Exploring the Novel Computational Drug Target and Associated Key Pathways of Oral Cancer

Oral cancer (OC) is a serious health concern that has a high fatality rate. The oral cavity has seven kinds of OC, including the lip, tongue, and floor of the mouth, as well as the buccal, hard palate, alveolar, retromolar trigone, and soft palate. The goal of this study is to look into new biomarkers and important pathways that might be used as diagnostic biomarkers and therapeutic candidates in OC. The publicly available repository the Gene Expression Omnibus (GEO) was to the source for the collection of OC-related datasets. GSE74530, GSE23558, and GSE3524 microarray datasets were collected for analysis. Minimum cut-off criteria of |log fold-change (FC)| > 1 and adjusted p < 0.05 were applied to calculate the upregulated and downregulated differential expression genes (DEGs) from the three datasets. After that only common DEGs in all three datasets were collected to apply further analysis. Gene ontology (GO) and pathway analysis were implemented to explore the functional behaviors of DEGs. Then protein–protein interaction (PPI) networks were built to identify the most active genes, and a clustering algorithm was also implemented to identify complex parts of PPI. TF-miRNA networks were also constructed to study OC-associated DEGs in-depth. Finally, top gene performers from PPI networks were used to apply drug signature analysis. After applying filtration and cut-off criteria, 2508, 3377, and 670 DEGs were found for GSE74530, GSE23558, and GSE3524 respectively, and 166 common DEGs were found in every dataset. The GO annotation remarks that most of the DEGs were associated with the terms of type I interferon signaling pathway. The pathways of KEGG reported that the common DEGs are related to the cell cycle and influenza A. The PPI network holds 88 nodes and 492 edges, and CDC6 had the highest number of connections. Four clusters were identified from the PPI. Drug signatures doxorubicin and resveratrol showed high significance according to the hub genes. We anticipate that our bioinformatics research will aid in the definition of OC pathophysiology and the development of new therapies for OC.

[1]  Hongwei Li,et al.  Identification of Hub Genes Associated With Tuberculous Pleurisy by Integrated Bioinformatics Analysis , 2021, Frontiers in Genetics.

[2]  Wei Li,et al.  Integrative investigation of the TF–miRNA coregulatory network involved in the inhibition of breast cancer cell proliferation by resveratrol , 2021, FEBS open bio.

[3]  J. Natesh,et al.  Identification of hub genes associated with EMT-induced chemoresistance in breast cancer using integrated bioinformatics analysis. , 2021, Gene.

[4]  Y. Yatabe,et al.  MYB mediates downregulation of the colorectal cancer metastasis suppressor heterogeneous nuclear ribonucleoprotein L‐like during epithelial‐mesenchymal transition , 2021, Cancer science.

[5]  F. Abbasi,et al.  Relationship between oral cancer stage and elapsed time from the onset of signs and symptoms to diagnosis and treatment. , 2021, Cancer treatment and research communications.

[6]  Karan P. Singh,et al.  Clinicopathologic significance and race-specific prognostic association of MYB overexpression in ovarian cancer , 2021, Scientific Reports.

[7]  G. Karimi,et al.  The role of microRNAs on doxorubicin drug resistance in breast cancer. , 2021, The Journal of pharmacy and pharmacology.

[8]  R. Sun,et al.  Gene co-expression network analysis reveals key pathways and hub genes in Chinese cabbage (Brassica rapa L.) during vernalization , 2021, BMC Genomics.

[9]  Nadezhda T. Doncheva,et al.  The STRING database in 2021: customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets , 2020, Nucleic Acids Res..

[10]  Chen Li,et al.  Analysis of differentially expressed genes in oral epithelial cells infected with Fusobacterium nucleatum for revealing genes associated with oral cancer , 2020, Journal of cellular and molecular medicine.

[11]  H. Luan,et al.  Identification of Key Prognostic Biomarker and Its Correlation with Immune Infiltrates in Pancreatic Ductal Adenocarcinoma , 2020, Disease markers.

[12]  O. Karatas,et al.  The roles of microRNAs in the stemness of oral cancer cells. , 2020, Oral oncology.

[13]  M. Dominiak,et al.  Oral cancer: The first symptoms and reasons for delaying correct diagnosis and appropriate treatment. , 2020, Advances in clinical and experimental medicine : official organ Wroclaw Medical University.

[14]  M. Dong,et al.  Hsa-MiR-590-3p Promotes the Malignancy Progression of Pancreatic Ductal Carcinoma by Inhibiting the Expression of p27 and PPP2R2A via G1/S Cell Cycle Pathway , 2020, OncoTargets and therapy.

[15]  O. Crosby,et al.  methyltransferases , 2020, Catalysis from A to Z.

[16]  Paulo Goberlânio de Barros-Silva,et al.  Clinical-pathological and sociodemographic factors associated with the distant metastasis and overall survival of oral cavity and oropharynx squamous cell carcinoma , 2020, Medicina oral, patologia oral y cirugia bucal.

[17]  Wanchun Wang,et al.  NOL6, a new founding oncogene in human prostate cancer and targeted by miR-590-3p , 2020, Cytotechnology.

[18]  Julian M. W. Quinn,et al.  Identification of molecular signatures and pathways to identify novel therapeutic targets in Alzheimer's disease: Insights from a systems biomedicine perspective. , 2020, Genomics.

[19]  P. Vedsted,et al.  Prevalence and incidence of oral cancer in low- and middle-income countries: A scoping review. , 2019, European journal of cancer care.

[20]  S. Mousa,et al.  Thyroid hormone-induced expression of inflammatory cytokines interfere with resveratrol-induced anti-proliferation of oral cancer cells. , 2019, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[21]  S. Warnakulasuriya White, red, and mixed lesions of oral mucosa: A clinicopathologic approach to diagnosis. , 2019, Periodontology 2000.

[22]  Ahmed A. Abd-Rabou,et al.  Selenium Overcomes Doxorubicin Resistance in Their Nano-platforms Against Breast and Colon Cancers , 2019, Biological Trace Element Research.

[23]  Shuai Jiang,et al.  Noncoding RNAs as Molecular Targets of Resveratrol Underlying Its Anticancer Effects. , 2019, Journal of agricultural and food chemistry.

[24]  Peter Csermely,et al.  The EntOptLayout Cytoscape plug-in for the efficient visualization of major protein complexes in protein–protein interaction and signalling networks , 2019, Bioinform..

[25]  Othman Soufan,et al.  NetworkAnalyst 3.0: a visual analytics platform for comprehensive gene expression profiling and meta-analysis , 2019, Nucleic Acids Res..

[26]  Chen Li,et al.  Identification of Potential Candidate Genes of Oral Cancer in Response to Chronic Infection With Porphyromonas gingivalis Using Bioinformatical Analyses , 2019, Front. Oncol..

[27]  Xi Li,et al.  MicroRNA‐1258, regulated by c‐Myb, inhibits growth and epithelial‐to‐mesenchymal transition phenotype via targeting SP1 in oral squamous cell carcinoma , 2019, Journal of cellular and molecular medicine.

[28]  X. Yang,et al.  SOX9, miR-495, miR-590-3p, and miR-320d were identified as chemoradiotherapy-sensitive genes and miRNAs in colorectal cancer patients based on a microarray dataset. , 2019, Neoplasma.

[29]  Katherine Gurdziel,et al.  Unanchored ubiquitin chains do not lead to marked alterations in gene expression in Drosophila melanogaster , 2019, Biology Open.

[30]  P. Tang,et al.  Hub genes and gene functions associated with postmenopausal osteoporosis predicted by an integrated method , 2018, Experimental and therapeutic medicine.

[31]  D M Parkin,et al.  Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods , 2018, International journal of cancer.

[32]  Daniel Toro-Domínguez,et al.  ImaGEO: integrative gene expression meta-analysis from GEO database , 2018, Bioinform..

[33]  A. Khatkar,et al.  Resveratrol in Various Pockets: A Review. , 2019, Current topics in medicinal chemistry.

[34]  P. Mitra,et al.  Transcription regulation of MYB: a potential and novel therapeutic target in cancer. , 2018, Annals of translational medicine.

[35]  Zhuo Lv,et al.  Atovaquone enhances doxorubicin’s efficacy via inhibiting mitochondrial respiration and STAT3 in aggressive thyroid cancer , 2018, Journal of Bioenergetics and Biomembranes.

[36]  Xing-ming Jiang,et al.  SP1-induced upregulation of lncRNA SPRY4-IT1 exerts oncogenic properties by scaffolding EZH2/LSD1/DNMT1 and sponging miR-101-3p in cholangiocarcinoma , 2018, Journal of experimental & clinical cancer research : CR.

[37]  Jérôme Galon,et al.  Comprehensive functional analysis of large lists of genes and proteins. , 2018, Journal of proteomics.

[38]  Vicky M. Avery,et al.  Doxorubicin resistance in breast cancer cells is mediated by extracellular matrix proteins , 2018, BMC Cancer.

[39]  Muhammad Sohail Zafar,et al.  Role of Salivary Biomarkers in Oral Cancer Detection. , 2018, Advances in clinical chemistry.

[40]  D. Wiesenfeld,et al.  Oral Cancer. , 2018, Australian dental journal.

[41]  Xiyun Deng,et al.  Autophagy and doxorubicin resistance in cancer. , 2018, Anti-cancer drugs.

[42]  Dangxia Zhou,et al.  Oral squamous cell carcinoma cells are resistant to doxorubicin through upregulation of miR-221 , 2017, Molecular medicine reports.

[43]  M. Zamanian-Azodi,et al.  Oral squamous cell cancer protein-protein interaction network interpretation in comparison to esophageal adenocarcinoma , 2017, Gastroenterology and hepatology from bed to bench.

[44]  Q. Mei,et al.  Doxorubicin and resveratrol co-delivery nanoparticle to overcome doxorubicin resistance , 2016, Scientific Reports.

[45]  W. Mesker,et al.  c-Myb Enhances Breast Cancer Invasion and Metastasis through the Wnt/β-Catenin/Axin2 Pathway. , 2016, Cancer research.

[46]  C. Dass,et al.  Increasing role of the cancer chemotherapeutic doxorubicin in cellular metabolism , 2016, The Journal of pharmacy and pharmacology.

[47]  Wanying Zhang,et al.  Resveratrol inhibits oral squamous cell carcinoma through induction of apoptosis and G2/M phase cell cycle arrest , 2016, Tumor Biology.

[48]  Jihye Kim,et al.  DSigDB: drug signatures database for gene set analysis , 2015, Bioinform..

[49]  Yung-Hyun Choi,et al.  Downregulation of Sp1 is involved in β-lapachone-induced cell cycle arrest and apoptosis in oral squamous cell carcinoma. , 2015, International journal of oncology.

[50]  Hui Liu,et al.  MiRNA and TF co-regulatory network analysis for the pathology and recurrence of myocardial infarction , 2015, Scientific Reports.

[51]  Bernadette A. Thomas,et al.  Global, regional, and national age–sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 , 2015, The Lancet.

[52]  S. Shojaosadati,et al.  Efficient delivery of therapeutic agents by using targeted albumin nanoparticles. , 2015, Advances in protein chemistry and structural biology.

[53]  M. Zeng,et al.  Down-regulation of Sp1 suppresses cell proliferation, clonogenicity and the expressions of stem cell markers in nasopharyngeal carcinoma , 2014, Journal of Translational Medicine.

[54]  Christie S. Chang,et al.  The BioGRID interaction database: 2013 update , 2012, Nucleic Acids Res..

[55]  Sean R. Davis,et al.  NCBI GEO: archive for functional genomics data sets—update , 2012, Nucleic Acids Res..

[56]  P. Álvarez,et al.  Doxorubicin-loaded nanoparticles: new advances in breast cancer therapy. , 2012, Anti-cancer agents in medicinal chemistry.

[57]  Stephen C. Harris,et al.  atBioNet– an integrated network analysis tool for genomics and biomarker discovery , 2012, BMC Genomics.

[58]  C. la Vecchia,et al.  Alcohol consumption and cancers of the oral cavity and pharynx from 1988 to 2009: an update , 2010, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[59]  Rafael A. Irizarry,et al.  A framework for oligonucleotide microarray preprocessing , 2010, Bioinform..

[60]  J. McDonald,et al.  Socio-economic factors and stage at presentation of head and neck cancer patients in Ottawa, Canada: a logistic regression analysis. , 2010, Oral oncology.

[61]  H. Logan,et al.  Factors associated with early-stage diagnosis of oral and pharyngeal cancer. , 2009, Community dentistry and oral epidemiology.

[62]  Dennis B. Troup,et al.  NCBI GEO: archive for high-throughput functional genomic data , 2008, Nucleic Acids Res..

[63]  John Boyle,et al.  Cytoscape: a community-based framework for network modeling. , 2009, Methods in molecular biology.

[64]  Nicole A. Johnson,et al.  Estrogen prevents sustained COLO-205 human colon cancer cell growth by inducing apoptosis, decreasing c-myb protein, and decreasing transcription of the anti-apoptotic protein bcl-2 , 2009, Tumor Biology.

[65]  Peter Boyle,et al.  Tobacco smoking and cancer: A meta‐analysis , 2008, International journal of cancer.

[66]  P. Petignat,et al.  Diagnosis and management of cervical cancer , 2007, BMJ : British Medical Journal.

[67]  Dennis B. Troup,et al.  NCBI GEO: mining tens of millions of expression profiles—database and tools update , 2006, Nucleic Acids Res..

[68]  S. Franceschi,et al.  Human Papillomavirus Types in Head and Neck Squamous Cell Carcinomas Worldwide: A Systematic Review , 2005, Cancer Epidemiology Biomarkers & Prevention.

[69]  C. Peters,et al.  Interferon-beta and interferon-gamma synergistically inhibit the replication of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) , 2004, Virology.

[70]  D. Hinton,et al.  Perforin and Gamma Interferon-Mediated Control of Coronavirus Central Nervous System Infection by CD8 T Cells in the Absence of CD4 T Cells , 2004, Journal of Virology.

[71]  Gary D. Bader,et al.  An automated method for finding molecular complexes in large protein interaction networks , 2003, BMC Bioinformatics.

[72]  M. Glick Burket's Oral Medicine , 2002 .

[73]  Alex E. Lash,et al.  Gene Expression Omnibus: NCBI gene expression and hybridization array data repository , 2002, Nucleic Acids Res..

[74]  K. Wakasa,et al.  Expression of p73 and p63 proteins in pancreatic adenocarcinoma: p73 overexpression is inversely correlated with biological aggressiveness. , 2001, International journal of molecular medicine.

[75]  M. Ogura [Adriamycin (doxorubicin)]. , 2001, Gan to kagaku ryoho. Cancer & chemotherapy.

[76]  M. Monden,et al.  Expression and Prognostic Role of Cyclin-Dependent Kinase 1 (cdc2) in Hepatocellular Carcinoma , 2000, Oncology.

[77]  F. Nally Screening for oral cancer. , 1992, The Practitioner.