Expression of HIF-1a and VEGF in human pituitary tumors and rodent pituitary tumor cell lines under hypoxia-mimicking condition

Hypoxia inducible factor 1a (HIF-1a) is a transcription factor regulating expression of several genes related to oxygen homeostasis in response to hypoxic stress. Many studies have shown that the level of HIF-1a is remarkably high in tumors to increase oxygen availability by promoting erythropoiesis and angiogenesis. Transcriptional regulation of vascular endothelial growth factor (VEGF) is critically dependent on HIF-1a, and VEGF is a key mediator of the angiogenic process. Although coexistence of high levels of both HIF-1a and VEGF has been demonstrated in several kinds of tumors, the situation in pituitary adenomas is still unclear. Preliminary immunohistochemical studies in cryostat sections of three corticotroph adenomas, five somatotroph tumors and two prolactinomas have shown that two corticotrophic adenomas and two somatotrophic adenomas have significantly higher levels of HIF-1a and VEGF compared with normal human pituitary. In order to investigate the regulation of HIF-1a and VEGF under hypoxic condition, we stimulated mouse folliculostellate-like TtT/GF and corticotroph AtT20 pituitary tumor cell lines with cobalt chloride, which is a well-known hypoxia-mimicking agent. Results from western blot have shown that the level of HIF-1a is time and dose dependently increased in both of the cell lines, and removing cobalt chloride led to a decrease of HIF-1a. VEGF was time and dose dependently stimulated in TtT/GF cells but not in AtT20 cells. Our preliminary findings suggest that the levels of HIF-1a and VEGF increase in some pituitary adenomas, even though the pituitary adenomas progress extremely slowly, and also increase in some pituitary cell lines under hypoxia-mimicking conditions. Whether RSUME (RWD-containing sumoylation enhancer) is involved in the regulation of HIF-1a under hypoxia in pituitary tumor cell lines is being studied. More recently, we have demonstrated that the level of HIF-1a increased after treatment with platelet-derived growth factor in TtT/GF cells and rat somatotroph MtT-S pituitary tumor cells, and we are currently investigating whether the ROS pathway is involved.