You are here

Article Text

Article menu
XML
Hepatology
Original article
Keratin 19: a key role player in the invasion of human hepatocellular carcinomas
  1. Olivier Govaere1,
  2. Mina Komuta1,
  3. Johannes Berkers1,
  4. Bart Spee1,
  5. Carl Janssen1,
  6. Francesca de Luca2,
  7. Aezam Katoonizadeh1,
  8. Jasper Wouters1,3,
  9. Léon C van Kempen4,
  10. Anne Durnez1,
  11. Chris Verslype5,
  12. Joery De Kock6,
  13. Vera Rogiers6,
  14. Leo A van Grunsven7,
  15. Baki Topal8,
  16. Jacques Pirenne9,
  17. Hugo Vankelecom3,
  18. Frederik Nevens5,
  19. Joost van den Oord1,
  20. Massimo Pinzani10,
  21. Tania Roskams1
  1. 1Department of Imaging and Pathology, KU Leuven and University Hospitals Leuven, Leuven, Belgium
  2. 2Dipartimento Oncologico AUSL 4, Institute Toscano Tumori (ITT), Prato, Italy
  3. 3Department of Development and Regeneration, KU Leuven, Leuven, Belgium
  4. 4Department of Pathology, McGill University/Jewish General Hospital, Montreal, Quebec, Canada
  5. 5Department of Hepatology, KU Leuven and University Hospitals Leuven, Leuven, Belgium
  6. 6Department of In Vitro Toxicology and Dermato-cosmetology (IVTD/FAFY), Vrije Universiteit Brussel, Brussels, Belgium
  7. 7Department of Cell Biology, Liver Cell Biology Lab, Vrije Universiteit Brussel, Brussels, Belgium
  8. 8Department of Abdominal Surgery, KU Leuven and University Hospitals Leuven, Leuven, Belgium
  9. 9Department of Abdominal Transplant Surgery, KU Leuven and University Hospitals Leuven, Leuven, Belgium
  10. 10University College London, Institute for Liver and Digestive Health, Royal Free Hospital, London, UK
  1. Correspondence to Dr Olivier Govaere, Translational Cell and Tissue Research, Department of Imaging and Pathology, University Hospitals Leuven, Minderbroedersstraat 12, Leuven B3000, Belgium; olivier.govaere{at}med.kuleuven.be

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.

Design 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.

  • HEPATOCELLULAR CARCINOMA
  • MOLECULAR PATHOLOGY
  • CYTOKERATINS
  • CELL MIGRATION

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/

https://doi.org/10.1136/gutjnl-2012-304351

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    View Full Text

    Supplementary materials

    Linked Articles

    • Digest
      Highlights from this issue
      Emad El-Omar Alexander Gerbes William Grady Thomas Rösch
      Gut 2014; 63 i-ii Published Online First: 27 Feb 2014. doi: 10.1136/gutjnl-2014-307028