Understanding the transcriptional regulation of cervix cancer using microarray gene expression data and promoter sequence analysis of a curated gene set.

Cervical cancer, the malignant neoplasm of the cervix uteri is the second most common cancer among women worldwide and the top-most cancer in India. Several factors are responsible for causing cervical cancer, which alter the expression of oncogenic genes resulting in up or down-regulation of gene expression and inactivation of tumor-suppressor genes/gene products. Gene expression is regulated by interactions between transcription factors (TFs) and specific regulatory elements in the promoter regions of target genes. Thus, it is important to decipher and analyze TFs that bind to regulatory regions of diseased genes and regulate their expression. In the present study, computational methods involving the combination of gene expression data from microarray experiments and promoter sequence analysis of a curated gene set involved in the cervical cancer causation have been utilized for identifying potential regulatory elements. Consensus predictions of two approaches led to the identification of twelve TFs that might be crucial to the regulation of cervical cancer progression. Subsequently, TF enrichment and oncomine expression analysis suggested that the transcription factor family E2F played an important role for the regulation of genes involve in cervical carcinogenesis. Our results suggest that E2F possesses diagnostic/prognostic value and can act as a potential drug target in cervical cancer.

[1]  Long Yu,et al.  YY1 Is a Novel Potential Therapeutic Target for the Treatment of HPV Infection-Induced Cervical Cancer by Arsenic Trioxide , 2011, International Journal of Gynecologic Cancer.

[2]  M. Bulyk.  Computational prediction of transcription-factor binding site locations , 2003, Genome Biology.

[3]  David Bryant,et al.  DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists , 2007, Nucleic Acids Res..

[4]  Eytan Domany,et al.  Identification of a proliferation gene cluster associated with HPV E6/E7 expression level and viral DNA load in invasive cervical carcinoma , 2005, Oncogene.

[5]  Zihua Hu,et al.  Identification of interacting transcription factors regulating tissue gene expression in human , 2010, BMC Genomics.

[6]  M. Mansukhani,et al.  Integrative genomics analysis of chromosome 5p gain in cervical cancer reveals target over-expressed genes, including Drosha , 2008, Molecular Cancer.

[7]  B. Rose,et al.  Analysis of mutations in the URR and E6/E7 oncogenes of HPV 16 cervical cancer isolates from central China , 2000, International journal of cancer.

[8]  Gajendra P. S. Raghava,et al.  CCDB: a curated database of genes involved in cervix cancer , 2010, Nucleic Acids Res..

[9]  S. Um,et al.  Abrogation of IRF-1 response by high-risk HPV E7 protein in vivo. , 2002, Cancer letters.

[10]  D. Spandidos,et al.  Deregulation of the G1/S phase transition in cancer and squamous intraepithelial lesions of the uterine cervix: a case control study. , 2008, Oncology reports.

[11]  E. Lundberg,et al.  Towards a knowledge-based Human Protein Atlas , 2010, Nature Biotechnology.

[12]  M Arbyn,et al.  Worldwide burden of cervical cancer in 2008. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[13]  M. Jung,et al.  Elevated Expression of Thymosin β4, Vascular Endothelial Growth Factor (VEGF), and Hypoxia Inducible Factor (HIF)-1α in Early-Stage Cervical Cancers , 2011, Pathology & Oncology Research.

[14]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[15]  Vladimir B. Bajic,et al.  Identification of estrogen responsive genes using esophageal squamous cell carcinoma (ESCC) as a model , 2012, BMC Systems Biology.

[16]  M. Mansukhani,et al.  Identification of copy number gain and overexpressed genes on chromosome arm 20q by an integrative genomic approach in cervical cancer: Potential role in progression , 2008, Genes, chromosomes & cancer.

[17]  Weiguo Lu,et al.  Identification of suitable reference genes for measurement of gene expression in human cervical tissues. , 2010, Analytical biochemistry.

[18]  D. Pim,et al.  Regulation of the human papillomavirus oncoproteins by differential phosphorylation. , 2001 .

[19]  F. Stubenrauch,et al.  Prevalence of deletions of YY1‐binding sites in episomal HPV 16 DNA from cervical cancers , 1994, International journal of cancer.

[20]  Je‐ho Lee,et al.  Alternative splicing variants of IRF-1 lacking exons 7, 8, and 9 in cervical cancer. , 2006, Biochemical and biophysical research communications.

[21]  D. Spandidos,et al.  Overexpression of VEGF and TGF-beta1 mRNA in Pap smears correlates with progression of cervical intraepithelial neoplasia to cancer: implication of YY1 in cervical tumorigenesis and HPV infection. , 2007, International journal of oncology.

[22]  N. Concin,et al.  Expression of the E2F Family of Transcription Factors and Its Clinical Relevance in Ovarian Cancer , 2006, Annals of the New York Academy of Sciences.

[23]  Bin Nan,et al.  Gene expression analysis of preinvasive and invasive cervical squamous cell carcinomas identifies HOXC10 as a key mediator of invasion. , 2007, Cancer research.

[24]  R. Kirby,et al.  Measurement of blood E2F3 mRNA in prostate cancer by quantitative RT-PCR: a preliminary study , 2007, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[25]  T. Barrette,et al.  Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. , 2007, Neoplasia.

[26]  S. Agarwal.  Evolutionary rate variation in eukaryotic lineage specific human intronless proteins. , 2005, Biochemical and biophysical research communications.

[27]  Martin Vingron,et al.  PASTAA: identifying transcription factors associated with sets of co-regulated genes , 2008, Bioinform..

[28]  D. Banerjee,et al.  E2F-1 as an anticancer drug target , 2011 .

[29]  F. Stubenrauch,et al.  The E6/E7 promoter of extrachromosomal HPV16 DNA in cervical cancers escapes from cellular repression by mutation of target sequences for YY1. , 1994, The EMBO journal.

[30]  Wyeth W. Wasserman,et al.  JASPAR: an open-access database for eukaryotic transcription factor binding profiles , 2004, Nucleic Acids Res..

[31]  Tzu-Hao Wang,et al.  Molecular characterization of adenocarcinoma and squamous carcinoma of the uterine cervix using microarray analysis of gene expression , 2006, International journal of cancer.

[32]  David I. Smith,et al.  Genome‐wide gene expression profiling of cervical cancer in Hong Kong women by oligonucleotide microarray , 2006, International journal of cancer.

[33]  Omodele Ibraheem,et al.  In silico analysis of cis-acting regulatory elements in 5' regulatory regions of sucrose transporter gene families in rice (Oryza sativa Japonica) and Arabidopsis thaliana , 2010, Comput. Biol. Chem..

[34]  Marrije R Buist,et al.  Gene expression in early stage cervical cancer. , 2008, Gynecologic oncology.

[35]  O. Elemento,et al.  Revealing global regulatory perturbations across human cancers. , 2009, Molecular cell.

[36]  Wen-Ting Yang,et al.  Krüppel‐like factor 4 functions as a tumor suppressor in cervical carcinoma , 2012, Cancer.

[37]  Eytan Domany,et al.  Wide-Scale Analysis of Human Functional Transcription Factor Binding Reveals a Strong Bias towards the Transcription Start Site , 2007, PloS one.

[38]  Wen-Chang Chang,et al.  Epidermal Growth Factor-activated Aryl Hydrocarbon Receptor Nuclear Translocator/HIF-1β Signal Pathway Up-regulates Cyclooxygenase-2 Gene Expression Associated with Squamous Cell Carcinoma* , 2009, Journal of Biological Chemistry.

[39]  Igor Jurisica,et al.  Gene Expression Profiling in Cervical Cancer: An Exploration of Intratumor Heterogeneity , 2006, Clinical Cancer Research.

[40]  M. Widschwendter,et al.  DNA Methylation in Serum and Tumors of Cervical Cancer Patients , 2004, Clinical Cancer Research.

[41]  Rajash Pallai,et al.  Ets1 and Elk1 transcription factors regulate cancerous inhibitor of protein phosphatase 2A expression in cervical and endometrial carcinoma cells , 2012, Transcription.

[42]  Nicolas Lützner,et al.  Gene Expression of the Tumour Suppressor LKB1 Is Mediated by Sp1, NF-Y and FOXO Transcription Factors , 2012, PloS one.

[43]  Wyeth W. Wasserman,et al.  ConSite: web-based prediction of regulatory elements using cross-species comparison , 2004, Nucleic Acids Res..

[44]  Vladimir B. Bajic,et al.  In Silico discovery of transcription factors as potential diagnostic biomarkers of ovarian cancer , 2011, BMC Systems Biology.

[45]  A. Fink-Retter,et al.  Gene profiling in Pap-cell smears of high-risk human papillomavirus-positive squamous cervical carcinoma. , 2007, Gynecologic oncology.

[46]  V. Leaner,et al.  Overexpression of Kpnβ1 and Kpnα2 Importin Proteins in Cancer Derives from Deregulated E2F Activity , 2011, PloS one.

[47]  T. Werner,et al.  Linking disease-associated genes to regulatory networks via promoter organization , 2005, Nucleic acids research.

[48]  M. Piris,et al.  E2F1 expression is deregulated and plays an oncogenic role in sporadic Burkitt's lymphoma. , 2009, Cancer research.

[49]  E. A. Ananko,et al.  Bioinformatical and experimental approaches to investigation of transcription factor binding sites in vertebrate genes , 2007, Biochemistry (Moscow).

[50]  Subhash Mohan Agarwal,et al.  Comparative analysis of human intronless proteins. , 2005, Biochemical and biophysical research communications.

[51]  Eugene Berezikov,et al.  CONREAL: conserved regulatory elements anchored alignment algorithm for identification of transcription factor binding sites by phylogenetic footprinting. , 2003, Genome research.

[52]  Martin S. Taylor,et al.  The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line , 2009, Nature Genetics.

[53]  T. Iftner,et al.  Gene expression profiles reveal an upregulation of E2F and downregulation of interferon targets by HPV18 but no changes between keratinocytes with integrated or episomal viral genomes. , 2006, Virology.