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UBC Theses and Dissertations

Semaphorin 3C in prostate cancer tumourigenesis Tam, Kevin J.


Prostate cancer (PCa) is among the most commonly-occurring cancers worldwide and a leading cause of cancer-related deaths in men. Local non-invasive PCa is highly treatable but limited treatment options exist for those with locally-advanced and metastatic forms of the disease. This underscores the need to identify mechanisms mediating PCa progression. One well-established driver of PCa progression is the androgen receptor protein whose transcriptional targets include genes related to cell growth and cell cycle progression. Consequently, the androgen receptor axis is the target of many therapies for those with PCa. Another important aspect of disease progression relates to cancer spread or metastasis. Epithelial-to-mesenchymal transition (EMT) is a cellular process executed during embryogenesis and is defined as the transition of cells from an epithelial phenotype to a mesenchymal phenotype. It is suspected that metastasis is, in part, due to inadvertent re-activation of EMT. Another theorized cause of cancer progression is due to the existence of tumour-initiating cells or ‘cancer stem cells’ which resist conventional radiation- and chemotherapies and seed relapse and metastasis. The semaphorins are a large grouping of membrane-associated or s¬ecreted signalling proteins whose normal roles reside in embryogenesis and neuronal development. During these processes the semaphorins establish chemotactic gradients and direct cell movement. Various semaphorin family members have been found to be up- or downregulated in a number of cancers. One family member, semaphorin 3C (SEMA3C), has been implicated in several types of cancer and its increased expression is correlated with PCa stage. Given SEMA3C’s roles in development and its augmented expression in PCa, we hypothesized that SEMA3C promotes cancer progression by driving EMT and stem-like characteristics. In the present study, we show that SEMA3C is a direct transcriptional target of the androgen receptor and further show that ectopic expression of SEMA3C in RWPE-1, a normal prostate epithelial cell line, leads to an upregulation of EMT and stem markers which is accompanied by acquisition of invasiveness and stem-like phenotypes. The broader impact of this work pertains to the clinical implications of SEMA3C’s involvement in PCa and linking SEMA3C and AR to metastatic recurrent PCa.

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