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Secreted microRNAs and their role in cancer promotion and detection Dickman, Christopher TD

Abstract

Oral squamous cell carcinoma (OSCC) is the most common form of head and neck cancer. Although there have been improvements in detection and treatment with the development of targeted therapies, OSCC has a low five-year survival rate which has shown little improvement in recent history. OSCCs are known to secrete extracellular vesicles (EVs) into the extracellular space including into the blood stream. These EVs contain a wide variety of different molecules capable of effecting cancer processes including mRNAs, miRNAs, and proteins. By performing an in depth analysis we will gain a better understanding on how OSCC secreted miRNAs are capable of acting as messages between cancerous and stromal cells. Additionally, I have presented data on how these miRNAs can be exploited for their ability to act as biomarkers. In this thesis I first described which miRNAs are altered in patients with oral cancer or carcinoma in situ and determined that this altered expression is capable of predicting cancer status. After validating the suitability of cell lines as an OSCC model, I examined if altered serum miRNAs overlap with miRNAs which are selectively secreted from oral cancer cell lines. Follow-up functional analysis was performed for miR-142-3p and it was determined that this miRNA was being secreted in order to remove it’s tumor suppressive effect within the cancer cell and additionally to transfer a tumor promoting signal to endothelial cells of the tumor stroma. To confirm that this was not an isolated phenomenon I examined the function of miR-142-3p when secreted from lung cancer cells and noticed a similar effect in endothelial cells and an additional effect on fibroblasts. Effected fibroblasts underwent changes associated with wound healing and tumor promotion. These data taken together provide a comprehensive analysis of the alterations of secreted miRNAs in OSCC and provide insight in the ability of some miRNAs to serve a dual role both within the tumor cells and cells of the tumor stroma. It is possible these results could lead to the creation of a diagnostic test with possible future applications to the diagnosis of oral cancer.

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Attribution-NonCommercial-NoDerivatives 4.0 International

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