1, PRKACB, ARRB1, APC, MAPK9, CAMK2A, PRKCB, CACNA1A, ERBB4, RASGRF1, NF1, RPS6KA2, MAPK8IP2, and PPM1A) derived from the PPI network of 135 genes were upregulated and involved in the regulation of cancer stem cell (CSC) development and relevant signaling pathways (Notch, Hedgehog, Wnt, and MAPK). The single-cell data analysis results indicated that 14 key genes were mainly expressed in oligodendrocyte progenitor cells, which could produce a CSC niche in the peritumoral region. The enrichment levels of 336 genes were identified as biomarkers for evaluating TMZ resistance in the solid tumor region. Eleven genes (ARID5A, CDC42EP3, CDKN1A, FLT3, JUNB, MAP2K3, MYBPC2, RGS14, RNASEK, TBC1D30, and TXNDC11) derived from the PPI network of 336 genes were upregulated and may be associated with a high risk of TMZ resistance; these genes were identified in both the TCGA and local cohorts. Furthermore, the expression patterns of ARID5A, CDKN1A, and MAP2K3 were identical to the gene signatures of TMZ-resistant cell lines. The identified enrichment levels of the two gene sets expressed in tumor and peritumoral regions are potentially helpful for evaluating TMZ resistance in GBM. Moreover, these key genes could be used as biomarkers, potentially providing new molecular strategies for GBM treatment.
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spelling pubmed-86255222021-11-27 Identification of Differentially Expressed Genes in Different Glioblastoma Regions and Their Association with Cancer Stem Cell Development and Temozolomide Response Hsu, Justin Bo-Kai Lee, Tzong-Yi Cheng, Sho-Jen Lee, Gilbert Aaron Chen, Yung-Chieh Le, Nguyen Quoc Khanh Huang, Shiu-Wen Kuo, Duen-Pang Li, Yi-Tien Chang, Tzu-Hao Chen, Cheng-Yu J Pers Med Article The molecular heterogeneity of gene expression profiles of glioblastoma multiforme (GBM) are the most important prognostic factors for tumor recurrence and drug resistance. Thus, the aim of this study was to identify potential target genes related to temozolomide (TMZ) resistance and GBM recurrence. The genomic data of patients with GBM from The Cancer Genome Atlas (TCGA; 154 primary and 13 recurrent tumors) and a local cohort (29 primary and 4 recurrent tumors), samples from different tumor regions from a local cohort (29 tumor and 25 peritumoral regions), and Gene Expression Omnibus data (GSE84465, single-cell RNA sequencing; 3589 cells) were included in this study. Critical gene signatures were identified based an analysis of differentially expressed genes (DEGs). DEGs were further used to evaluate gene enrichment levels among primary and recurrent GBMs and different tumor regions through gene set enrichment analysis. Protein–protein interactions (PPIs) were incorporated into gene regulatory networks to identify the affected metabolic pathways. The enrichment levels of 135 genes were identified in the peritumoral regions as being risk signatures for tumor recurrence. Fourteen genes (DVL1, PRKACB, ARRB1, APC, MAPK9, CAMK2A, PRKCB, CACNA1A, ERBB4, RASGRF1, NF1, RPS6KA2, MAPK8IP2, and PPM1A) derived from the PPI network of 135 genes were upregulated and involved in the regulation of cancer stem cell (CSC) development and relevant signaling pathways (Notch, Hedgehog, Wnt, and MAPK). The single-cell data analysis results indicated that 14 key genes were mainly expressed in oligodendrocyte progenitor cells, which could produce a CSC niche in the peritumoral region. The enrichment levels of 336 genes were identified as biomarkers for evaluating TMZ resistance in the solid tumor region. Eleven genes (ARID5A, CDC42EP3, CDKN1A, FLT3, JUNB, MAP2K3, MYBPC2, RGS14, RNASEK, TBC1D30, and TXNDC11) derived from the PPI network of 336 genes were upregulated and may be associated with a high risk of TMZ resistance; these genes were identified in both the TCGA and local cohorts. Furthermore, the expression patterns of ARID5A, CDKN1A, and MAP2K3 were identical to the gene signatures of TMZ-resistant cell lines. The identified enrichment levels of the two gene sets expressed in tumor and peritumoral regions are potentially helpful for evaluating TMZ resistance in GBM. Moreover, these key genes could be used as biomarkers, potentially providing new molecular strategies for GBM treatment. MDPI 2021-10-20 /pmc/articles/PMC8625522/ /pubmed/34834399 http://dx.doi.org/10.3390/jpm11111047 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hsu, Justin Bo-Kai
Lee, Tzong-Yi
Cheng, Sho-Jen
Lee, Gilbert Aaron
Chen, Yung-Chieh
Le, Nguyen Quoc Khanh
Huang, Shiu-Wen
Kuo, Duen-Pang
Li, Yi-Tien
Chang, Tzu-Hao
Chen, Cheng-Yu
Identification of Differentially Expressed Genes in Different Glioblastoma Regions and Their Association with Cancer Stem Cell Development and Temozolomide Response
title Identification of Differentially Expressed Genes in Different Glioblastoma Regions and Their Association with Cancer Stem Cell Development and Temozolomide Response
title_full Identification of Differentially Expressed Genes in Different Glioblastoma Regions and Their Association with Cancer Stem Cell Development and Temozolomide Response
title_fullStr Identification of Differentially Expressed Genes in Different Glioblastoma Regions and Their Association with Cancer Stem Cell Development and Temozolomide Response
title_full_unstemmed Identification of Differentially Expressed Genes in Different Glioblastoma Regions and Their Association with Cancer Stem Cell Development and Temozolomide Response
title_short Identification of Differentially Expressed Genes in Different Glioblastoma Regions and Their Association with Cancer Stem Cell Development and Temozolomide Response
title_sort identification of differentially expressed genes in different glioblastoma regions and their association with cancer stem cell development and temozolomide response
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625522/
https://www.ncbi.nlm.nih.gov/pubmed/34834399
http://dx.doi.org/10.3390/jpm11111047
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