The metabolism of retinoids and the regulation of gene expression by retinoids (vitamin A) (retinol, its metabolites and analogs) are profoundly altered in human head and neck squamous cell carcinomas (HNSCCs). We hypothesize that these changes contribute to carcinogenesis and tumor progression. Over the past grant period we have demonstrated that human HNSCC lines exhibit greatly reduced levels of the enzyme involved in esterifying vitamin A lecithin:retinol acyltransferase (LRAT). As a result of this very low or absent expression of LRAT, the tumor cells are essentially vitamin A deficient as compared to normal epithelial cell strains from the oral cavity or skin. We have also generated transgenic mice, which overexpress the LRAT protein in different layers of the oral cavity epithelium. We have developed an improved model for the study of the development and treatment of HNSCC. In this model, CBA or C57B1/6 mice are given a carcinogen, 4-nitroquiniline oxide (4-NQO), in their drinking water. Over the next grant period we propose to define the molecular bases for the failure of many human HNSCC lines to express genes in retinoid metabolism (e.g. LRAT), and genes involved in retinoid signaling (e.g. the retinoid receptors, RARs and RXRs), by employing chromatin immunoprecipitation (CHIP) and real time RT-PCR assays to study their transcriptional regulation (AIM la). To attempt to restore normal retinoid signaling and growth inhibition pathways in HNSCC lines, we will use pharmacological doses of retinoids in combination with other drugs, including dietary RXR (retinoid X receptor) agonists (e.g. the omega-3 fatty acid docosahexaenoic acid), histone deacetylase inhibitors such as valproic acid, and demethylating agents (AIM lb). We will also determine if these drug combinations can restore normal vitamin A uptake and metabolism in the human HNSCC lines (AIM lc). These cancer chemoprevention and therapeutic strategies will be tested concurrently in the mouse model of HNSCC, which we have developed (AIM 2). In this mouse model of 4-NQO-induced HNSCC, we will determine whether retinoid signaling abnormalities develop during the carcinogenesis process, and whether the combination therapies involving retinoids plus transcription modulating drugs either prevent tumors from forming and/or slow tumor progression (AIM 2a). The possible protective role of LRAT in the carcinogenesis process will be assessed by employing the LRAT overexpressing transgenic mice (AIM 2b). The importance of individual receptors will be assessed by using RARalpha RARgamma, or RARbeta null mice in the 4-NQO HNSCC model (AIM 2c). The proposed experiments will define key changes in retinoid metabolism and signaling in the progression of tumors of the oral cavity, allow us to develop strategies to reverse some of these changes, provide a rationale and preclinical data to support the development of improved therapies for humans, and allow further development of a mouse model of HNSCC which is amenable to genetic manipulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE010389-15
Application #
7454171
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Shirazi, Yasaman
Project Start
1992-06-01
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2010-04-30
Support Year
15
Fiscal Year
2008
Total Cost
$336,748
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Laursen, Kristian B; Gudas, Lorraine J (2018) Combinatorial knockout of RAR?, RAR?, and RAR? completely abrogates transcriptional responses to retinoic acid in murine embryonic stem cells. J Biol Chem 293:11891-11900
Tang, Xiao-Han; Urvalek, Alison M; Osei-Sarfo, Kwame et al. (2015) Gene expression profiling signatures for the diagnosis and prevention of oral cavity carcinogenesis-genome-wide analysis using RNA-seq technology. Oncotarget 6:24424-35
Urvalek, Alison M; Osei-Sarfo, Kwame; Tang, Xiao-Han et al. (2015) Identification of Ethanol and 4-Nitroquinoline-1-Oxide Induced Epigenetic and Oxidative Stress Markers During Oral Cavity Carcinogenesis. Alcohol Clin Exp Res 39:1360-72
Trasino, Steven E; Tang, Xiao-Han; Jessurun, Jose et al. (2015) Obesity Leads to Tissue, but not Serum Vitamin A Deficiency. Sci Rep 5:15893
Trasino, Steven E; Benoit, Yannick D; Gudas, Lorraine J (2015) Vitamin A deficiency causes hyperglycemia and loss of pancreatic ?-cell mass. J Biol Chem 290:1456-73
Osei-Sarfo, Kwame; Urvalek, Alison M; Tang, Xiao-Han et al. (2015) Initiation of esophageal squamous cell carcinoma (ESCC) in a murine 4-nitroquinoline-1-oxide and alcohol carcinogenesis model. Oncotarget 6:6040-52
Marcinkiewicz, Katarzyna M; Gudas, Lorraine J (2014) Altered histone mark deposition and DNA methylation at homeobox genes in human oral squamous cell carcinoma. J Cell Physiol 229:1405-16
Urvalek, Alison; Laursen, Kristian Bruun; Gudas, Lorraine J (2014) The roles of retinoic acid and retinoic acid receptors in inducing epigenetic changes. Subcell Biochem 70:129-49
Marcinkiewicz, Katarzyna M; Gudas, Lorraine J (2014) Altered epigenetic regulation of homeobox genes in human oral squamous cell carcinoma cells. Exp Cell Res 320:128-43
Tang, Xiao-Han; Osei-Sarfo, Kwame; Urvalek, Alison M et al. (2014) Combination of bexarotene and the retinoid CD1530 reduces murine oral-cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide. Proc Natl Acad Sci U S A 111:8907-12

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