title: Keratin 19: a key role player in the invasion of human hepatocellular carcinomas.
abstract: OBJECTIVE
  Keratin (K)19, a biliary/hepatic progenitor cell (HPC) marker, is expressed in a subset of hepatocellular carcinomas (HCC) with poor prognosis. The underlying mechanisms driving this phenotype of K19-positive HCC remain elusive.
  
  
  METHODS
  Clinicopathological value of K19 was compared with EpCAM, and α-fetoprotein, in a Caucasian cohort of 242 consecutive patients (167 surgical specimens, 75 needle biopsies) with different underlying aetiologies. Using microarrays and microRNA profiling the molecular phenotype of K19-positive HCCs was identified. Clinical primary HCC samples were submitted to in vitro invasion assays and to side population analysis. HCC cell lines were transfected with synthetic siRNAs against KRT19 and submitted to invasion and cytotoxicity assays.
  
  
  RESULTS
  In the cohort of surgical specimens, K19 expression showed the strongest correlation with increased tumour size (p<0.01), decreased tumour differentiation (p<0.001), metastasis (p<0.05) and microvascular invasion (p<0.001). The prognostic value of K19 was also confirmed in a set of 75 needle biopsies. Profiling showed that K19-positive HCCs highly express invasion-related/metastasis-related markers (eg, VASP, TACSTD2, LAMB1, LAMC2, PDGFRA), biliary/HPC markers (eg, CD133, GSTP1, NOTCH2, JAG1) and members of the miRNA family 200 (eg, miR-141, miR-200c). In vitro, primary human K19-positive tumour cells showed increased invasiveness, and reside in the chemoresistant side population. Functionally, K19/KRT19 knockdown results in reduced invasion, loss of invadopodia formation and decreased resistance to doxorubicin, 5-fluorouracil and sorafenib.
  
  
  CONCLUSIONS
  Giving the distinct invasive properties, the different molecular profile and the poor prognostic outcome, K19-positive HCCs should be considered as a seperate entity of HCCs.
authors: Department of Imaging and Pathology, KU Leuven and University Hospitals Leuven, , Leuven, Belgium.
authors: Olivier
authors: O
authors: Govaere
authors: Mina
authors: M
authors: Komuta
authors: Johannes
authors: J
authors: Berkers
authors: Bart
authors: B
authors: Spee
authors: Carl
authors: C
authors: Janssen
authors: Francesca
authors: F
authors: de Luca
authors: Aezam
authors: A
authors: Katoonizadeh
authors: Jasper
authors: J
authors: Wouters
authors: Léon C
authors: LC
authors: van Kempen
authors: Anne
authors: A
authors: Durnez
authors: Chris
authors: C
authors: Verslype
authors: Joery
authors: J
authors: De Kock
authors: Vera
authors: V
authors: Rogiers
authors: Leo A
authors: LA
authors: van Grunsven
authors: Baki
authors: B
authors: Topal
authors: Jacques
authors: J
authors: Pirenne
authors: Hugo
authors: H
authors: Vankelecom
authors: Frederik
authors: F
authors: Nevens
authors: Joost
authors: J
authors: van den Oord
authors: Massimo
authors: M
authors: Pinzani
authors: Tania
authors: T
authors: Roskams
mesh_terms: D000951:Antigens, Neoplasm / Q000502:physiology; D015415:Biomarkers / Q000032:analysis; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000175:diagnosis / Q000473:pathology / Q000503:physiopathology*; D015815:Cell Adhesion Molecules / Q000502:physiology; D045744:Cell Line, Tumor; D000071858:Epithelial Cell Adhesion Molecule; D055785:Gene Knockdown Techniques; D006801:Humans; D053539:Keratin-19 / Q000032:analysis / Q000502:physiology*; D008113:Liver Neoplasms / Q000737:chemistry / Q000175:diagnosis / Q000473:pathology / Q000503:physiopathology*; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D000509:alpha-Fetoproteins / Q000502:physiology
chemical_list: D000951:Antigens, Neoplasm; D015415:Biomarkers; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D053539:Keratin-19; D000509:alpha-Fetoproteins
keywords: CELL MIGRATION; CYTOKERATINS; HEPATOCELLULAR CARCINOMA; MOLECULAR PATHOLOGY
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