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An N-terminal truncated carboxypeptidase E splice isoform induces metastasis by activating nedd9 and other metastasis inducing genes

Monday, October 24, 2011 — Poster Session I

Noon – 2:00 p.m.

Natcher Conference Center



* FARE Award Winner


  • SRK Murthy
  • TK Lee
  • NX Cawley
  • SM Hewitt
  • K Pacak
  • RT Poon
  • YP Loh


Cancer mortality is often from metastatic disease rather than the direct effect of the primary tumor. 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 cell lines. Suppression of CPE-DELTA-N expression in these cell lines by si-RNA significantly inhibited their growth and invasion. In an in vivo orthotopic nude mouse model, the mice implanted with a tumor derived from CPE-DELTA-N suppressed HCC cells in the liver did not show tumor growth or metastasis, compared to controls. In HCC cells, cytosolic CPE-DELTA-N protein upregulated Nedd9 gene expression through interaction with histone deacetylase (HDAC) 1/2. cDNA microarray studies of HCC cells overexpressing CPE-DELTA-N showed elevated expression of 27 genes associated with metastasis and down-regulation of 30 genes associated with tumor suppression. Increased levels of protranscriptional acetylated histone H3 and H4 in these cells suggest epigenetic regulation of downstream genes by CPE-DELTA-N. In clinical studies of 14 patients with thyroid papillary carcinoma, resected tumors having high copy numbers of CPE-DELTA-N mRNA was correlated with metastasis. Thus CPE-DELTA-N may be a potentially useful biomarker for diagnosing metastasis

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