Bladder cancer (BC) is among the most common cancers in the Western world. Because high-grade invasive bladder cancers (HGIBC) can progress to life threatening metastases, understanding the molecular mechanisms underlying BC Invasion is of tremendous Importance for reducing the mortality of this disease. The X-linked inhibitor of apoptosis protein (XIAP) is a member ofthe inhibitors of apoptosis protein (lAP) family. In addition to its well-established role in apoptosis inhibition, we recently discovered a new role of XIAP in regulating cancer cell Invasion in vitro. First, knockout of XIAP decreased colon cancer cell migration and invasion in vitro and metastasis of these cells to the lungs in vivo. Conversely, resumption of XIAP expression in XIAP-depleted cancer cells restored their migration. Second, Rho dissociation Inhibitor (RhoGDI) is a principal downstream target of XIAP in regulating cancer cell migration. XIAP Interacted with RhoGDI and in so doing inhibited RhoGDI SUMOylation via its RING domain. Third, XIAP was highly expressed in human invasive BC tissues, but not in adjacent normal urothelial tissues. XIAP expression was also markedly elevated in N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-lnduced invasive BC tissues in p53- l-lpRb-l- mice, while it was almost undetectable in wild-type mouse urothelia and was low in oncogenic Ras- induced low-grade BCs. Fourth, knockdown of XIAP led to a marked decrease of HGIBC cell migration. Finally, XIAP was significantly up-regulated in the cells harboring p53 mutations, a genetic alteration highly prevalent in HGIBC. Our data from cell culture, transgenic mice and human tissues, demonstrating XIAP over-expression in the invasive BCs, prompt us to hypothesize that XIAP plays an important role in promoting/enhancing BC invasion. We will examine this hypothesis with three Specific Aims: 1: To test the hypothesis that p53 mutations activate XIAP expression via the upregulation of Spl and/or NFKB in BC cells;2: To define the functional domain and molecular mechanisms whereby XIAP regulates BC cell invasion;3: To examine the hypothesis that urothelium-specific over-expression of XIAP in transgenic mice can promote BC Invasion in vivo and that loss of XIAP in knockout mice or its RING domain in XIAPARNG knockin mice renders these mice resistant to invasive BC development. Our proposed studies will contribute in a major way to the understanding of the molecular basis of invasive BC. They will also pave the way for us to use XIAP as a novel prognostic biomarker and a therapeutic target for invasive BC. This should in turn help improve the clinical outcome of these patients.

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Although the invasive form of bladder cancer (BC) is responsible for all the deaths resulting from this disease, little is known biologically about what triggers BC invasion. We recently found a new role of XIAP previously known as an inhibitor of apoptosis, in cell migration and invasion. By studying the mechanisms leading to increased XIAP in BC cells and the role of XIAP in BC invasion using mouse models, we hope to determine whether XIAP can be used a prognostic marker and/or a therapeutic target of Invasive BC.

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