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:	Justin Bo-Kai Hsu, Tzong-Yi Lee, Sho-Jen Cheng, Gilbert Aaron Lee, Yung-Chieh Chen, Nguyen Quoc Khanh Le, Shiu-Wen Huang, Duen-Pang Kuo, Yi-Tien Li, Tzu-Hao Chang, Cheng-Yu Chen
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	glioblastoma tumor recurrence TMZ resistance biomarker Medicine R
Acceso en línea:	https://doaj.org/article/c8ef5cf1ce0c4db6b4e32d215e18894d
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spelling	oai:doaj.org-article:c8ef5cf1ce0c4db6b4e32d215e18894d2021-11-25T18:06:42ZIdentification of Differentially Expressed Genes in Different Glioblastoma Regions and Their Association with Cancer Stem Cell Development and Temozolomide Response10.3390/jpm111110472075-4426https://doaj.org/article/c8ef5cf1ce0c4db6b4e32d215e18894d2021-10-01T00:00:00Zhttps://www.mdpi.com/2075-4426/11/11/1047https://doaj.org/toc/2075-4426The 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 (<i>DVL1</i>, <i>PRKACB</i>, <i>ARRB1</i>, <i>APC</i>, <i>MAPK9</i>, <i>CAMK2A</i>, <i>PRKCB</i>, <i>CACNA1A</i>, <i>ERBB4</i>, <i>RASGRF1</i>, <i>NF1</i>, <i>RPS6KA2</i>, <i>MAPK8IP2</i>, and <i>PPM1A</i>) 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 (<i>ARID5A</i>, <i>CDC42EP3</i>, <i>CDKN1A</i>, <i>FLT3</i>, <i>JUNB</i>, <i>MAP2K3</i>, <i>MYBPC2</i>, <i>RGS14</i>, <i>RNASEK</i>, <i>TBC1D30</i>, and <i>TXNDC11</i>) 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 <i>ARID5A</i>, <i>CDKN1A</i>, and <i>MAP2K3</i> 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.Justin Bo-Kai HsuTzong-Yi LeeSho-Jen ChengGilbert Aaron LeeYung-Chieh ChenNguyen Quoc Khanh LeShiu-Wen HuangDuen-Pang KuoYi-Tien LiTzu-Hao ChangCheng-Yu ChenMDPI AGarticleglioblastomatumor recurrenceTMZ resistancebiomarkerMedicineRENJournal of Personalized Medicine, Vol 11, Iss 1047, p 1047 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	glioblastoma tumor recurrence TMZ resistance biomarker Medicine R
spellingShingle	glioblastoma tumor recurrence TMZ resistance biomarker Medicine R Justin Bo-Kai Hsu Tzong-Yi Lee Sho-Jen Cheng Gilbert Aaron Lee Yung-Chieh Chen Nguyen Quoc Khanh Le Shiu-Wen Huang Duen-Pang Kuo Yi-Tien Li Tzu-Hao Chang Cheng-Yu Chen Identification of Differentially Expressed Genes in Different Glioblastoma Regions and Their Association with Cancer Stem Cell Development and Temozolomide Response
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 (<i>DVL1</i>, <i>PRKACB</i>, <i>ARRB1</i>, <i>APC</i>, <i>MAPK9</i>, <i>CAMK2A</i>, <i>PRKCB</i>, <i>CACNA1A</i>, <i>ERBB4</i>, <i>RASGRF1</i>, <i>NF1</i>, <i>RPS6KA2</i>, <i>MAPK8IP2</i>, and <i>PPM1A</i>) 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 (<i>ARID5A</i>, <i>CDC42EP3</i>, <i>CDKN1A</i>, <i>FLT3</i>, <i>JUNB</i>, <i>MAP2K3</i>, <i>MYBPC2</i>, <i>RGS14</i>, <i>RNASEK</i>, <i>TBC1D30</i>, and <i>TXNDC11</i>) 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 <i>ARID5A</i>, <i>CDKN1A</i>, and <i>MAP2K3</i> 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.
format	article
author	Justin Bo-Kai Hsu Tzong-Yi Lee Sho-Jen Cheng Gilbert Aaron Lee Yung-Chieh Chen Nguyen Quoc Khanh Le Shiu-Wen Huang Duen-Pang Kuo Yi-Tien Li Tzu-Hao Chang Cheng-Yu Chen
author_facet	Justin Bo-Kai Hsu Tzong-Yi Lee Sho-Jen Cheng Gilbert Aaron Lee Yung-Chieh Chen Nguyen Quoc Khanh Le Shiu-Wen Huang Duen-Pang Kuo Yi-Tien Li Tzu-Hao Chang Cheng-Yu Chen
author_sort	Justin Bo-Kai Hsu
title	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_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_sort	identification of differentially expressed genes in different glioblastoma regions and their association with cancer stem cell development and temozolomide response
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/c8ef5cf1ce0c4db6b4e32d215e18894d
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Identification of Differentially Expressed Genes in Different Glioblastoma Regions and Their Association with Cancer Stem Cell Development and Temozolomide Response

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