Characterization of Clinical and Molecular Features Related to the Downregulated Expression of μ-Protocadherin in Colorectal Cancer

Abstract

Mu-protocadherin is a membrane protein belonging to the cadherin superfamily that, as the other members, promotes inter-cellular adhesion and proliferation arrest. Notably, both these onco-suppressive activities are mediated by its capacity to inhibit the β-catenin signaling pathway, that is constitutively activated in colorectal cancer (CRC) and, not surprisingly, its expression undergoes a remarkable down-regulation in CRC, although this finding has been to date only achieved in a limited set of patients. Based on this premise, the aims of our study were: (1) to confirm the down-regulated expression of μ-protocadherin in a larger cohort of CRC patients; (2) to assess the possible relationship existing between the expression levels of this protein and the clinical-pathological parameters of the disease; (3) to identify the molecular mechanism underlying the decrease of its expression occuring in CRC.To address these issues, we developed a database containing more than one thousand CRC expression profiles, recovered by GEO (Gene Expression Omnibus) and supplied with a significant set of clinical information, that was subsequently used to perform a bioinformatic analysis of cadherin genes. A methylation analysis of μ-protocadherin gene promoter was also carried out, using the bisulfite pyro-sequencing procedure, in an independent series of CRC samples. The results obtained confirmed the down-regulation of μ-protocadherin expression in CRC, suggested a possible prognostic role for this alteration and indicated the promoter hyper-methylation of its gene as the responsible mechanism.