AbstractsBiology & Animal Science

Glioblastoma multiforme (GBM) is the most common form of cancer in the central nervous system in adults. Because of the infiltrative and aggressive nature of GBM, current treatments including surgical resection, radiation and chemotherapy provide little benefit to patients diagnosed with this tumor. Median survival, after treatment, is less than one year. Despite advances in the basic understanding of cancer biology, this poor prognosis has remained virtually unchanged for several decades. Given the continuing difficulty of clinical treatment of GBMs, a molecular appreciation of relevant signaling pathways has grown. Signal Transducers and Activators of Transcription (STATs) function to activate gene transcription in response to numerous cytokines, controlling proliferation, gene expression and apoptosis. The transcriptional activation of STAT proteins, including STAT-3, is positively regulated by tyrosine phosphorylation and enhanced by serine phosphorylation. STAT-3 is a transcription factor whose aberrant activation has been identified in GBM and a number of other human cancers including breast, lung, ovarian, pancreatic, skin, and prostate cancers, as well as Hodgkins lymphoma, myeloma, and acute myeloid leukemia. In this dissertation, we characterized the expression of STAT-3, as well as its endogenous inhibitors, in human GBM. Using tissue samples from both control and GBM brains, this study examined expression of STAT-3, and its negative regulator, Protein Inhibitor of Activated STAT-3 (PIAS3). We demonstrated that STAT-3 activation, as assessed by tyrosine and serine phosphorylation, was elevated in GBM tissue compared to control tissue. Interestingly, we detected expression of PIAS3 in control tissue, while PIAS3 protein expression in GBM tissue was greatly reduced. Using siRNA to reduce constitutive PIAS3 expression in glioblastoma cell lines, enhanced cellular proliferation was observed. Conversely, over-expression of PIAS3 inhibited STAT-3 transcriptional activity and proliferation of GBM cells. Thus, the loss of PIAS3 in GBM may contribute to enhanced STAT-3 signaling and proliferation of glioma cells. STAT-3 remains a clinically relevant target in the treatment of many cancers, including GBM. Future studies should be aimed at defining the molecular basis underlying the loss of PIAS3 protein in GBM tissues. vii, 92 p. : ill., digital, PDF file Cell Biology Joint Health Sciences Gliomas Signal transduction STATs UNRESTRICTED