HDA / ARTURO SANTIAGO, DMD
STUDENT SCIENTIFIC RESEARCH COMPETITION
(SPONSORED BY DENTSPLY INTERNATIONAL)

Winner of the $1,000 award for best scientific research



Bojana Bojovic and David L. Crowe
University of Illinois College of Dentistry

Scientific Abstract Title
Shortened Telomeres and Increased Metastasis inTelomerase Deficient Oral Cancer

Telomerase is a ribonucleoprotein which maintains chromosomal ends (telomeres) and is overexpressed in many cancers. Oral cancer arises from the telomerase-positive basal cell layer of oral stratified squamous epithelium. Telomerase activity is repressed as basal cells differentiate but continues to be expressed in oral cancer cells. Telomerase is considered an important molecular target for cancer therapy. Objectives: To determine the effects of telomere length on oral carcinogenesis, we developed a new mouse oral cancer model in which the telomerase RNA component Terc was disrupted by homologous recombination. Methods: Following institutional guidelines, first (G1, long telomeres) and fifth (G5, short telomeres) generation Terc -/- mice were orally dosed with 25 ug of the carcinogen 9,10-dimethyl-1,2- benzanthracene twice weekly. Terc +/+ animals were used as a control group. Complete necropsy was performed on all mice. Tumor tissue was processed for histopathologic and immunohistochemical analysis. Total RNA was extracted from microdissected tumor tissue for gene expression analysis (Affymetrix GeneChip mouse genome 430 2.0 microarray). Results: Compared to Terc +/+ mice, G1 Terc -/- animals developed significantly fewer metastatic cervical lymph nodes (p < 0.001). However, G5 Terc -/-mice with shortened telomeres showed no significant differences in the number of metastatic lymph nodes compared to Terc +/+ animals (p < 0.09). Transcriptional profiling showed distinct gene expression signatures between metastatic tumors in wild type and Terc -/- mice. In primary tumors, there were no significant differences in latency period or histopathologic grade between wild type and Terc -/- animals. Primary tumors recapitulated gene expression changes frequently observed in human oral cancer (epidermal growth factor receptor overexpression, loss of cyclin dependent kinase inhibitor p16INK4A expression). Conclusion: We concluded that telomere length and telomerase activity were important regulators of cervical lymph node metastasis in a novel mouse model of oral carcinogenesis. Supported by NIH grant DE14283.