APRIL-NF-κB-Snail signaling regulates E-cadherin in colon carcinoma

E-cadherin is a member of transmembrane glycoproteins that mediates calcium-dependent cell-cell adhesion in epithelial tissues. E-cadherin, which blocks tumor cell invasion by restraining cells and preventing cell movement, is negatively regulated by the transcriptional repressor Snail, and stabilization of Snail is dependent on activation of NF-κB signaling. Provided that a proliferation-inducing ligand (APRIL) is highly expressed in colorectal cancer (CRC) tissues and cell lines, in this study, we tested the hypothesis that APRIL-p65 NF-κB-Snail signaling regulates E-cadherin in CRC. We found that expression of Snail was inversely related to that of E-cadherin in CRC tissues and colon carcinoma cell line T84. In addition, APRIL treatment induced Snail at protein level only but not mRNA level, and COP9 signalosome subunit 2 (CSN2) that acts to block ubiquitination and degradation of Snail at both mRNA and protein levels. Similarly, depletion of p65 by siRNAs led to up-regulation of Snail at protein level only, but not at mRNA level in T84 cells. Moreover, silencing of Snail resulted in decrease of E-cadherin at both protein and mRNA levels. These results suggest that APRIL-p65 NF-κB-Snail signaling plays a critical role in regulation of E-cadherin and provide insights into mechanisms for paracrine inflammation-induced metastasis in CRC.