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¹ Department of Oral Biology, Faculty of Dentistry, Health Sciences Center, University of Manitoba, Winnipeg, Manitoba, Canada; ² Department of Oral and Maxillofacial Surgery and Oral Diagnostic Sciences, College of Dentistry, University of Florida, Gainesville, Florida; and ³ Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas

Requests for reprints: Abhijit G. Banerjee, Department of Oral Biology, Faculty of Dentistry, Health Sciences Center, University of Manitoba, D-303, 780 Bannatyne Avenue, Winnipeg, Manitoba, Canada R3E 0W2. Phone: 204-789-3708; Fax: 204-789-3913. E-mail: banerjea{at}cc.umanitoba.ca

An early interventional effort in oral premalignancy requires novel molecular targets and diagnostic biomarkers to delay or reverse incidences of malignant progression. Microarray-based transcriptional profiling in disease states provides global insight into the causal biomolecular processes and novel pathways involved. In this study, we investigated transcript profiles in precancerous oral lesions to identify nearly 1,700 genes as significantly overexpressed or underexpressed and a primarily affected metabolic pathway that may be responsible for irreversible transition to progressive stages of oral cancer. For the first time, we show a convergence of several genes and pathways known for their oncogenic capabilities, in progression of premalignant oral epithelial tissues. This study consequently provides a molecular basis for persistent proinflammatory conditions in oral premalignant tissues. We found that lipocalin-type prostaglandin D₂ synthase (PTGDS), a key enzyme in the arachidonic acid metabolism pathway, as repressed in premalignant stages. We show the protective role of these enzyme-derived metabolites in inhibiting cell proliferation using an in vitro oral cancer progression model. We have also confirmed the overexpression of two invasion-related biomarkers, psoriasin (PSOR1) and versican (CSPG2), in oral premalignant and malignant archival tissues. Our results clearly indicate that pharmacologic intervention with anti-inflammatory prostaglandin D₂–like analogues may help prevent or delay oral epithelial carcinogenesis because of metabolic restoration of a negative feedback regulatory loop through its several cognate receptors or target molecules. Further studies directed toward a multitude of possible protective mechanisms of this lipocalin-type enzyme or its products in oral cancer progression are warranted.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: All authors were previously associated with University of Nebraska Medical Center. The studies were done at the senior author (J.K. Vishwanatha)'s laboratories at University of Nebraska Medical Center.

⁴ Softwares available at http://rana.stanford.edu/software

⁵ http://www.affymetrix.com/analysis/index.affx

⁶ http://david.niaid.nih.gov/david/ease.htm

⁷ http://www.genome.ad.jp/kegg/kegg2.html

⁸ http://analysis.ingenuity.com

⁹ http://www.GenMAPP.org

¹⁰ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 2/ 1/05; revised 3/ 9/05; accepted 4/13/05.