Abstract 2003: CPE-delta-N promotes metastasis by regulating Nedd9 and Yap1 expression

We report here that the carboxypeptidase E gene (CPE) is alternatively spliced in human tumors to yield an N-terminal truncated protein (CPE-DELTA-N) that drives metastasis. CPE-DELTA-N mRNA was elevated in human metastatic colon, breast and HCC cell lines. Suppression of CPE-DELTA-N expression in these cell lines by si-RNA significantly inhibited their growth migration and invasion. To confirm these observations in vivo, an orthotopic nude mouse model was established. The mice implanted with a tumor derived from HCC cells transfected with si- CPE-DELTA-N RNA in the liver did not show tumor growth or metastasis, compared to scrambled controls. In HCC cytosolic CPE-DELTA-N protein was translocated to the nucleus and upregulated the expression of neural precursor cell expressed, developmentally downregulated gene 9 (Nedd9), through interaction with histone deacetylase (HDAC) 1/2. Inhibition of HDAC activity by the HDAC inhibitors suppressed expression of NEDD9, without effecting CPE-DELTA-N expression. The enhanced invasive phenotype of HCC cells stably transfected with CPE-DELTA-N was suppressed when Nedd9 was silenced by si-RNA. Furthermore CPE-DELTA-N protein up-regulation also increased Yes Associated Protein 1 (YAP1), Carcinoembryonic Antigen-related Cell Adhesion Molecule 5 (ceacam5) and Carbonyl Reductase 1(cbr1) and silencing CPE-DELTA-N with siRNA suppressed YAP1, CEACAM5 and CBR1 protein expression. cDNA Microarray studies of HCC cells overexpressing CPE-DELTA-N showe...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Tumor Biology Source Type: research