Squamous cell carcinomas account for nearly 90% of the cancers in the oral cavity and there is dramatic new clinical evidence that retinoids (vitamin A and its natural and synthetic derivatives, including retinoic acid (RA) can suppress the development of oral squamous cell carcinomas in humans. The mechanism by which retinoids act to inhibit neoplastic transformation is unknown. Therefore, this grant proposes experiments aimed at measuring a number of different effects of retinoids in a variety of cultured normal human epithelia and in several human squamous cell carcinoma (SCC) lines from various regions of the oral cavity and facial epidermis. The normal human epithelial cell strains that will be analyzed include those from the soft palate, floor of mouth, buccal mucosa, ventral tongue, gingiva, hard palate, and facial epidermis. The squamous cell carcinoma (SCC) lines to be analyzed include those from the soft palate, the floor of mouth, the ventral tongue, and the facial epidermis. Preliminary experiments have shown that normal epithelial cell subtypes from different areas of the oral cavity display different degrees of responsiveness to the same concentration of retinoic acid added to the culture medium. A goal of future experiments is to understand the molecular basis for such differences in RA responsiveness. Specifically, we will quantitate the levels of expression of the genes that mediate RA action--the receptors RAR alpha, RAR beta, RAR gamma and RXR alpha; the CRABP and CRABP-II; and the CRBP. Because the intracellular metabolism of retinol and RA may differ in normal epithelial cell subtypes from different locations in the oral cavity, the metabolism of these agents will also be assessed. We have shown that the SCC lines display aberrant responses to RA. Specifically, the keratin K19 gene is aberrantly regulated (i.e., either expressed constitutively or not expressed at all) in the SCC lines; in contrast, in normal epithelial cells K19 expression is regulated by RA. Thus, the K19 gene will be analyzed to ascertain why it is no longer regulated by RA in SCC cells. Furthermore, no RAR beta mRNA expression is detected in the six SCC lines tested to date, even when the SCC lines are derived from a region of the oral cavity such as the soft palate, where normal epithelial cells exhibit high levels of RAR beta mRNA. Therefore, in future studies the RAR beta gene will be examined to determine why it is not expressed in SCC lines, and a functional RAR beta gene in an expression vector will be reintroduced into the SCC cells to determine if overexpression of the RAR beta gene reverses any of the tumorigenic properties of the SCCs. The metabolism of RA in the SCC lines will also be measured, as aberrant catabolism of RA may be related to the observed abnormalities in K19 and RAR beta expression in the SCC cells. These experiments should provide a greater understanding of the actions of RA in epithelial cells. More knowledge of the differences among normal epithelial cell subtypes from different regions of the oral cavity and between normal and malignant transformed epithelia will also be gained. These studies should lead to advances in the clinical treatment of cancerous and precancerous lesions in the oral cavity.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Oral Biology and Medicine Subcommittee 1 (OBM)
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Weill Medical College of Cornell University
Schools of Medicine
New York
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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
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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
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
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

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