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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
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TitleDLK1-DIO3 genomic imprinted microRNA cluster at 14q32.2 defines a stemlike subtype of hepatocellular carcinoma associated with poor survival
 
AuthorsLuk, JM7
Burchard, J1 4
Zhang, C4 3
Liu, AM2 7
Wong, KF7
Shek, FH2
Lee, NP2
Fan, ST2
Poon, RT2
Ivanovska, I4 3
Philippar, U3
Cleary, MA1 5
Buser, CA5
Shaw, PM5
Lee, CN7
Tenen, DG6 7
Dai, H4 3
Mao, M8 4
 
Issue Date2011
 
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
 
CitationJournal of Biological Chemistry, 2011, v. 286 n. 35, p. 30706-30713 [How to Cite?]
DOI: http://dx.doi.org/10.1074/jbc.M111.229831
 
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.
 
ISSN0021-9258
2013 Impact Factor: 4.600
 
DOIhttp://dx.doi.org/10.1074/jbc.M111.229831
 
ISI Accession Number IDWOS:000294283600050
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorLuk, JM
 
dc.contributor.authorBurchard, J
 
dc.contributor.authorZhang, C
 
dc.contributor.authorLiu, AM
 
dc.contributor.authorWong, KF
 
dc.contributor.authorShek, FH
 
dc.contributor.authorLee, NP
 
dc.contributor.authorFan, ST
 
dc.contributor.authorPoon, RT
 
dc.contributor.authorIvanovska, I
 
dc.contributor.authorPhilippar, U
 
dc.contributor.authorCleary, MA
 
dc.contributor.authorBuser, CA
 
dc.contributor.authorShaw, PM
 
dc.contributor.authorLee, CN
 
dc.contributor.authorTenen, DG
 
dc.contributor.authorDai, H
 
dc.contributor.authorMao, M
 
dc.date.accessioned2012-10-30T06:26:31Z
 
dc.date.available2012-10-30T06:26:31Z
 
dc.date.issued2011
 
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.
 
dc.description.naturelink_to_OA_fulltext
 
dc.identifier.citationJournal of Biological Chemistry, 2011, v. 286 n. 35, p. 30706-30713 [How to Cite?]
DOI: http://dx.doi.org/10.1074/jbc.M111.229831
 
dc.identifier.doihttp://dx.doi.org/10.1074/jbc.M111.229831
 
dc.identifier.epage30713
 
dc.identifier.hkuros192472
 
dc.identifier.isiWOS:000294283600050
 
dc.identifier.issn0021-9258
2013 Impact Factor: 4.600
 
dc.identifier.issue35
 
dc.identifier.pmid21737452
 
dc.identifier.scopuseid_2-s2.0-80052245751
 
dc.identifier.spage30706
 
dc.identifier.urihttp://hdl.handle.net/10722/173017
 
dc.identifier.volume286
 
dc.languageeng
 
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
 
dc.publisher.placeUnited States
 
dc.relation.ispartofJournal of Biological Chemistry
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshCarcinoma, Hepatocellular - Genetics - Mortality
 
dc.subject.meshChromosomes, Human, Pair 14 - Genetics
 
dc.subject.meshCohort Studies
 
dc.subject.meshHumans
 
dc.subject.meshIntercellular Signaling Peptides And Proteins - Genetics
 
dc.subject.meshIodide Peroxidase - Genetics
 
dc.subject.meshLiver - Metabolism
 
dc.subject.meshLiver Neoplasms - Genetics - Mortality
 
dc.subject.meshMembrane Proteins - Genetics
 
dc.subject.meshMicrornas - Genetics - Metabolism
 
dc.subject.meshMultigene Family
 
dc.subject.meshPrognosis
 
dc.subject.meshTissue Distribution
 
dc.subject.meshTreatment Outcome
 
dc.subject.meshTumor Markers, Biological - Metabolism
 
dc.subject.meshUp-Regulation
 
dc.titleDLK1-DIO3 genomic imprinted microRNA cluster at 14q32.2 defines a stemlike subtype of hepatocellular carcinoma associated with poor survival
 
dc.typeArticle
 
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Author Affiliations
  1. Sirna Therapeutics Inc.
  2. The University of Hong Kong
  3. Merck Research Laboratories
  4. Rosetta Inpharmatics LLC
  5. Merck &amp; Co.
  6. Harvard Stem Cell Institute
  7. National University of Singapore
  8. Pfizer