Gastrin Releasing Peptide Receptor Attenuates the Invasiveness of Colorectal Cancer Cells

Gastrin releasing peptide receptor (GRPR) is a heptaspanning transmembrane G-protein coupled receptor which modulates the release of gastric acid in the gut. In cancer however, GRPR and its cognate ligand (GRP) are known to be aberrantly expressed. In patients with colorectal cancer, GRP and GRPR expression have been associated with improved five-year survival and decreased likelihood of disease recurrence. It has therefore been proposed that GRPR expression improves the prognosis of patients with colorectal cancer. A potential mechanism by which this may occur is through the up-regulation of heterochromatin protein 1 beta (HP1B), an epigenetic modifier of gene transcription associated with improved survival in a number of cancers. Herein, we show that GRPR up-regulates the expression of HP1B in human colorectal cancer cells, reducing their invasiveness. Furthermore, we show that HP1B expression reduces invasiveness by repressing the expression of the HECT type E3 ubiquitin ligase WWP2, a known oncogene. This protein is known to reduce the expression of PTEN, a tumor suppressor gene commonly under-expressed in many aggressive cancers. In this thesis we show for the first time a mechanism whereby GRP/GRPR signaling may improve survival in patients with colorectal cancer by up-regulating HP1B and consequently decreasing the expression of WWP2.