This is a competitive renewal of grant """"""""Genomic Scanning for Epigenetic and Genetic alterations in Head and neck cancer"""""""". The previous grant has been successfully completed and resulted in a wealth of data describing altered DMA methylation and DMA amplification in head and neck squamous cell carcinoma (HNSCC). One of the novel genes (transcription factor 21 orTCF21), identified on chromosome 6q23-24, a region frequently lost in HNSCC, as well as other malignancies has tumor suppressor function, as well as metastasis suppressing activity. TCF21 is a frequent target for altered DMA methylation in human tumors and is transcriptionally silenced by DMA methylation. We provide preliminary data supporting our hypothesis that TCF21 is a novel tumor/metastasis suppressor gene. To address this hypothesis, we propose three specific aims. (1) In aim 1 we will investigate expression patterns of TCF21 and possible alternative splice forms in various normal tissues and cancer cell lines and evaluate in detail how DMA methylation contributes to DMA silencing. We will next evaluate the mutational spectrum of TCF21 in HNSCC and lung cancer to determine the importance of TCF21 silencing in each tumor type. (2) In aim 2 we propose experiments that will help to understand how TCF21 contributes to tumorgenesis and identify binding partners and target genes specific for different tissues using a combination of expression array, ChIP, yeast two hybrid and luciferase assays. (3) In aim 3 we will utilize mouse models to further investigate the role of TCF21. We are planning nude mouse tumorigenicity and metastasis assays, we are proposing a carcinogenesis experiment with Tcf21 heterozygous knock out mice;and will investigate Tcf21 and downstream targets in a mouse model for oral cavity carcinogenesis and lung carcinogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE013123-09
Application #
7795936
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Venkatachalam, Sundaresan
Project Start
2000-04-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
9
Fiscal Year
2010
Total Cost
$259,281
Indirect Cost
Name
German Cancer Research Center
Department
Type
DUNS #
325989556
City
Heidelberg
State
Country
Germany
Zip Code
69120
Chaisaingmongkol, J; Popanda, O; Warta, R et al. (2012) Epigenetic screen of human DNA repair genes identifies aberrant promoter methylation of NEIL1 in head and neck squamous cell carcinoma. Oncogene 31:5108-16
Claus, Rainer; Hackanson, Björn; Poetsch, Anna R et al. (2012) Quantitative analyses of DAPK1 methylation in AML and MDS. Int J Cancer 131:E138-42
Park, Yoon Jung; Claus, Rainer; Weichenhan, Dieter et al. (2011) Genome-wide epigenetic modifications in cancer. Prog Drug Res 67:25-49
Arab, Khelifa; Smith, Laura T; Gast, Andreas et al. (2011) Epigenetic deregulation of TCF21 inhibits metastasis suppressor KISS1 in metastatic melanoma. Carcinogenesis 32:1467-73
Bennett, Kristi L; Romigh, Todd; Arab, Khelifa et al. (2009) Activator protein 2 alpha (AP2alpha) suppresses 42 kDa C/CAAT enhancer binding protein alpha (p42(C/EBPalpha)) in head and neck squamous cell carcinoma. Int J Cancer 124:1285-92
Lin, Mauting; Morrison, Carl D; Jones, Susie et al. (2009) Copy number gain and oncogenic activity of YWHAZ/14-3-3zeta in head and neck squamous cell carcinoma. Int J Cancer 125:603-11
Pallasch, Christian Philipp; Patz, Michaela; Park, Yoon Jung et al. (2009) miRNA deregulation by epigenetic silencing disrupts suppression of the oncogene PLAG1 in chronic lymphocytic leukemia. Blood 114:3255-64
Schmezer, P; Plass, C (2008) [Epigenetic aspects in carcinomas of the head and neck] HNO 56:594-602
Bennett, Kristi L; Karpenko, Matthew; Lin, Mau-Ting et al. (2008) Frequently methylated tumor suppressor genes in head and neck squamous cell carcinoma. Cancer Res 68:4494-9
Smiraglia, Dominic J; Kazhiyur-Mannar, Ramakrishnan; Oakes, Christopher C et al. (2007) Restriction landmark genomic scanning (RLGS) spot identification by second generation virtual RLGS in multiple genomes with multiple enzyme combinations. BMC Genomics 8:446

Showing the most recent 10 out of 27 publications