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Article: An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers

TitleAn N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers
Authors
Issue Date2011
PublisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.org
Citation
Journal Of Clinical Investigation, 2011, v. 121 n. 3, p. 880-892 How to Cite?
AbstractMetastasis 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.
Persistent Identifierhttp://hdl.handle.net/10722/135549
ISSN
2015 Impact Factor: 12.575
2015 SCImago Journal Rankings: 8.764
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
NICHD, NIH
Natural Sciences and Engineering Research Council of Canada
University of Hong Kong
Funding Information:

We thank Tamara Prodanov and Alicja Woronowicz (NICHD) for helpful discussions, Rebecca McGirr (Lawson Health Research Institute) for technical assistance, David Carter (London Regional Genomics Centre) for microarray analysis, Jana Wo and Simon Yau (University of Hong Kong) for animal work and qRT-PCR of the clinical tumor samples, respectively, and Chikao Morimoto (Tokyo University) for NEDD9 N-terminal antibody. We thank Steven Coon (NICHD) for assisting in Northern blots. This research was supported by the Intramural Research Program of the NICHD, NIH; a Natural Sciences and Engineering Research Council of Canada Discovery Grant to S. Dhanvantari; and University of Hong Kong research grants to R.T. Poon and I.O. Ng. I.O. Ng is Loke Yew Professor in Pathology.

References

 

DC FieldValueLanguage
dc.contributor.authorLee, TKen_HK
dc.contributor.authorMurthy, SRKen_HK
dc.contributor.authorCawley, NXen_HK
dc.contributor.authorDhanvantari, Sen_HK
dc.contributor.authorHewitt, SMen_HK
dc.contributor.authorLou, Hen_HK
dc.contributor.authorLau, Ten_HK
dc.contributor.authorMa, Sen_HK
dc.contributor.authorHuynh, Ten_HK
dc.contributor.authorWesley, RAen_HK
dc.contributor.authorNg, IOen_HK
dc.contributor.authorPacak, Ken_HK
dc.contributor.authorPoon, RTen_HK
dc.contributor.authorLoh, YPen_HK
dc.date.accessioned2011-07-27T01:36:57Z-
dc.date.available2011-07-27T01:36:57Z-
dc.date.issued2011en_HK
dc.identifier.citationJournal Of Clinical Investigation, 2011, v. 121 n. 3, p. 880-892en_HK
dc.identifier.issn0021-9738en_HK
dc.identifier.urihttp://hdl.handle.net/10722/135549-
dc.description.abstractMetastasis 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.en_HK
dc.languageengen_US
dc.publisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.orgen_HK
dc.relation.ispartofJournal of Clinical Investigationen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.meshAdaptor Proteins, Signal Transducing - metabolismen_HK
dc.subject.meshCarboxypeptidase H - chemistry - geneticsen_HK
dc.subject.meshGene Expression Regulation, Neoplasticen_HK
dc.subject.meshProtein Isoformsen_HK
dc.subject.meshProtein Structure, Tertiaryen_HK
dc.titleAn N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancersen_HK
dc.typeArticleen_HK
dc.identifier.emailLee, TK: tkwlee@hkucc.hku.hken_HK
dc.identifier.emailMa, S: sma@pathology.hku.hken_HK
dc.identifier.emailNg, IO: iolng@hkucc.hku.hken_HK
dc.identifier.emailPoon, RT: poontp@hkucc.hku.hken_HK
dc.identifier.authorityLee, TK=rp00447en_HK
dc.identifier.authorityMa, S=rp00506en_HK
dc.identifier.authorityNg, IO=rp00335en_HK
dc.identifier.authorityPoon, RT=rp00446en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1172/JCI40433en_HK
dc.identifier.pmid21285511-
dc.identifier.pmcidPMC3049392-
dc.identifier.scopuseid_2-s2.0-79952216567en_HK
dc.identifier.hkuros188087en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79952216567&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume121en_HK
dc.identifier.issue3en_HK
dc.identifier.spage880en_HK
dc.identifier.epage892en_HK
dc.identifier.eissn1558-8238-
dc.identifier.isiWOS:000287991000010-
dc.publisher.placeUnited Statesen_HK
dc.identifier.f100010046957-
dc.identifier.scopusauthoridLee, TK=7501439435en_HK
dc.identifier.scopusauthoridMurthy, SRK=36987545600en_HK
dc.identifier.scopusauthoridCawley, NX=6701921242en_HK
dc.identifier.scopusauthoridDhanvantari, S=6602627904en_HK
dc.identifier.scopusauthoridHewitt, SM=7103254557en_HK
dc.identifier.scopusauthoridLou, H=36561891000en_HK
dc.identifier.scopusauthoridLau, T=17341008600en_HK
dc.identifier.scopusauthoridMa, S=16444895800en_HK
dc.identifier.scopusauthoridHuynh, T=7101891024en_HK
dc.identifier.scopusauthoridWesley, RA=7103154061en_HK
dc.identifier.scopusauthoridNg, IO=7102753722en_HK
dc.identifier.scopusauthoridPacak, K=7005612628en_HK
dc.identifier.scopusauthoridPoon, RT=7103097223en_HK
dc.identifier.scopusauthoridLoh, YP=7103149720en_HK
dc.identifier.citeulike9219108-

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