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Differential Wnt Pathway Gene Expression and E-Cadherin Truncation in Sporadic Colorectal Cancers with and without Microsatellite Instability

Authors' Affiliations: ¹ Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense, and ² Servicios de Anatomía Patológica and ³ Cirugía, Hospital Clínico San Carlos, Madrid, Spain

Requests for reprints: Manuel Benito, Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense, Madrid, Spain. Phone: 34-91-394-17-77; Fax: 34-91-394-17-79; E-mail: benito{at}farm.ucm.es.

Purpose: Alterations in the Wnt pathway play a major role in colorectal cancer with high (MSI-H) or low microsatellite instability (MSS/MSI-L). However, the differential impact of the Wnt pathway components on these tumors is poorly understood. MMP-3 (stromelysin-1) promoter is a target of the mutator phenotype in sporadic colorectal cancer. Among MMP-3 targets, we investigated E-cadherin integrity status in both groups of tumors. Because beta-catenin is the main effector of the Wnt pathway, we have also investigated the differential cellular status of beta-catenin.

Experimental Design: Expression profiles of 114 genes related to the Wnt pathway were analyzed by oligo microarrays in 48 tumors classified by their MSI status. In addition, we analyzed 48 sporadic colorectal cancers for E-cadherin integrity status. We performed investigation of beta-catenin and cyclin D1 by immunohistochemistry using tissue arrays containing 96 tumors.

Results: Our data show that a group of genes that negatively regulate Wnt signaling are downregulated in MSS/MSI-L as compared with MSI-H colorectal tumors. E-cadherin truncation was significantly higher in MSS/MSI-L as compared with MSI-H tumors. Moreover, MSI-H tumors showed low or null beta-catenin nuclear presence, whereas the group of tumors classified as MSS or MSI-L displayed a high content of the nuclear beta-catenin location.

Conclusions: Our results suggest that the differential expression of genes that negatively regulate the Wnt pathway, as well as the status of E-cadherin and beta-catenin in MSI-H or MSS/MSI-L colorectal tumors, shed some light on the different clinical behavior showed by the two groups.