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Role of GL12 in oral mucosa maintenance and carcinogenesis

Institution: University of California, San Francisco
Investigator(s): Antoine Snijders, Ph.D.
Award Cycle: 2005 (Cycle 14) Grant #: 14FT-0011 Award: $73,485
Subject Area: Cancer
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract
Cancer is a disease where cells continue to grow without restrictions. Cancer cells invade and thereby destroy surrounding tissues and eventually lead to death. Cancer cells, unlike normal cells, grow without restrictions. This occurs through mutations in genes that are important in cell proliferation, cell death or cell differentiation, a process where immature, unspecialized cells become mature and take on a specific function within the organism. When enough mutations accumulate, a cell could become tumorigenic. Carcinogens present in tobacco smoke have shown to induce mutations that can lead to the development of cancer. Smoking tobacco is the primary etiological agent for oral cancer and all forms of tobacco smoking including cigarette, pipe and cigar, are strongly linked to oral cancer in a dose-dependent manner. Recently new high throughput techniques that identify molecular differences between normal and tumor cells have been applied to characterize oral cancers. These studies have revealed a number of previously unappreciated genes as candidates for participation in the process of oral cancer disease initiation or progression. Now, the challenge is to discover the role these genes might play in this disease.

Our previous research indicated that in some oral cancers the gene GLI2 (Gli-Kruppel Family Member 2) was activated far above levels of activation seen in normal oral tissue. This clearly indicates an important role of this gene in the development of oral cancer. However, a role for GLI2 in normal or tumorigenic oral tissue has not previously been established. GLI2 is a transcription factor, which functions by turning on other genes. The oral lining, which functions as a barrier between the oral lumen and the underlying tissue, is constantly renewed. Cells in the bottom layer of the oral lining, called the basal layer, furthest away from the oral lumen and tightly packed against the underlying tissue, constantly divide giving rise to two daughter cells. Subsequently, these cells move up towards the oral lumen, flatten out, die and eventually slough off into the oral lumen. It is known, from studies on other tissues, that GLI2 plays an important role in regulating this process. Therefore, we hypothesize that the main function of GLI2 is to maintain the normal architecture of the oral lining. In this proposal, we intend to explore the role of GLI2 in both normal and tumor oral tissue by first investigating where in the normal oral tissue architecture this gene is expressed. We will then ask where GLI2 is expressed in oral cancer and investigate if GLI2 expressing cells can be associated with any histologically observed tumor tissue structures. Finally, we will use an animal model system to investigate how overexpression of GLI2, as seen in a tumor, might result in the development of malignant lesions after exposure to a tobacco derived carcinogen. The specific question we ask is if GLI2 overexpression together with carcinogen exposure collaborate in the development, progression or maintenance of oral cancer.

In the United States, annually approximately 30,000 new cases of oral cancer are diagnosed. Smoking tobacco is the primary causative agent for oral cancer. In spite of treatment, which can be very disfiguring, only 40% of patients are alive 5 years after diagnosis. This diagnosis has not improved over the past 40 years. The development of targeted therapeutics for oral cancer demands a comprehensive understanding of the disease. The proposed experiments are relevant to achieve this goal since nearly 50% of oral cancer overexpress GLI2 while the function of GLI2 in normal and/or tumorigenic oral tissue is largely unknown. Therefore, this research will help us answer some of these questions in oral cancer.