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Microrna deregulation within optically altered oral cancer fields of non-smoker patients. Gorenchtein, Mike


BACKGROUND: Oral cancer is a devastating disease with a five-year survival rate of 50%. While tobacco remains a key etiological factor for oral cancer, cases in non-smoker patients are also reported. An improved understanding of the molecular basis of oral cancer, including the alterations contributing to disease in non-smokers, is essential. To date, the role of microRNAs (miRNAs) in oral tumorigenesis – and oral premalignant lesions specifically, is largely unknown. The objectives of this study were (1) to identify miRNAs that are deregulated at the premalignant and malignant stages of oral cancer in non-smoker patients, and (2) to elucidate their expression patterns throughout disease progression. METHODS: To remove variation due to timing differences in sampling, we analyzed global miRNA expression in varied stages of precancerous, cancerous and adjacent normal tissue biopsies obtained simultaneously from a single, contiguous field in a patient’s mouth. Total RNA was isolated from each microdissected specimen and profiled for the expression of 742 human miRNAs using Real-Time PCR. The expression of selected candidate miRNAs was further validated in an independent cohort of premalignant and malignant tissues via in situ hybridization (ISH). RESULTS: Overall, the amount of miRNA alterations was associated with lesion severity, suggesting that miRNA changes are accumulated during premalignant progression. In addition, we have identified distinct lists of candidate miRNAs that were consistently deregulated at specific histopathological disease states. Examination of the individual expression profiles of these candidates across sequential premalignant/malignant stages demonstrated that they follow distinct patterns of deregulation over time and may therefore function differently throughout oral tumorigenesis. ISH staining for one of the selected up-regulated candidates, miR-155, corresponded with its previous Real-Time PCR expression data and was further validated in independent dysplastic and malignant tissues. CONCLUSIONS: Our unique sample set allowed us to investigate intralesional progression within a single surgical field and delineate miRNA aberrations that may be driving this process. Collectively, our results suggest that miR-155 may represent a key driver of oral tumorigenesis and that molecular heterogeneity across fields of diseased tissue has significant implications when selecting candidates for development of novel targeted therapies or prognostic screening protocols.

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