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Altered Localization of p120 Catenin During Epithelial to Mesenchymal Transition of Colon Carcinoma Is Prognostic for Aggressive Disease

¹ Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School; ² Biostatistics Center, Massachusetts General Hospital, Boston Massachusetts; and ³ Department of Pathology, Yale University Medical School, New Haven, Connecticut

Requests for reprints: Arthur M. Mercurio, Department of Cancer Biology, University of Massachusetts Medical School, LRB-408, 364 Plantation Street, Worcester, MA 01605. Phone: 508-856-8676; Fax: 508-856-1310; E-mail: arthur.mercurio{at}umassmed.edu.

We examined the expression and localization of p120 catenin (p120ctn) as a consequence of the epithelial to mesenchymal transition (EMT) of highly differentiated colon carcinoma cells (LIM1863 cells). This unique line grows in suspension as spheroids and undergoes an EMT within 24 hours following stimulation with transforming growth factor-ß and tumor necrosis factor-. Although p120ctn expression remains stable during the EMT, its localization shifts from cell-cell junctions to the cytoplasm. Interestingly, a marked decrease in RhoA activation coincident with E-cadherin loss occurs during the EMT and correlates with the formation of a p120ctn/RhoA complex. Use of RNA interference showed that p120ctn reduction results in increased RhoA activity and a significant decrease in the motility of post-EMT cells. To determine the relevance of these findings to colorectal cancer progression, we assessed p120ctn expression by immunohistochemistry in 557 primary tumors. Of note, we observed that 53% of tumors presented cytoplasmic staining for p120ctn, and statistical analysis revealed that this localization is predictive of poor patient outcome. Cytoplasmic p120ctn correlated with later-stage tumors, significantly reduced 5- and 10-year survival times and a greater propensity for metastasis to lymph nodes compared with junctional p120ctn. We also confirmed that altered localization of p120ctn corresponded with loss or cytoplasmic localization of E-cadherin. These alterations in E-cadherin are also associated with a significant reduction in patient survival time and an increase in tumor stage and lymph node metastasis. These data provide a compelling argument for the importance of both p120ctn and the EMT itself in the progression of colorectal carcinoma.

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