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Integrative analysis of gene expression profiles reveals distinct molecular characteristics in oral tongue squamous cell carcinoma.

ABSTRACT: Oral tongue squamous cell carcinoma (OTSCC) is the most common type of oral cancer. Despite advances in knowledge regarding the genome-scale gene expression pattern of oral cancer, the molecular portrait of OTSCC biology has remained unclear over the last few decades. Furthermore, studies concerning OTSCC gene-expression profiles are limited or inconsistent owing to tissue heterogeneity in single-cohort studies. Consequently, the present study integrated the profile datasets of three cohorts in order to screen for differentially expressed genes (DEGs), and subsequently identified the potential candidate genes and pathways in OTSCC through gene enrichment analysis and protein-protein interaction (PPI) network construction. Using the selected Gene Expression Omnibus datasets GSE13601, GSE31056 and GSE78060, 206 DEGs (125 upregulated and 81 downregulated) were identified in OTSCC, principally associated with extracellular matrix (ECM) organization and the phosphoinositide 3-kinase/protein kinase B signaling pathway. Furthermore, 146/206 DEGs were filtered into the PPI network and 20 hub genes were sorted. Further results indicated that the two most significant modules filtered from the PPI network were associated with ECM organization and human papillomavirus infection, which are important factors affecting OTSCC pathology. Overall, a set of OTSCC-associated DEGs has been identified, including certain key candidate genes that may be of vital importance for diagnosis, therapy and prevention of this disease.

SUBMITTER: Wang R

PROVIDER: S-EPMC6341834 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Integrative analysis of gene expression profiles reveals distinct molecular characteristics in oral tongue squamous cell carcinoma.

Wang Ranran R Zhou Xiao X Wang Hui H Zhou Bo B Dong Shanshan S Ding Qi Q Peng Mingjing M Sheng Xiaowu X Yao Jianfeng J Huang Rongfu R Zeng Yong Y Long Ying Y

Oncology letters 20181221 2

Oral tongue squamous cell carcinoma (OTSCC) is the most common type of oral cancer. Despite advances in knowledge regarding the genome-scale gene expression pattern of oral cancer, the molecular portrait of OTSCC biology has remained unclear over the last few decades. Furthermore, studies concerning OTSCC gene-expression profiles are limited or inconsistent owing to tissue heterogeneity in single-cohort studies. Consequently, the present study integrated the profile datasets of three cohorts in ...[more]

PMID: 30675303

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Project description:Oral Tongue Squamous cell carcinoma (OTSCC), the most frequently affected oral cancer sub-site, is associated with a poor therapeutic outcome and survival despite aggressive multi- modality management. Till date, there are no established biomarkers to indicate prognosis and outcome in patients presenting with tongue cancer. There is an urgent need for reliable molecular prognostic factors to enable identification of patients with high risk of recurrence and treatment failure in OTSCC management. In the current study, we present the meta-analysis of OTSCC microarray based gene expression profiles, deriving a comprehensive molecular portrait of tongue cancer biology, showing the relevant genes and pathways which can be pursued further to derive novel, tailored therapeutics as well as for prognostication. We have studied 5 gene expression profiling data sets available on exclusively oral tongue subsite comprising of sample size; n = 190, consisting of 111 tumors and 79 normals. The meta- analysis results showed 2405 genes differentially regulated comparing OTSCC tumor and normal. The top up regulated genes were found to be involved in Extracellular matrix degradation (ECM) and Epithelial to mesenchymal transition (EMT) pathways. The top down regulated genes were found to be involved in detoxication pathways. We validated the results in clinical samples (n = 206), comprising of histologically normals (n = 10), prospective (n = 29) and retrospective (n = 167) OTSCC by evaluating MMP9 and E-cadherin gene expression by qPCR and immunohistochemistry. Consistent with meta-analysis results, MMP9 mRNA expression was significantly up regulated in OTSCC primary tumors compared to normals. MMP9 protein over expression was found to be a significant predictor of poor prognosis, disease recurrence and poor Disease Free Survival (DFS) in OTSCC patients. Analysis by univariate and multivariate Cox proportional hazard model showed patients with loss of E-cadherin expression in OTSCC tumors having a poorer DFS (HR = 1.566; P value = 0.045) and poorer Overall Survival (OS) (HR = 1.224; P value = 0.003) respectively. Combined over-expression of MMP9 and loss of E-cadherin membrane positivity in the invasive tumor front (ITF) of OTSCC had a significant association with poorer DFS (Log Rank = 16.040; P value = 0.001). These results suggest that along with known clinical indicators of prognosis like occult node positivity, assessment of MMP9 and E-cadherin expression at ITF can be useful to identify patients at high risk and requiring a more intensive treatment strategy for OTSCC. Meta-analysis study of gene expression profiles indicates that OTSCC is a disease of ECM degradation leading to activated EMT processes implying the aggressive nature of the disease. The triggers for these processes should be studied further. Newer clinical application with agents that can inhibit the mediators of ECM degradation may be a key to achieving clinical control of invasion and metastasis of OTSCC.

Project description:Studies on the microbiome of oral squamous cell carcinoma (OSCC) have been limited to 16S rRNA gene sequencing. Here, laser microdissection coupled with brute-force, deep metatranscriptome sequencing was employed to simultaneously characterize the microbiome and host transcriptomes and predict their interaction in OSCC. The analysis involved 20 HPV16/18-negative OSCC tumor/adjacent normal tissue pairs (TT and ANT) along with deep tongue scrapings from 20 matched healthy controls (HC). Standard bioinformatic tools coupled with in-house algorithms were used to map, analyze, and integrate microbial and host data. Host transcriptome analysis identified enrichment of known cancer-related gene sets, not only in TT versus ANT and HC, but also in the ANT versus HC contrast, consistent with field cancerization. Microbial analysis identified a low abundance yet transcriptionally active, unique multi-kingdom microbiome in OSCC tissues predominated by bacteria and bacteriophages. HC showed a different taxonomic profile yet shared major microbial enzyme classes and pathways with TT/ANT, consistent with functional redundancy. Key taxa enriched in TT/ANT compared with HC were Cutibacterium acnes, Malassezia restricta, Human Herpes Virus 6B, and bacteriophage Yuavirus. Functionally, hyaluronate lyase was overexpressed by C. acnes in TT/ANT. Microbiome-host data integration revealed that OSCC-enriched taxa were associated with upregulation of proliferation-related pathways. In a preliminary in vitro validation experiment, infection of SCC25 oral cancer cells with C. acnes resulted in upregulation of MYC expression. The study provides a new insight into potential mechanisms by which the microbiome can contribute to oral carcinogenesis, which can be validated in future experimental studies.SignificanceStudies have shown that a distinct microbiome is associated with OSCC, but how the microbiome functions within the tumor interacts with the host cells remains unclear. By simultaneously characterizing the microbial and host transcriptomes in OSCC and control tissues, the study provides novel insights into microbiome-host interactions in OSCC which can be validated in future mechanistic studies.

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Integrative analysis of gene expression profiles reveals distinct molecular characteristics in oral tongue squamous cell carcinoma.

Publications

Integrative analysis of gene expression profiles reveals distinct molecular characteristics in oral tongue squamous cell carcinoma.

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