Abstract 1087: Semaphorin 3C drives invasiveness in prostate cells through epithelial-to-mesenchymal transition and stemness
Authors: Kevin J. Tam, Daniel H. Hui, Wilson C. Lee, Mingshu Dong, Tabitha Tombe, Ivy Z. Jiao, Shahram Khosravi, Ario Takeuchi, James W. Peacock, Larissa Ivanova, Igor Moskalev, Martin E. Gleave, Ralph Buttyan, Michael E. Cox, Christopher J. Ong
Journal: Cancer Research (2018)

Abstract Our work sets out to show that semaphorin 3C is a driver of epithelial-to-mesenchymal transition and stemness in prostate cancer. Prostate cancer (PCa) is among the most commonly-occurring non-cutaneous cancers 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 underscoring the need to identify mechanisms mediating PCa progression. The semaphorins are a large grouping of membrane-associated or secreted chemotactic proteins whose normal functions reside in embryogenesis and development where they are responsible for directing cell movement. Semaphorins act through autocrine, paracrine, and juxtacrine signaling and have been implicated in a broad range of biological functions ranging from tissue morphogenesis to immunity; altered semaphorin expression has also been observed in numerous cancers. One member of the class 3 semaphorins, semaphorin 3C (SEMA3C), has been implicated in several forms of cancer and its increased expression is correlated with prostate cancer severity. Additionally, SEMA3C has been shown to be upregulated in response to chemotherapy and radiation treatment, promote metastasis to the lung, and promote tumourigenicity of glioma cells. SEMA3C has also been documented to increase cell proliferation and migration, decrease apoptosis, and promote integrin signaling and VEGF secretion in endothelial cells. SEMA3C was shown to drive migration of breast cancer cells and recent studies have highlighted the importance and prognostic value of SEMA3C in prostate cancer. Given SEMA3C's roles in development and its augmented expression in PCa, we hypothesized that SEMA3C promotes cancer progression by driving mesenchymal and stem-like phenotypes. Other class 3 semaphorins have been shown to drive EMT and the link between SEMA3C and stemness has been established in glioma cells. In the present study, using gain of function studies coupled to gene expression (qPCR, Western blot, FACS, immunofluorescence microscopy) and functional studies (migration, invasion, and sphere-forming assays) we show that ectopic expression of SEMA3C in RWPE-1, a normal prostate epithelial cell line, promotes epithelial-to-mesenchymal transition and stemness. Specifically, we find that overexpression of SEMA3C leads to an upregulation of EMT markers and migratory and invasive phenotypes. SEMA3C overexpression was also associated with an upregulation of the cancer stem cell marker, CD44, and heightened sphere-forming capabilities. Additionally, using ultrasound-guided intracardiac injection of SEMA3C-overexpressing cells, we show that SEMA3C drives cell dissemination in vivo. We conclude from our studies that SEMA3C is a driver of prostate cancer by promoting epithelial-to-mesenchymal transition and stemness. Citation Format: Kevin J. Tam, Daniel H. Hui, Wilson C. Lee, Mingshu Dong, Tabitha Tombe, Ivy Z. Jiao, Shahram Khosravi, Ario Takeuchi, James W. Peacock, Larissa Ivanova, Igor Moskalev, Martin E. Gleave, Ralph Buttyan, Michael E. Cox, Christopher J. Ong. Semaphorin 3C drives invasiveness in prostate cells through epithelial-to-mesenchymal transition and stemness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1087.