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, C2 4
Liu, AM3 7
Wong, KF7
Shek, FH3
Lee, NP3
Fan, ST3
Poon, RT3
Ivanovska, I2 4
Philippar, U2
Cleary, MA1 5
Buser, CA5
Shaw, PM5
Lee, CN7
Tenen, DG6 7
Dai, H2 4
Mao, M4 8
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
2011 Impact Factor: 4.773
2011 SCImago Journal Rankings: 0.793
DOIhttp://dx.doi.org/10.1074/jbc.M111.229831
ReferencesReferences in Scopus
DC Field
Value
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.issn0021-9258
2011 Impact Factor: 4.773
2011 SCImago Journal Rankings: 0.793
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
Author Affiliations
  1. Sirna Therapeutics Inc.
  2. Merck Research Laboratories
  3. The University of Hong Kong
  4. Rosetta Inpharmatics LLC
  5. Merck & Co.
  6. Harvard Stem Cell Institute
  7. National University of Singapore
  8. Pfizer