NE-AUA 2006 Annual Meeting, September 28 - 30, 2006, The Westin Hotel & Rhode Island Convention Center Providence, Rhode Island
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Altered Localization of p120 catenin in Bladder Cancer is Prognostic for Node Involvement
Chad Wotkowicz, MD, Baumgart Egbert, MD, Micah Jacobs, MD, Michael Cohen, MD, Brasil Silva Neto, MD, Kimberly M. Rieger Christ, PhD, John A. Libertino, MD, Ian C. Summerhayes, PhD.
Lahey Clinic, Burlington, MA,

Background: P120 catenin was originally identified as a substrate of src kinase and hence was implicated in the cancer process. Subsequently, p120 was shown to bind to cadherin in the juxtamembrane region aiding in cadherin complex stabilization. Interestingly, we have found alternative p120 isoforms expressed in invasive bladder carcinoma cells consistent with a role for p120 in eliciting the invasive phenotype. In this study we have identified the frequency of change in the expression and localization of p120 in bladder tumors linked to clinical outcome.
Methods: A total of 301 superficial tumor specimens (Ta and T1) from 237 patients and 329 invasive (T2-T4) tumor specimens from 265 patients were assembled in ten tissue microarrays (TMA). Each TMA consisted of 400 tissue cores with 4 cores per specimen and control tissue cores for immunohistochemistry (IHC) validation and orientation. Cancer registry and hospital chart data were reviewed for clinical relevance. P120 expression was scored for intensity with notation of cellular localization (membrane, cytoplasm or nucleus). Chi-square tests were used for outcomes analysis (pathological stage, grade, lymphovascular invasion and nodal disease). Cancer specific and recurrence free survival were analyzed with respect to p120 location. Knockdown of p120 was achieved in bladder carcinoma cell lines using siRNA. Standard in vitro migration and invasion assays were performed.
Results: Expression levels of p120 catenin inversely correlated with pathological tumor stage (p<0.001), histological grade (p=0.018), lymphovascular invasion (p<0.001) but not node involvement (p=0.101). In contrast, non-membranous localization of p120 correlated with stage (p=<0.001), grade (p=<0.001), lymphovascular invasion (p<0.001) and node positive disease (p=0.006). Neither location nor expression levels of p120 had prognostic significance for cancer specific survival. However, time to recurrence in superficial disease (pTa, T1, N=172) was significantly shorter in patients with cytoplasmic localization of p120 (p=0.045). This difference was even more pronounced when sub analysis for grade 1-2 (N=136) versus grade 3 (N=36) (p=0.007) was performed. Knockdown of p120 in bladder cell lines resulted in a significant change in the migration and invasive potential of these cells dependent on their cadherin expression profile.
Conclusions: A change in the cellular localization of p120 was found to be prognostic for nodal involvement in bladder cancer. The same p120 change also reflected a significantly shorter time to recurrence in patients with superficial disease. Confirmation of p120 as a primary player in the invasive phenotype in bladder carcinomas was established in siRNA knockdown experiments.


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