title: DLK1-DIO3 genomic imprinted microRNA cluster at 14q32.2 defines a stemlike subtype of hepatocellular carcinoma associated with poor survival.
abstract: Hepatocellular 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.
authors: Cancer Science Institute, National University of Singapore, 117597, Singapore; Departments of Pharmacology, National University of Singapore, 117597, Singapore; Surgery, National University of Singapore, 117597, Singapore. Electronic address: jmluk@nus.edu.sg.
authors: John M
authors: JM
authors: Luk
authors: Rosetta Inpharmatics LLC, Merck & Co., Seattle, Washington 98109; Sirna Therapeutics, Inc., Merck & Co., San Francisco, California 94158.
authors: Julja
authors: J
authors: Burchard
authors: Rosetta Inpharmatics LLC, Merck & Co., Seattle, Washington 98109; Merck Research Laboratories, Boston, Massachusetts 02115.
authors: Chunsheng
authors: C
authors: Zhang
authors: Departments of Pharmacology, National University of Singapore, 117597, Singapore; Department of Surgery, Queen Mary Hospital, University of Hong Kong, Hong Kong, China.
authors: Angela M
authors: AM
authors: Liu
authors: Cancer Science Institute, National University of Singapore, 117597, Singapore.
authors: Kwong F
authors: KF
authors: Wong
authors: Department of Surgery, Queen Mary Hospital, University of Hong Kong, Hong Kong, China.
authors: Felix H
authors: FH
authors: Shek
authors: Department of Surgery, Queen Mary Hospital, University of Hong Kong, Hong Kong, China.
authors: Nikki P
authors: NP
authors: Lee
authors: Department of Surgery, Queen Mary Hospital, University of Hong Kong, Hong Kong, China.
authors: Sheung Tat
authors: ST
authors: Fan
authors: Department of Surgery, Queen Mary Hospital, University of Hong Kong, Hong Kong, China.
authors: Ronnie T
authors: RT
authors: Poon
authors: Rosetta Inpharmatics LLC, Merck & Co., Seattle, Washington 98109; Merck Research Laboratories, Boston, Massachusetts 02115.
authors: Irena
authors: I
authors: Ivanovska
authors: Merck Research Laboratories, Boston, Massachusetts 02115.
authors: Ulrike
authors: U
authors: Philippar
authors: Sirna Therapeutics, Inc., Merck & Co., San Francisco, California 94158; Merck & Co., Inc., West Point, Pennsylvania 19486.
authors: Michele A
authors: MA
authors: Cleary
authors: Merck & Co., Inc., West Point, Pennsylvania 19486.
authors: Carolyn A
authors: CA
authors: Buser
authors: Merck & Co., Inc., Upper Gwynedd, Pennsylvania 19454.
authors: Peter M
authors: PM
authors: Shaw
authors: Surgery, National University of Singapore, 117597, Singapore.
authors: Chuen-Neng
authors: CN
authors: Lee
authors: Cancer Science Institute, National University of Singapore, 117597, Singapore; Harvard Stem Cell Institute, Boston, Massachusetts 02115.
authors: Daniel G
authors: DG
authors: Tenen
authors: Rosetta Inpharmatics LLC, Merck & Co., Seattle, Washington 98109; Merck Research Laboratories, Boston, Massachusetts 02115. Electronic address: Hongyue_dai@merck.com.
authors: Hongyue
authors: H
authors: Dai
authors: Rosetta Inpharmatics LLC, Merck & Co., Seattle, Washington 98109. Electronic address: mao.mao@pfizer.com.
authors: Mao
authors: M
authors: Mao
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D002135:Calcium-Binding Proteins; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality*; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics*; D015331:Cohort Studies; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007453:Iodide Peroxidase / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality*; D008565:Membrane Proteins / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D005810:Multigene Family; D011379:Prognosis; D014018:Tissue Distribution; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D035683:MicroRNAs; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase