Identification of p53-target genes in human papillomavirus-associated head and neck cancer by integrative bioinformatics analysis

IntroductionHead and neck cancer (HNC) is a highly prevalent and heterogeneous malignancy. Although extensive efforts have been made to advance its treatment, the prognosis remained poor with increased mortality. Human papillomaviruses (HPV) have been associated with high risk in HNC. TP53, a tumor suppressor, is the most frequently altered gene in HNC, therefore, investigating its target genes for the identification of novel biomarkers or therapeutic targets in HPV-related HNC progression is highly recommended.MethodsTranscriptomic profiles from three independent gene expression omnibus (GEO) datasets, including 44 HPV+ and 70 HPV- HNC patients, were subjected to integrative statistical and Bioinformatics analyses. For the top-selected marker, further in-silico validation in TCGA and GTEx databases and experimental validation in 65 (51 HPV- and 14 HPV+) subjects with histologically confirmed head and neck squamous cell carcinoma (HNSCC) have been performed.ResultsA total of 498 differentially expressed genes (DEGs) were identified including 291 up-regulated genes and 207 down-regulated genes in HPV+ compared to HPV- HNSCC patients. Functional annotations and gene set enrichment analysis (GSEA) showed that the up-regulated genes were significantly involved in p53-related pathways. The integrative analysis between the Hub-genes identified in the complex protein-protein network and the top frequent genes resulting from GSEA showed an intriguing correlation with five biomarkers which are EZH2, MDM2, PCNA, STAT5A and TYMS. Importantly, the MDM2 gene showed the highest gene expression difference between HPV+ and HPV- HNSCC (Average log2FC = 1.89). Further in-silico validation in a large HNSCC cohort from TCGA and GTEx databases confirmed the over-expression of MDM2 in HPV+ compared to HPV- HNSCC patients (p = 2.39E-05). IHC scoring showed that MDM2 protein expression was significantly higher in HPV+ compared to HPV- HNSCC patients (p = 0.031).DiscussionOur findings showed evidence that over-expression of MDM2, proto-oncogene, may affect the occurrence and proliferation of HPV-associated HNSCC by disturbing the p53-target genes and consequently the p53-related pathways. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Amal Bouzid [verfasserIn] Muwaffaq Al Ani [verfasserIn] David de la Fuente [verfasserIn] Zainab Mohamed Al Shareef [verfasserIn] Asif Quadri [verfasserIn] Rifat Hamoudi [verfasserIn] Natheer Al-Rawi [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	head and neck cancer oral squamous cell carcinoma HPV p53-target genes MDM2 Prognosis biomarkers

Übergeordnetes Werk:	In: Frontiers in Oncology - Frontiers Media S.A., 2012, 13(2023)
Übergeordnetes Werk:	volume:13 ; year:2023

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3389/fonc.2023.1128753

Katalog-ID:	DOAJ088714233

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520			\|a IntroductionHead and neck cancer (HNC) is a highly prevalent and heterogeneous malignancy. Although extensive efforts have been made to advance its treatment, the prognosis remained poor with increased mortality. Human papillomaviruses (HPV) have been associated with high risk in HNC. TP53, a tumor suppressor, is the most frequently altered gene in HNC, therefore, investigating its target genes for the identification of novel biomarkers or therapeutic targets in HPV-related HNC progression is highly recommended.MethodsTranscriptomic profiles from three independent gene expression omnibus (GEO) datasets, including 44 HPV+ and 70 HPV- HNC patients, were subjected to integrative statistical and Bioinformatics analyses. For the top-selected marker, further in-silico validation in TCGA and GTEx databases and experimental validation in 65 (51 HPV- and 14 HPV+) subjects with histologically confirmed head and neck squamous cell carcinoma (HNSCC) have been performed.ResultsA total of 498 differentially expressed genes (DEGs) were identified including 291 up-regulated genes and 207 down-regulated genes in HPV+ compared to HPV- HNSCC patients. Functional annotations and gene set enrichment analysis (GSEA) showed that the up-regulated genes were significantly involved in p53-related pathways. The integrative analysis between the Hub-genes identified in the complex protein-protein network and the top frequent genes resulting from GSEA showed an intriguing correlation with five biomarkers which are EZH2, MDM2, PCNA, STAT5A and TYMS. Importantly, the MDM2 gene showed the highest gene expression difference between HPV+ and HPV- HNSCC (Average log2FC = 1.89). Further in-silico validation in a large HNSCC cohort from TCGA and GTEx databases confirmed the over-expression of MDM2 in HPV+ compared to HPV- HNSCC patients (p = 2.39E-05). IHC scoring showed that MDM2 protein expression was significantly higher in HPV+ compared to HPV- HNSCC patients (p = 0.031).DiscussionOur findings showed evidence that over-expression of MDM2, proto-oncogene, may affect the occurrence and proliferation of HPV-associated HNSCC by disturbing the p53-target genes and consequently the p53-related pathways.
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allfields	10.3389/fonc.2023.1128753 doi (DE-627)DOAJ088714233 (DE-599)DOAJf2e2998544ec4010b9aa87b7dc45be63 DE-627 ger DE-627 rakwb eng RC254-282 Amal Bouzid verfasserin aut Identification of p53-target genes in human papillomavirus-associated head and neck cancer by integrative bioinformatics analysis 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier IntroductionHead and neck cancer (HNC) is a highly prevalent and heterogeneous malignancy. Although extensive efforts have been made to advance its treatment, the prognosis remained poor with increased mortality. Human papillomaviruses (HPV) have been associated with high risk in HNC. TP53, a tumor suppressor, is the most frequently altered gene in HNC, therefore, investigating its target genes for the identification of novel biomarkers or therapeutic targets in HPV-related HNC progression is highly recommended.MethodsTranscriptomic profiles from three independent gene expression omnibus (GEO) datasets, including 44 HPV+ and 70 HPV- HNC patients, were subjected to integrative statistical and Bioinformatics analyses. For the top-selected marker, further in-silico validation in TCGA and GTEx databases and experimental validation in 65 (51 HPV- and 14 HPV+) subjects with histologically confirmed head and neck squamous cell carcinoma (HNSCC) have been performed.ResultsA total of 498 differentially expressed genes (DEGs) were identified including 291 up-regulated genes and 207 down-regulated genes in HPV+ compared to HPV- HNSCC patients. Functional annotations and gene set enrichment analysis (GSEA) showed that the up-regulated genes were significantly involved in p53-related pathways. The integrative analysis between the Hub-genes identified in the complex protein-protein network and the top frequent genes resulting from GSEA showed an intriguing correlation with five biomarkers which are EZH2, MDM2, PCNA, STAT5A and TYMS. Importantly, the MDM2 gene showed the highest gene expression difference between HPV+ and HPV- HNSCC (Average log2FC = 1.89). Further in-silico validation in a large HNSCC cohort from TCGA and GTEx databases confirmed the over-expression of MDM2 in HPV+ compared to HPV- HNSCC patients (p = 2.39E-05). IHC scoring showed that MDM2 protein expression was significantly higher in HPV+ compared to HPV- HNSCC patients (p = 0.031).DiscussionOur findings showed evidence that over-expression of MDM2, proto-oncogene, may affect the occurrence and proliferation of HPV-associated HNSCC by disturbing the p53-target genes and consequently the p53-related pathways. head and neck cancer oral squamous cell carcinoma HPV p53-target genes MDM2 Prognosis biomarkers Neoplasms. Tumors. Oncology. Including cancer and carcinogens Muwaffaq Al Ani verfasserin aut David de la Fuente verfasserin aut Zainab Mohamed Al Shareef verfasserin aut Zainab Mohamed Al Shareef verfasserin aut Asif Quadri verfasserin aut Rifat Hamoudi verfasserin aut Rifat Hamoudi verfasserin aut Rifat Hamoudi verfasserin aut Natheer Al-Rawi verfasserin aut Natheer Al-Rawi verfasserin aut In Frontiers in Oncology Frontiers Media S.A., 2012 13(2023) (DE-627)684965518 (DE-600)2649216-7 2234943X nnns volume:13 year:2023 https://doi.org/10.3389/fonc.2023.1128753 kostenfrei https://doaj.org/article/f2e2998544ec4010b9aa87b7dc45be63 kostenfrei https://www.frontiersin.org/articles/10.3389/fonc.2023.1128753/full kostenfrei https://doaj.org/toc/2234-943X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2023
spelling	10.3389/fonc.2023.1128753 doi (DE-627)DOAJ088714233 (DE-599)DOAJf2e2998544ec4010b9aa87b7dc45be63 DE-627 ger DE-627 rakwb eng RC254-282 Amal Bouzid verfasserin aut Identification of p53-target genes in human papillomavirus-associated head and neck cancer by integrative bioinformatics analysis 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier IntroductionHead and neck cancer (HNC) is a highly prevalent and heterogeneous malignancy. Although extensive efforts have been made to advance its treatment, the prognosis remained poor with increased mortality. Human papillomaviruses (HPV) have been associated with high risk in HNC. TP53, a tumor suppressor, is the most frequently altered gene in HNC, therefore, investigating its target genes for the identification of novel biomarkers or therapeutic targets in HPV-related HNC progression is highly recommended.MethodsTranscriptomic profiles from three independent gene expression omnibus (GEO) datasets, including 44 HPV+ and 70 HPV- HNC patients, were subjected to integrative statistical and Bioinformatics analyses. For the top-selected marker, further in-silico validation in TCGA and GTEx databases and experimental validation in 65 (51 HPV- and 14 HPV+) subjects with histologically confirmed head and neck squamous cell carcinoma (HNSCC) have been performed.ResultsA total of 498 differentially expressed genes (DEGs) were identified including 291 up-regulated genes and 207 down-regulated genes in HPV+ compared to HPV- HNSCC patients. Functional annotations and gene set enrichment analysis (GSEA) showed that the up-regulated genes were significantly involved in p53-related pathways. The integrative analysis between the Hub-genes identified in the complex protein-protein network and the top frequent genes resulting from GSEA showed an intriguing correlation with five biomarkers which are EZH2, MDM2, PCNA, STAT5A and TYMS. Importantly, the MDM2 gene showed the highest gene expression difference between HPV+ and HPV- HNSCC (Average log2FC = 1.89). Further in-silico validation in a large HNSCC cohort from TCGA and GTEx databases confirmed the over-expression of MDM2 in HPV+ compared to HPV- HNSCC patients (p = 2.39E-05). IHC scoring showed that MDM2 protein expression was significantly higher in HPV+ compared to HPV- HNSCC patients (p = 0.031).DiscussionOur findings showed evidence that over-expression of MDM2, proto-oncogene, may affect the occurrence and proliferation of HPV-associated HNSCC by disturbing the p53-target genes and consequently the p53-related pathways. head and neck cancer oral squamous cell carcinoma HPV p53-target genes MDM2 Prognosis biomarkers Neoplasms. Tumors. Oncology. Including cancer and carcinogens Muwaffaq Al Ani verfasserin aut David de la Fuente verfasserin aut Zainab Mohamed Al Shareef verfasserin aut Zainab Mohamed Al Shareef verfasserin aut Asif Quadri verfasserin aut Rifat Hamoudi verfasserin aut Rifat Hamoudi verfasserin aut Rifat Hamoudi verfasserin aut Natheer Al-Rawi verfasserin aut Natheer Al-Rawi verfasserin aut In Frontiers in Oncology Frontiers Media S.A., 2012 13(2023) (DE-627)684965518 (DE-600)2649216-7 2234943X nnns volume:13 year:2023 https://doi.org/10.3389/fonc.2023.1128753 kostenfrei https://doaj.org/article/f2e2998544ec4010b9aa87b7dc45be63 kostenfrei https://www.frontiersin.org/articles/10.3389/fonc.2023.1128753/full kostenfrei https://doaj.org/toc/2234-943X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2023
allfields_unstemmed	10.3389/fonc.2023.1128753 doi (DE-627)DOAJ088714233 (DE-599)DOAJf2e2998544ec4010b9aa87b7dc45be63 DE-627 ger DE-627 rakwb eng RC254-282 Amal Bouzid verfasserin aut Identification of p53-target genes in human papillomavirus-associated head and neck cancer by integrative bioinformatics analysis 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier IntroductionHead and neck cancer (HNC) is a highly prevalent and heterogeneous malignancy. Although extensive efforts have been made to advance its treatment, the prognosis remained poor with increased mortality. Human papillomaviruses (HPV) have been associated with high risk in HNC. TP53, a tumor suppressor, is the most frequently altered gene in HNC, therefore, investigating its target genes for the identification of novel biomarkers or therapeutic targets in HPV-related HNC progression is highly recommended.MethodsTranscriptomic profiles from three independent gene expression omnibus (GEO) datasets, including 44 HPV+ and 70 HPV- HNC patients, were subjected to integrative statistical and Bioinformatics analyses. For the top-selected marker, further in-silico validation in TCGA and GTEx databases and experimental validation in 65 (51 HPV- and 14 HPV+) subjects with histologically confirmed head and neck squamous cell carcinoma (HNSCC) have been performed.ResultsA total of 498 differentially expressed genes (DEGs) were identified including 291 up-regulated genes and 207 down-regulated genes in HPV+ compared to HPV- HNSCC patients. Functional annotations and gene set enrichment analysis (GSEA) showed that the up-regulated genes were significantly involved in p53-related pathways. The integrative analysis between the Hub-genes identified in the complex protein-protein network and the top frequent genes resulting from GSEA showed an intriguing correlation with five biomarkers which are EZH2, MDM2, PCNA, STAT5A and TYMS. Importantly, the MDM2 gene showed the highest gene expression difference between HPV+ and HPV- HNSCC (Average log2FC = 1.89). Further in-silico validation in a large HNSCC cohort from TCGA and GTEx databases confirmed the over-expression of MDM2 in HPV+ compared to HPV- HNSCC patients (p = 2.39E-05). IHC scoring showed that MDM2 protein expression was significantly higher in HPV+ compared to HPV- HNSCC patients (p = 0.031).DiscussionOur findings showed evidence that over-expression of MDM2, proto-oncogene, may affect the occurrence and proliferation of HPV-associated HNSCC by disturbing the p53-target genes and consequently the p53-related pathways. head and neck cancer oral squamous cell carcinoma HPV p53-target genes MDM2 Prognosis biomarkers Neoplasms. Tumors. Oncology. Including cancer and carcinogens Muwaffaq Al Ani verfasserin aut David de la Fuente verfasserin aut Zainab Mohamed Al Shareef verfasserin aut Zainab Mohamed Al Shareef verfasserin aut Asif Quadri verfasserin aut Rifat Hamoudi verfasserin aut Rifat Hamoudi verfasserin aut Rifat Hamoudi verfasserin aut Natheer Al-Rawi verfasserin aut Natheer Al-Rawi verfasserin aut In Frontiers in Oncology Frontiers Media S.A., 2012 13(2023) (DE-627)684965518 (DE-600)2649216-7 2234943X nnns volume:13 year:2023 https://doi.org/10.3389/fonc.2023.1128753 kostenfrei https://doaj.org/article/f2e2998544ec4010b9aa87b7dc45be63 kostenfrei https://www.frontiersin.org/articles/10.3389/fonc.2023.1128753/full kostenfrei https://doaj.org/toc/2234-943X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2023
allfieldsGer	10.3389/fonc.2023.1128753 doi (DE-627)DOAJ088714233 (DE-599)DOAJf2e2998544ec4010b9aa87b7dc45be63 DE-627 ger DE-627 rakwb eng RC254-282 Amal Bouzid verfasserin aut Identification of p53-target genes in human papillomavirus-associated head and neck cancer by integrative bioinformatics analysis 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier IntroductionHead and neck cancer (HNC) is a highly prevalent and heterogeneous malignancy. Although extensive efforts have been made to advance its treatment, the prognosis remained poor with increased mortality. Human papillomaviruses (HPV) have been associated with high risk in HNC. TP53, a tumor suppressor, is the most frequently altered gene in HNC, therefore, investigating its target genes for the identification of novel biomarkers or therapeutic targets in HPV-related HNC progression is highly recommended.MethodsTranscriptomic profiles from three independent gene expression omnibus (GEO) datasets, including 44 HPV+ and 70 HPV- HNC patients, were subjected to integrative statistical and Bioinformatics analyses. For the top-selected marker, further in-silico validation in TCGA and GTEx databases and experimental validation in 65 (51 HPV- and 14 HPV+) subjects with histologically confirmed head and neck squamous cell carcinoma (HNSCC) have been performed.ResultsA total of 498 differentially expressed genes (DEGs) were identified including 291 up-regulated genes and 207 down-regulated genes in HPV+ compared to HPV- HNSCC patients. Functional annotations and gene set enrichment analysis (GSEA) showed that the up-regulated genes were significantly involved in p53-related pathways. The integrative analysis between the Hub-genes identified in the complex protein-protein network and the top frequent genes resulting from GSEA showed an intriguing correlation with five biomarkers which are EZH2, MDM2, PCNA, STAT5A and TYMS. Importantly, the MDM2 gene showed the highest gene expression difference between HPV+ and HPV- HNSCC (Average log2FC = 1.89). Further in-silico validation in a large HNSCC cohort from TCGA and GTEx databases confirmed the over-expression of MDM2 in HPV+ compared to HPV- HNSCC patients (p = 2.39E-05). IHC scoring showed that MDM2 protein expression was significantly higher in HPV+ compared to HPV- HNSCC patients (p = 0.031).DiscussionOur findings showed evidence that over-expression of MDM2, proto-oncogene, may affect the occurrence and proliferation of HPV-associated HNSCC by disturbing the p53-target genes and consequently the p53-related pathways. head and neck cancer oral squamous cell carcinoma HPV p53-target genes MDM2 Prognosis biomarkers Neoplasms. Tumors. Oncology. Including cancer and carcinogens Muwaffaq Al Ani verfasserin aut David de la Fuente verfasserin aut Zainab Mohamed Al Shareef verfasserin aut Zainab Mohamed Al Shareef verfasserin aut Asif Quadri verfasserin aut Rifat Hamoudi verfasserin aut Rifat Hamoudi verfasserin aut Rifat Hamoudi verfasserin aut Natheer Al-Rawi verfasserin aut Natheer Al-Rawi verfasserin aut In Frontiers in Oncology Frontiers Media S.A., 2012 13(2023) (DE-627)684965518 (DE-600)2649216-7 2234943X nnns volume:13 year:2023 https://doi.org/10.3389/fonc.2023.1128753 kostenfrei https://doaj.org/article/f2e2998544ec4010b9aa87b7dc45be63 kostenfrei https://www.frontiersin.org/articles/10.3389/fonc.2023.1128753/full kostenfrei https://doaj.org/toc/2234-943X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2023
allfieldsSound	10.3389/fonc.2023.1128753 doi (DE-627)DOAJ088714233 (DE-599)DOAJf2e2998544ec4010b9aa87b7dc45be63 DE-627 ger DE-627 rakwb eng RC254-282 Amal Bouzid verfasserin aut Identification of p53-target genes in human papillomavirus-associated head and neck cancer by integrative bioinformatics analysis 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier IntroductionHead and neck cancer (HNC) is a highly prevalent and heterogeneous malignancy. Although extensive efforts have been made to advance its treatment, the prognosis remained poor with increased mortality. Human papillomaviruses (HPV) have been associated with high risk in HNC. TP53, a tumor suppressor, is the most frequently altered gene in HNC, therefore, investigating its target genes for the identification of novel biomarkers or therapeutic targets in HPV-related HNC progression is highly recommended.MethodsTranscriptomic profiles from three independent gene expression omnibus (GEO) datasets, including 44 HPV+ and 70 HPV- HNC patients, were subjected to integrative statistical and Bioinformatics analyses. For the top-selected marker, further in-silico validation in TCGA and GTEx databases and experimental validation in 65 (51 HPV- and 14 HPV+) subjects with histologically confirmed head and neck squamous cell carcinoma (HNSCC) have been performed.ResultsA total of 498 differentially expressed genes (DEGs) were identified including 291 up-regulated genes and 207 down-regulated genes in HPV+ compared to HPV- HNSCC patients. Functional annotations and gene set enrichment analysis (GSEA) showed that the up-regulated genes were significantly involved in p53-related pathways. The integrative analysis between the Hub-genes identified in the complex protein-protein network and the top frequent genes resulting from GSEA showed an intriguing correlation with five biomarkers which are EZH2, MDM2, PCNA, STAT5A and TYMS. Importantly, the MDM2 gene showed the highest gene expression difference between HPV+ and HPV- HNSCC (Average log2FC = 1.89). Further in-silico validation in a large HNSCC cohort from TCGA and GTEx databases confirmed the over-expression of MDM2 in HPV+ compared to HPV- HNSCC patients (p = 2.39E-05). IHC scoring showed that MDM2 protein expression was significantly higher in HPV+ compared to HPV- HNSCC patients (p = 0.031).DiscussionOur findings showed evidence that over-expression of MDM2, proto-oncogene, may affect the occurrence and proliferation of HPV-associated HNSCC by disturbing the p53-target genes and consequently the p53-related pathways. head and neck cancer oral squamous cell carcinoma HPV p53-target genes MDM2 Prognosis biomarkers Neoplasms. Tumors. Oncology. Including cancer and carcinogens Muwaffaq Al Ani verfasserin aut David de la Fuente verfasserin aut Zainab Mohamed Al Shareef verfasserin aut Zainab Mohamed Al Shareef verfasserin aut Asif Quadri verfasserin aut Rifat Hamoudi verfasserin aut Rifat Hamoudi verfasserin aut Rifat Hamoudi verfasserin aut Natheer Al-Rawi verfasserin aut Natheer Al-Rawi verfasserin aut In Frontiers in Oncology Frontiers Media S.A., 2012 13(2023) (DE-627)684965518 (DE-600)2649216-7 2234943X nnns volume:13 year:2023 https://doi.org/10.3389/fonc.2023.1128753 kostenfrei https://doaj.org/article/f2e2998544ec4010b9aa87b7dc45be63 kostenfrei https://www.frontiersin.org/articles/10.3389/fonc.2023.1128753/full kostenfrei https://doaj.org/toc/2234-943X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2023
language	English
source	In Frontiers in Oncology 13(2023) volume:13 year:2023
sourceStr	In Frontiers in Oncology 13(2023) volume:13 year:2023
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	head and neck cancer oral squamous cell carcinoma HPV p53-target genes MDM2 Prognosis biomarkers Neoplasms. Tumors. Oncology. Including cancer and carcinogens
isfreeaccess_bool	true
container_title	Frontiers in Oncology
authorswithroles_txt_mv	Amal Bouzid @@aut@@ Muwaffaq Al Ani @@aut@@ David de la Fuente @@aut@@ Zainab Mohamed Al Shareef @@aut@@ Asif Quadri @@aut@@ Rifat Hamoudi @@aut@@ Natheer Al-Rawi @@aut@@
publishDateDaySort_date	2023-01-01T00:00:00Z
hierarchy_top_id	684965518
id	DOAJ088714233
language_de	englisch
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Although extensive efforts have been made to advance its treatment, the prognosis remained poor with increased mortality. Human papillomaviruses (HPV) have been associated with high risk in HNC. TP53, a tumor suppressor, is the most frequently altered gene in HNC, therefore, investigating its target genes for the identification of novel biomarkers or therapeutic targets in HPV-related HNC progression is highly recommended.MethodsTranscriptomic profiles from three independent gene expression omnibus (GEO) datasets, including 44 HPV+ and 70 HPV- HNC patients, were subjected to integrative statistical and Bioinformatics analyses. For the top-selected marker, further in-silico validation in TCGA and GTEx databases and experimental validation in 65 (51 HPV- and 14 HPV+) subjects with histologically confirmed head and neck squamous cell carcinoma (HNSCC) have been performed.ResultsA total of 498 differentially expressed genes (DEGs) were identified including 291 up-regulated genes and 207 down-regulated genes in HPV+ compared to HPV- HNSCC patients. Functional annotations and gene set enrichment analysis (GSEA) showed that the up-regulated genes were significantly involved in p53-related pathways. The integrative analysis between the Hub-genes identified in the complex protein-protein network and the top frequent genes resulting from GSEA showed an intriguing correlation with five biomarkers which are EZH2, MDM2, PCNA, STAT5A and TYMS. Importantly, the MDM2 gene showed the highest gene expression difference between HPV+ and HPV- HNSCC (Average log2FC = 1.89). Further in-silico validation in a large HNSCC cohort from TCGA and GTEx databases confirmed the over-expression of MDM2 in HPV+ compared to HPV- HNSCC patients (p = 2.39E-05). IHC scoring showed that MDM2 protein expression was significantly higher in HPV+ compared to HPV- HNSCC patients (p = 0.031).DiscussionOur findings showed evidence that over-expression of MDM2, proto-oncogene, may affect the occurrence and proliferation of HPV-associated HNSCC by disturbing the p53-target genes and consequently the p53-related pathways.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">head and neck cancer</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">oral squamous cell carcinoma</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">HPV</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">p53-target genes</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">MDM2</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Prognosis biomarkers</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Neoplasms. 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callnumber-first	R - Medicine
author	Amal Bouzid
spellingShingle	Amal Bouzid misc RC254-282 misc head and neck cancer misc oral squamous cell carcinoma misc HPV misc p53-target genes misc MDM2 misc Prognosis biomarkers misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens Identification of p53-target genes in human papillomavirus-associated head and neck cancer by integrative bioinformatics analysis
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topic_title	RC254-282 Identification of p53-target genes in human papillomavirus-associated head and neck cancer by integrative bioinformatics analysis head and neck cancer oral squamous cell carcinoma HPV p53-target genes MDM2 Prognosis biomarkers
topic	misc RC254-282 misc head and neck cancer misc oral squamous cell carcinoma misc HPV misc p53-target genes misc MDM2 misc Prognosis biomarkers misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_unstemmed	misc RC254-282 misc head and neck cancer misc oral squamous cell carcinoma misc HPV misc p53-target genes misc MDM2 misc Prognosis biomarkers misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_browse	misc RC254-282 misc head and neck cancer misc oral squamous cell carcinoma misc HPV misc p53-target genes misc MDM2 misc Prognosis biomarkers misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
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title	Identification of p53-target genes in human papillomavirus-associated head and neck cancer by integrative bioinformatics analysis
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title_full	Identification of p53-target genes in human papillomavirus-associated head and neck cancer by integrative bioinformatics analysis
author_sort	Amal Bouzid
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author_browse	Amal Bouzid Muwaffaq Al Ani David de la Fuente Zainab Mohamed Al Shareef Asif Quadri Rifat Hamoudi Natheer Al-Rawi
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author-letter	Amal Bouzid
doi_str_mv	10.3389/fonc.2023.1128753
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title_sort	identification of p53-target genes in human papillomavirus-associated head and neck cancer by integrative bioinformatics analysis
callnumber	RC254-282
title_auth	Identification of p53-target genes in human papillomavirus-associated head and neck cancer by integrative bioinformatics analysis
abstract	IntroductionHead and neck cancer (HNC) is a highly prevalent and heterogeneous malignancy. Although extensive efforts have been made to advance its treatment, the prognosis remained poor with increased mortality. Human papillomaviruses (HPV) have been associated with high risk in HNC. TP53, a tumor suppressor, is the most frequently altered gene in HNC, therefore, investigating its target genes for the identification of novel biomarkers or therapeutic targets in HPV-related HNC progression is highly recommended.MethodsTranscriptomic profiles from three independent gene expression omnibus (GEO) datasets, including 44 HPV+ and 70 HPV- HNC patients, were subjected to integrative statistical and Bioinformatics analyses. For the top-selected marker, further in-silico validation in TCGA and GTEx databases and experimental validation in 65 (51 HPV- and 14 HPV+) subjects with histologically confirmed head and neck squamous cell carcinoma (HNSCC) have been performed.ResultsA total of 498 differentially expressed genes (DEGs) were identified including 291 up-regulated genes and 207 down-regulated genes in HPV+ compared to HPV- HNSCC patients. Functional annotations and gene set enrichment analysis (GSEA) showed that the up-regulated genes were significantly involved in p53-related pathways. The integrative analysis between the Hub-genes identified in the complex protein-protein network and the top frequent genes resulting from GSEA showed an intriguing correlation with five biomarkers which are EZH2, MDM2, PCNA, STAT5A and TYMS. Importantly, the MDM2 gene showed the highest gene expression difference between HPV+ and HPV- HNSCC (Average log2FC = 1.89). Further in-silico validation in a large HNSCC cohort from TCGA and GTEx databases confirmed the over-expression of MDM2 in HPV+ compared to HPV- HNSCC patients (p = 2.39E-05). IHC scoring showed that MDM2 protein expression was significantly higher in HPV+ compared to HPV- HNSCC patients (p = 0.031).DiscussionOur findings showed evidence that over-expression of MDM2, proto-oncogene, may affect the occurrence and proliferation of HPV-associated HNSCC by disturbing the p53-target genes and consequently the p53-related pathways.
abstractGer	IntroductionHead and neck cancer (HNC) is a highly prevalent and heterogeneous malignancy. Although extensive efforts have been made to advance its treatment, the prognosis remained poor with increased mortality. Human papillomaviruses (HPV) have been associated with high risk in HNC. TP53, a tumor suppressor, is the most frequently altered gene in HNC, therefore, investigating its target genes for the identification of novel biomarkers or therapeutic targets in HPV-related HNC progression is highly recommended.MethodsTranscriptomic profiles from three independent gene expression omnibus (GEO) datasets, including 44 HPV+ and 70 HPV- HNC patients, were subjected to integrative statistical and Bioinformatics analyses. For the top-selected marker, further in-silico validation in TCGA and GTEx databases and experimental validation in 65 (51 HPV- and 14 HPV+) subjects with histologically confirmed head and neck squamous cell carcinoma (HNSCC) have been performed.ResultsA total of 498 differentially expressed genes (DEGs) were identified including 291 up-regulated genes and 207 down-regulated genes in HPV+ compared to HPV- HNSCC patients. Functional annotations and gene set enrichment analysis (GSEA) showed that the up-regulated genes were significantly involved in p53-related pathways. The integrative analysis between the Hub-genes identified in the complex protein-protein network and the top frequent genes resulting from GSEA showed an intriguing correlation with five biomarkers which are EZH2, MDM2, PCNA, STAT5A and TYMS. Importantly, the MDM2 gene showed the highest gene expression difference between HPV+ and HPV- HNSCC (Average log2FC = 1.89). Further in-silico validation in a large HNSCC cohort from TCGA and GTEx databases confirmed the over-expression of MDM2 in HPV+ compared to HPV- HNSCC patients (p = 2.39E-05). IHC scoring showed that MDM2 protein expression was significantly higher in HPV+ compared to HPV- HNSCC patients (p = 0.031).DiscussionOur findings showed evidence that over-expression of MDM2, proto-oncogene, may affect the occurrence and proliferation of HPV-associated HNSCC by disturbing the p53-target genes and consequently the p53-related pathways.
abstract_unstemmed	IntroductionHead and neck cancer (HNC) is a highly prevalent and heterogeneous malignancy. Although extensive efforts have been made to advance its treatment, the prognosis remained poor with increased mortality. Human papillomaviruses (HPV) have been associated with high risk in HNC. TP53, a tumor suppressor, is the most frequently altered gene in HNC, therefore, investigating its target genes for the identification of novel biomarkers or therapeutic targets in HPV-related HNC progression is highly recommended.MethodsTranscriptomic profiles from three independent gene expression omnibus (GEO) datasets, including 44 HPV+ and 70 HPV- HNC patients, were subjected to integrative statistical and Bioinformatics analyses. For the top-selected marker, further in-silico validation in TCGA and GTEx databases and experimental validation in 65 (51 HPV- and 14 HPV+) subjects with histologically confirmed head and neck squamous cell carcinoma (HNSCC) have been performed.ResultsA total of 498 differentially expressed genes (DEGs) were identified including 291 up-regulated genes and 207 down-regulated genes in HPV+ compared to HPV- HNSCC patients. Functional annotations and gene set enrichment analysis (GSEA) showed that the up-regulated genes were significantly involved in p53-related pathways. The integrative analysis between the Hub-genes identified in the complex protein-protein network and the top frequent genes resulting from GSEA showed an intriguing correlation with five biomarkers which are EZH2, MDM2, PCNA, STAT5A and TYMS. Importantly, the MDM2 gene showed the highest gene expression difference between HPV+ and HPV- HNSCC (Average log2FC = 1.89). Further in-silico validation in a large HNSCC cohort from TCGA and GTEx databases confirmed the over-expression of MDM2 in HPV+ compared to HPV- HNSCC patients (p = 2.39E-05). IHC scoring showed that MDM2 protein expression was significantly higher in HPV+ compared to HPV- HNSCC patients (p = 0.031).DiscussionOur findings showed evidence that over-expression of MDM2, proto-oncogene, may affect the occurrence and proliferation of HPV-associated HNSCC by disturbing the p53-target genes and consequently the p53-related pathways.
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title_short	Identification of p53-target genes in human papillomavirus-associated head and neck cancer by integrative bioinformatics analysis
url	https://doi.org/10.3389/fonc.2023.1128753 https://doaj.org/article/f2e2998544ec4010b9aa87b7dc45be63 https://www.frontiersin.org/articles/10.3389/fonc.2023.1128753/full https://doaj.org/toc/2234-943X
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Identification of p53-target genes in human papillomavirus-associated head and neck cancer by integrative bioinformatics analysis

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