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Lookup NU author(s): Dr Olivier GovaereORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
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. Design: Clinicopathological value of K19 was compared with EpCAM, and รก-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.
Author(s): Govaere O, Komuta M, Berkers J, Spee B, Janssen C, De Luca F, Katoonizadeh A, Wouters J, Van Kempen LC, Durnez A, Verslype C, De Kock J, Rogiers V, Van Grunsven LA, Topal B, Pirenne J, Vankelecom H, Nevens F, Van Den Oord J, Pinzani M, Roskams T
Publication type: Article
Publication status: Published
Journal: Gut
Year: 2014
Volume: 63
Issue: 4
Pages: 674-685
Online publication date: 19/08/2013
Acceptance date: 28/06/2013
Date deposited: 08/12/2017
ISSN (print): 0017-5749
ISSN (electronic): 1468-3288
Publisher: BMJ Publishing Group
URL: https://doi.org/10.1136/gutjnl-2012-304351
DOI: 10.1136/gutjnl-2012-304351
PubMed id: 23958557
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