An examination of the functional role of TMEFF2 in prostate cancer and the translational regulatory mechanisms controlling its expression
Overcash, Ryan Franklin
Prostate cancer is the most commonly diagnosed cancer in American men and accounts for approximately 11% of cancer-related deaths. Although promising treatment strategies have been developed and are currently being tested in clinical trials, standard practices in the treatment of prostate cancer remain inadequate. This is due in large part to the heterogeneous and multifocal nature of prostate tumors which severely complicates efforts to stratify patients and to identify therapeutic targets to effectively treat prostate cancer. A better understanding of the molecular mechanisms that drive prostate cancer initiation and progression to advanced stages is needed in order to design effective diagnostic and treatment strategies. The transmembrane protein with EGF-like and two follistatin domains 2 (TMEFF2) is selectively expressed in the adult brain and the prostate and is overexpressed in prostate cancer, suggesting a potential role in the establishment and/or progression of the disease. Previous reports on TMEFF2 function have revealed a complex biology with seemingly diverse cellular effects, and its role in prostate cancer has remained unclear. The studies presented here examine the biological function of TMEFF2 in prostate cancer in order to evaluate its potential as a molecular target for prostate cancer or as a diagnostic/prognostic biomarker. Data obtained using prostate cancer cell lines pointed to a role for TMEFF2 as a tumor suppressor as its overexpression resulted in a potent inhibition of anchorage-independent growth, reduced proliferation rates, the promotion of apoptosis, and a decrease in invasion. The tumor suppressor function of TMEFF2 was further demonstrated through the inhibition of subcutaneous tumor development in a TRAMP-C2 allograft model. Evidence that TMEFF2 expression can be upregulated by androgen stimulation in a post-transcriptional fashion suggests a potential mechanism by which its expression can be modulated in prostate cancer. We therefore investigated the post-transcriptional regulatory pathway controlling the expression of TMEFF2 in prostate cancer cells and its connection with androgen signaling. The presence of conserved upstream open reading frames (uORFs) in the 5' leader region of its mRNA transcript prompted us to investigate the possibility that androgen signaling stimulates TMEFF2 translation through these regulatory sequences. Our results show that TMEFF2 translation is inhibited by its uORFs under normal conditions; however, the uORFs mediate a translational increase in TMEFF2 expression in response to androgen stimulation through the phosphorylation of the initiation factor eIF2α. This effect is dependent on a functional androgen receptor (AR). During the course of prostate tumorigenesis, the selective translational increase in uORF-containing transcripts by androgen signaling may represent a mechanism by which certain transcripts are selectively regulated to influence tumor progression. As a tool to study role of TMEFF2 in prostate tumorigenesis in vivo and to evaluate its potential as a biomarker, we generated and initiated the characterization of a novel transgenic mouse model with TMEFF2 expression exclusively in the prostate epithelium. Ultimately this model will be used to study the function of TMEFF2 in the development/function of the prostate gland and in prostate cancer.
Overcash, Ryan Franklin. (January 2012). An examination of the functional role of TMEFF2 in prostate cancer and the translational regulatory mechanisms controlling its expression (Doctoral Dissertation, East Carolina University). Retrieved from the Scholarship. (http://hdl.handle.net/10342/4107.)
Overcash, Ryan Franklin. An examination of the functional role of TMEFF2 in prostate cancer and the translational regulatory mechanisms controlling its expression. Doctoral Dissertation. East Carolina University, January 2012. The Scholarship. http://hdl.handle.net/10342/4107. October 14, 2019.
Overcash, Ryan Franklin, “An examination of the functional role of TMEFF2 in prostate cancer and the translational regulatory mechanisms controlling its expression” (Doctoral Dissertation., East Carolina University, January 2012).
Overcash, Ryan Franklin. An examination of the functional role of TMEFF2 in prostate cancer and the translational regulatory mechanisms controlling its expression [Doctoral Dissertation]. Greenville, NC: East Carolina University; January 2012.
East Carolina University