TY - JOUR
T1 - Keratin 19
T2 - a key role player in the invasion of human hepatocellular carcinomas
AU - Govaere, Olivier
AU - Komuta, Mina
AU - Berkers, Johannes
AU - Spee, Bart
AU - Janssen, Carl
AU - de Luca, Francesca
AU - Katoonizadeh, Aezam
AU - Wouters, Jasper
AU - van Kempen, Léon C
AU - Durnez, Anne
AU - Verslype, Chris
AU - De Kock, Joery
AU - Rogiers, Vera
AU - van Grunsven, Leo A
AU - Topal, Baki
AU - Pirenne, Jacques
AU - Vankelecom, Hugo
AU - Nevens, Frederik
AU - van den Oord, Joost
AU - Pinzani, Massimo
AU - Roskams, Tania
PY - 2014/4
Y1 - 2014/4
N2 - 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.
AB - 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.
KW - Antigens, Neoplasm/physiology
KW - Biomarkers/analysis
KW - Carcinoma, Hepatocellular/chemistry
KW - Cell Adhesion Molecules/physiology
KW - Cell Line, Tumor
KW - Epithelial Cell Adhesion Molecule
KW - Gene Knockdown Techniques
KW - Humans
KW - Keratin-19/analysis
KW - Liver Neoplasms/chemistry
KW - Neoplasm Invasiveness/physiopathology
KW - Oligonucleotide Array Sequence Analysis
KW - Prognosis
KW - Real-Time Polymerase Chain Reaction
KW - alpha-Fetoproteins/physiology
U2 - 10.1136/gutjnl-2012-304351
DO - 10.1136/gutjnl-2012-304351
M3 - Article
C2 - 23958557
SN - 0017-5749
VL - 63
SP - 674
EP - 685
JO - Gut
JF - Gut
IS - 4
ER -