Dataset Information

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.

Design

Clinicopathological value of K19 was compared with EpCAM, and ?-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.

SUBMITTER: Govaere O

PROVIDER: S-EPMC3963546 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Publications

Keratin 19: a key role player in the invasion of human hepatocellular carcinomas.

Govaere Olivier O Komuta Mina M Berkers Johannes J Spee Bart B Janssen Carl C de Luca Francesca F Katoonizadeh Aezam A Wouters Jasper J van Kempen Léon C LC Durnez Anne A Verslype Chris C De Kock Joery J Rogiers Vera V van Grunsven Leo A LA Topal Baki B Pirenne Jacques J Vankelecom Hugo H Nevens Frederik F van den Oord Joost J Pinzani Massimo M Roskams Tania T

Gut 20130819 4

<h4>Objective</h4>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.<h4>Design</h4>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 microR ...[more]

PMID: 23958557

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Project description:Human hepatocellular carcinomas (HCCs) expressing the biliary/hepatic progenitor cell marker keratin 19 (K19) have been linked with a poor prognosis and exhibit an increase in platelet-derived growth factor receptor ? (PDGFR?) and laminin beta 1 (LAMB1) expression. PDGFR? has been reported to induce de novo synthesis of LAMB1 protein in a Sjogren syndrome antigen B (La/SSB)-dependent manner in a murine metastasis model. However, the role of this cascade in human HCC remains unclear. This study focused on the functional role of the PDGFR?-La/SSB-LAMB1 pathway and its molecular link to K19 expression in human HCC. In surgical HCC specimens from a cohort of 136 patients, PDGFR? expression correlated with K19 expression, microvascular invasion and metastatic spread. In addition, PDGFR? expression in pre-operative needle biopsy specimens predicted poor overall survival during a 5-year follow-up period. Consecutive histological staining demonstrated that the signaling components of the PDGFR?-La/SSB-LAMB1 pathway were strongly expressed at the invasive front. K19-positive HCC cells displayed high levels of ?2?1 integrin (ITG) receptor, both in vitro and in vivo. In vitro activation of PDGFR? signaling triggered the translocation of nuclear La/SSB into the cytoplasm, enhanced the protein synthesis of LAMB1 by activating its internal ribosome entry site, which in turn led to increased secretion of laminin-111. This effect was abrogated by the PDGFR?-specific inhibitor crenolanib. Importantly LAMB1 stimulated ITG-dependent focal adhesion kinase/Src proto-oncogene non-receptor tyrosine kinase signaling. It also promoted the ITG-specific downstream target Rho-associated coiled-coil containing protein kinase 2, induced K19 expression in an autocrine manner, invadopodia formation and cell invasion. Finally, we showed that the knockdown of LAMB1 or K19 in subcutaneous xenograft mouse models resulted in significant loss of cells invading the surrounding stromal tissue and reduced HepG2 colonization into lung and liver after tail vein injection. The PDGFR?-LAMB1 pathway supports tumor progression at the invasive front of human HCC through K19 expression.

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Dataset Information

Keratin 19: a key role player in the invasion of human hepatocellular carcinomas.

Objective

Design

Results

Conclusions

Publications

Keratin 19: a key role player in the invasion of human hepatocellular carcinomas.

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