title: An N-terminal truncated carboxypeptidase E  splice isoform induces tumor growth  and is a biomarker for predicting  future metastasis in human cancers.
abstract: Metastasis is a major cause of mortality in cancer patients. However, the mechanisms governing the metastatic process remain elusive, and few accurate biomarkers exist for predicting whether metastasis will occur, something that would be invaluable for guiding therapy. We report here that the carboxypeptidase E gene (CPE) is alternatively spliced in human tumors to yield an N-terminal truncated protein (CPE-ΔN) that drives metastasis. mRNA encoding CPE-ΔN was found to be elevated in human metastatic colon, breast, and hepatocellular carcinoma (HCC) cell lines. In HCC cells, cytosolic CPE-ΔN was translocated to the nucleus and interacted with histone deacetylase 1/2 to upregulate expression of the gene encoding neural precursor cell expressed, developmentally downregulated gene 9 (Nedd9)--which has been shown to promote melanoma metastasis. Nedd9 upregulation resulted in enhanced in vitro proliferation and invasion. Quantification of mRNA encoding CPE-ΔN in HCC patient samples predicted intrahepatic metastasis with high sensitivity and specificity, independent of cancer stage. Similarly, high CPE-ΔN mRNA copy numbers in resected pheochromocytomas/paragangliomas (PHEOs/PGLs), rare neuroendocrine tumors, accurately predicted future metastasis or recurrence. Thus, CPE-ΔN induces tumor metastasis and should be investigated as a potentially powerful biomarker for predicting future metastasis and recurrence in HCC and PHEO/PGL patients.
authors.affiliation: Department of Surgery, University of Hong Kong, Pokfulam, Hong Kong, China.
authors.forename: Terence K
authors.initials: TK
authors.lastname: Lee
authors.forename: Saravana R K
authors.initials: SR
authors.lastname: Murthy
authors.forename: Niamh X
authors.initials: NX
authors.lastname: Cawley
authors.forename: Savita
authors.initials: S
authors.lastname: Dhanvantari
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.forename: Hong
authors.initials: H
authors.lastname: Lou
authors.forename: Tracy
authors.initials: T
authors.lastname: Lau
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ma
authors.forename: Thanh
authors.initials: T
authors.lastname: Huynh
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wesley
authors.forename: Irene O
authors.initials: IO
authors.lastname: Ng
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.forename: Ronnie T
authors.initials: RT
authors.lastname: Poon
authors.forename: Y Peng
authors.initials: YP
authors.lastname: Loh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017398:Alternative Splicing; D014408:Biomarkers, Tumor / Q000378:metabolism; D043423:Carboxypeptidase H / Q000737:chemistry* / Q000235:genetics*; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010235:Paraganglioma / Q000378:metabolism; D010673:Pheochromocytoma / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D012008:Recurrence
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C099942:NEDD9 protein, human; D010750:Phosphoproteins; D020033:Protein Isoforms; D043423:Carboxypeptidase H