Evolution of the Perlecan/HSPG2 gene and Regulation of its Expression by Inflammatory Cytokines in Normal Tissue Models and Cancer
Warren, Curtis Robert
Gustin, Michael C.
Doctor of Philosophy
Perlecan is the large heparan sulfate proteoglycan common to all basement membranes. It has numerous functions in maintenance of BM integrity, cell signaling and scaffolding protein interactions. Perlecan accumulation is elevated in wound healing and is essential to organismal development. In this work the evolution of perlecan and its role in the simplest and most ancient animals are explored. Transcriptional regulation of the HSPG2 gene also is examined in human prostate cancer and associated stromal cells. The protein was elevated in the reactive stroma of primary prostate cancer and TNF-α was identified as the primary driver of HSPG2 expression induction in various prostate cancer, prostate stromal and bone marrow stromal cell lines. Various aspects of this response echo the fibroblastic response to wounding and tumor progression. HSPG2 homologues were found in the genomes of the cnidarian, Nematostella vectensis, and the placozoan, Trichoplax adhaerens. Thus the last common ancestor to encode a perlecan homologue is the placozoan Trichoplax adhaerens. N. vectensis perl elevation was identified as part of the gene expression profile of complex regenerating structures in the oral region of the animal following wounding. This is a conserved expression pattern of the gene which is still found in wound healing of modern mammals. These studies both demonstrate a role for perlecan in wound healing and pathological states, corroborating the hypothesis that the perlecan gene’s primary evolutionary role is to support tissues in times of remodeling.