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Article: DLK1-DIO3 genomic imprinted microRNA cluster at 14q32.2 defines a stemlike subtype of hepatocellular carcinoma associated with poor survival

TitleDLK1-DIO3 genomic imprinted microRNA cluster at 14q32.2 defines a stemlike subtype of hepatocellular carcinoma associated with poor survival
Authors
Issue Date2011
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal of Biological Chemistry, 2011, v. 286 n. 35, p. 30706-30713 How to Cite?
AbstractHepatocellular carcinoma (HCC) is a heterogeneous and highly aggressive malignancy, for which there are no effective cures. Identification of a malignant stemlike subtype of HCC may offer patients with a dismal prognosis a potential targeted therapy using c-MET and Wnt pathway inhibitors. MicroRNAs (miRNAs) show promise as diagnostic and prognostic tools for cancer detection and stratification. Using a TRE-c-Met-driven transgenic HCC mouse model, we identified a cluster of 23 miRNAs that is encoded within the Dlk1-Gtl2 imprinted region on chromosome 12qF1 overexpressed in all of the isolated liver tumors. Interestingly, this region is conserved among mammalian species and maps to the human DLK1-DIO3 region on chromosome 14q32.2. We thus examined the expression of the DLK1-DIO3 miRNA cluster in a cohort of 97 hepatitis B virus-associated HCC patients and identified a subgroup (n = 18) of patients showing strong coordinate overexpression of miRNAs in this cluster but not in other cancer types (breast, lung, kidney, stomach, and colon) that were tested. Expression levels of imprinted gene transcripts from neighboring loci in this 14q32.2 region and from a subset of other imprinted sites were concomitantly elevated in human HCC. Interestingly, overexpression of the DLK1-DIO3 miRNA cluster was positively correlated with HCC stem cell markers (CD133, CD90, EpCAM, Nestin) and associated with a high level of serum α-fetoprotein, a conventional biomarker for liver cancer, and poor survival rate in HCC patients. In conclusion, our findings suggest that coordinate up-regulation of the DLK1-DIO3 miRNA cluster at 14q32.2 may define a novel molecular (stem cell-like) subtype of HCC associated with poor prognosis. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/173017
ISSN
2014 Impact Factor: 4.573
2014 SCImago Journal Rankings: 2.734
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLuk, JMen_US
dc.contributor.authorBurchard, Jen_US
dc.contributor.authorZhang, Cen_US
dc.contributor.authorLiu, AMen_US
dc.contributor.authorWong, KFen_US
dc.contributor.authorShek, FHen_US
dc.contributor.authorLee, NPen_US
dc.contributor.authorFan, STen_US
dc.contributor.authorPoon, RTen_US
dc.contributor.authorIvanovska, Ien_US
dc.contributor.authorPhilippar, Uen_US
dc.contributor.authorCleary, MAen_US
dc.contributor.authorBuser, CAen_US
dc.contributor.authorShaw, PMen_US
dc.contributor.authorLee, CNen_US
dc.contributor.authorTenen, DGen_US
dc.contributor.authorDai, Hen_US
dc.contributor.authorMao, Men_US
dc.date.accessioned2012-10-30T06:26:31Z-
dc.date.available2012-10-30T06:26:31Z-
dc.date.issued2011en_US
dc.identifier.citationJournal of Biological Chemistry, 2011, v. 286 n. 35, p. 30706-30713en_US
dc.identifier.issn0021-9258en_US
dc.identifier.urihttp://hdl.handle.net/10722/173017-
dc.description.abstractHepatocellular carcinoma (HCC) is a heterogeneous and highly aggressive malignancy, for which there are no effective cures. Identification of a malignant stemlike subtype of HCC may offer patients with a dismal prognosis a potential targeted therapy using c-MET and Wnt pathway inhibitors. MicroRNAs (miRNAs) show promise as diagnostic and prognostic tools for cancer detection and stratification. Using a TRE-c-Met-driven transgenic HCC mouse model, we identified a cluster of 23 miRNAs that is encoded within the Dlk1-Gtl2 imprinted region on chromosome 12qF1 overexpressed in all of the isolated liver tumors. Interestingly, this region is conserved among mammalian species and maps to the human DLK1-DIO3 region on chromosome 14q32.2. We thus examined the expression of the DLK1-DIO3 miRNA cluster in a cohort of 97 hepatitis B virus-associated HCC patients and identified a subgroup (n = 18) of patients showing strong coordinate overexpression of miRNAs in this cluster but not in other cancer types (breast, lung, kidney, stomach, and colon) that were tested. Expression levels of imprinted gene transcripts from neighboring loci in this 14q32.2 region and from a subset of other imprinted sites were concomitantly elevated in human HCC. Interestingly, overexpression of the DLK1-DIO3 miRNA cluster was positively correlated with HCC stem cell markers (CD133, CD90, EpCAM, Nestin) and associated with a high level of serum α-fetoprotein, a conventional biomarker for liver cancer, and poor survival rate in HCC patients. In conclusion, our findings suggest that coordinate up-regulation of the DLK1-DIO3 miRNA cluster at 14q32.2 may define a novel molecular (stem cell-like) subtype of HCC associated with poor prognosis. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.en_US
dc.languageengen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/en_US
dc.relation.ispartofJournal of Biological Chemistryen_US
dc.subject.meshCarcinoma, Hepatocellular - Genetics - Mortalityen_US
dc.subject.meshChromosomes, Human, Pair 14 - Geneticsen_US
dc.subject.meshCohort Studiesen_US
dc.subject.meshHumansen_US
dc.subject.meshIntercellular Signaling Peptides And Proteins - Geneticsen_US
dc.subject.meshIodide Peroxidase - Geneticsen_US
dc.subject.meshLiver - Metabolismen_US
dc.subject.meshLiver Neoplasms - Genetics - Mortalityen_US
dc.subject.meshMembrane Proteins - Geneticsen_US
dc.subject.meshMicrornas - Genetics - Metabolismen_US
dc.subject.meshMultigene Familyen_US
dc.subject.meshPrognosisen_US
dc.subject.meshTissue Distributionen_US
dc.subject.meshTreatment Outcomeen_US
dc.subject.meshTumor Markers, Biological - Metabolismen_US
dc.subject.meshUp-Regulationen_US
dc.titleDLK1-DIO3 genomic imprinted microRNA cluster at 14q32.2 defines a stemlike subtype of hepatocellular carcinoma associated with poor survivalen_US
dc.typeArticleen_US
dc.identifier.emailLuk, JM: jmluk@hkucc.hku.hken_US
dc.identifier.emailLee, NP: nikkilee@hku.hken_US
dc.identifier.emailFan, ST: stfan@hku.hken_US
dc.identifier.emailPoon, RT: poontp@hkucc.hku.hken_US
dc.identifier.authorityLuk, JM=rp00349en_US
dc.identifier.authorityLee, NP=rp00263en_US
dc.identifier.authorityFan, ST=rp00355en_US
dc.identifier.authorityPoon, RT=rp00446en_US
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1074/jbc.M111.229831en_US
dc.identifier.pmid21737452en_US
dc.identifier.scopuseid_2-s2.0-80052245751en_US
dc.identifier.hkuros192472-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-80052245751&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume286en_US
dc.identifier.issue35en_US
dc.identifier.spage30706en_US
dc.identifier.epage30713en_US
dc.identifier.isiWOS:000294283600050-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridLuk, JM=7006777791en_US
dc.identifier.scopusauthoridBurchard, J=35586927300en_US
dc.identifier.scopusauthoridZhang, C=9747304800en_US
dc.identifier.scopusauthoridLiu, AM=36134439500en_US
dc.identifier.scopusauthoridWong, KF=49362744900en_US
dc.identifier.scopusauthoridShek, FH=36094922800en_US
dc.identifier.scopusauthoridLee, NP=7402722690en_US
dc.identifier.scopusauthoridFan, ST=7402678224en_US
dc.identifier.scopusauthoridPoon, RT=7103097223en_US
dc.identifier.scopusauthoridIvanovska, I=6507113691en_US
dc.identifier.scopusauthoridPhilippar, U=6506975144en_US
dc.identifier.scopusauthoridCleary, MA=7202006129en_US
dc.identifier.scopusauthoridBuser, CA=7004680051en_US
dc.identifier.scopusauthoridShaw, PM=7401651642en_US
dc.identifier.scopusauthoridLee, CN=35330090000en_US
dc.identifier.scopusauthoridTenen, DG=7006789087en_US
dc.identifier.scopusauthoridDai, H=7402206916en_US
dc.identifier.scopusauthoridMao, M=7102960472en_US

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