| dc.description.abstract | Acquisition of ectopic expression of type 1 receptor for the fibroblast growth
factor receptor type1 (FGFR1) in prostate cancer (PCa) is well documented.
However, while it is known that FGFR confers a growth advantage and promotes
cell survival, how this aberrantly expressed transmembrane receptor tyrosine
kinase contributes to PCa progression is not fully understood. Therefore, we
investigated the roles of FGF signaling in both cancer metabolism and tumor
angiogenesis. In first part of our study, we used a TRAMP mouse model with
tissue specific deletion of fibroblast growth factor receptor substrate 2α (Frs2α),
a key adaptor protein of the FGF signaling, in the prostate epithelium to
investigate whether epithelial FGF signaling affects blood vessel cell
functionality. Results showed that deletion of Frs2α decreased the blood vessels
in prostate tumors. Similarly, conditioned medium of Frs2α knockdown prostate
cancer cells inhibited the tube formation of human umbilical vein endothelial
cells (HUVEC). Frs2α knockdown also decreased the ability of tumor cells to
recruit HUVECs. We also discovered that ablation of Frs2α decreased the
production of vascular endothelial growth factor A (VEGFA) primarily through
preventing the binding of transcription factors HIF1α and c-Jun to its promoter
region in prostate cancer cells and in vivo. We also demonstrated that
hyperactivity of Frs2α, as well as upregulation of c-Jun and HIF1α, were
positively associated with vessel density and progression of human PCa. In the
second part of this study, we reported that FGFR1 tyrosine kinase promoted
aerobic glycolysis via regulating the expression pattern of lactate
dehydrogenase (LDH): it tyrosine phosphorylated type A LDH (LDHA) and
enhanced its stability, which favors the conversion of pyruvate to lactate, and
therefore, decreases oxidative phosphorylation. Concurrently, FGFR1
downregulated the expression of type B LDH (LDHB) via increasing promoter
methylation, which favors the conversion of lactate to pyruvate. Furthermore,
consistent with the expression level of ectopic FGFR1, high levels of
phosphorylated LDHA accompanied by diminished LDHB were associated with
short overall survival and biochemical recurrence free survival time in PCa
patients. This suggests that the dysregulated expression of LDH isozymes is of
clinical value for PCa prognosis. | en |
