Project description:Two secreted proteins, osteomodulin (OMD) and proline/arginine-rich end leucine repeat protein (PRELP), are specifically expressed in bladder epithelial umbrella cells. At the initiation of human bladder cancer, their expression levels are dramatically down-regulated. To reveal the functional role of both proteins in bladder cancer, we constructed OMD or PRELP knockout mice and found that, in bladder epithelia, tight junctions between umbrella cells are strongly reduced while adherens junctions are remained as observed as a typical partial epithelial-mesenchymal transition (EMT). In addition, OMD or PRELP knockout mouse bladder showed many spontaneous breakdown sites in the umbrella cell layer. Furthermore, a third of the PRELP-/- mice developed non-muscle invasive papillary bladder cancer (NMIBC). mRNA expression profiling and in vitro functional analysis revealed that OMD and PRELP strongly regulate cell-cell adhesion and EMT via tight junction regulation through inhibition of TGF-b and EGF pathways. Interestingly, we found that activation of OMD or PRELP in bladder cancer cells strongly inhibits anchorage independent growth in vitro and tumorigenicity in in vivo mouse xenograft studies associating with the transition from mesenchymal cancer cells to epithelial-like cells as well as with tight junctions. Our data indicate that OMD and PRELP are involved in NMIBC initiation through regulation of the transition between epithelial and mesenchymal cells. Thus, it suggests that OMD and/or PRELP mediated EMT may have a potential target for bladder cancer therapy.
