title: MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a.
abstract: OBJECTIVE
  Hepatocellular carcinoma (HCC) is a heterogeneous tumor that develops via activation of multiple pathways and molecular alterations. It has been a challenge to identify molecular classes of HCC and design treatment strategies for each specific subtype. MicroRNAs (miRNAs) are involved in HCC pathogenesis, and their expression profiles have been used to classify cancers. We analyzed miRNA expression in human HCC samples to identify molecular subclasses and oncogenic miRNAs.
  
  
  METHODS
  We performed miRNA profiling of 89 HCC samples using a ligation-mediated amplification method. Subclasses were identified by unsupervised clustering analysis. We identified molecular features specific for each subclass using expression pattern (Affymetrix U133 2.0; Affymetrix, Santa Clara, CA), DNA change (Affymetrix STY Mapping Array), mutation (CTNNB1), and immunohistochemical (phosphor[p]-protein kinase B, p-insulin growth factor-IR, p-S6, p-epidermal growth factor receptor, β-catenin) analyses. The roles of selected miRNAs were investigated in cell lines and in an orthotopic model of HCC.
  
  
  RESULTS
  We identified 3 main clusters of HCCs: the wingless-type MMTV integration site (32 of 89; 36%), interferon-related (29 of 89; 33%), and proliferation (28 of 89; 31%) subclasses. A subset of patients with tumors in the proliferation subclass (8 of 89; 9%) overexpressed a family of poorly characterized miRNAs from chr19q13.42. Expression of miR-517a and miR-520c (from ch19q13.42) increased proliferation, migration, and invasion of HCC cells in vitro. MiR-517a promoted tumorigenesis and metastatic dissemination in vivo.
  
  
  CONCLUSIONS
  We propose miRNA-based classification of 3 subclasses of HCC. Among the proliferation class, miR-517a is an oncogenic miRNA that promotes tumor progression. There is rationale for developing therapies that target miR-517a for patients with HCC.
authors.affiliation: Mount Sinai Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, New York, New York, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Toffanin
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hoshida
authors.forename: Anja
authors.initials: A
authors.lastname: Lachenmayer
authors.forename: Augusto
authors.initials: A
authors.lastname: Villanueva
authors.forename: Laia
authors.initials: L
authors.lastname: Cabellos
authors.forename: Beatriz
authors.initials: B
authors.lastname: Minguez
authors.forename: Radoslav
authors.initials: R
authors.lastname: Savic
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Ward
authors.forename: Swan
authors.initials: S
authors.lastname: Thung
authors.forename: Derek Y
authors.initials: DY
authors.lastname: Chiang
authors.forename: Clara
authors.initials: C
authors.lastname: Alsinet
authors.forename: Victoria
authors.initials: V
authors.lastname: Tovar
authors.forename: Sasan
authors.initials: S
authors.lastname: Roayaie
authors.forename: Myron
authors.initials: M
authors.lastname: Schwartz
authors.forename: Jordi
authors.initials: J
authors.lastname: Bruix
authors.forename: Samuel
authors.initials: S
authors.lastname: Waxman
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
authors.forename: Todd
authors.initials: T
authors.lastname: Golub
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Mazzaferro
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000145:classification* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000145:classification* / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012334:RNA, Neoplasm / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: C546349:MIRN517 microRNA, human; D035683:MicroRNAs; D012334:RNA, Neoplasm