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

Abstract

ObjectiveKeratin (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.DesignClinicopathological 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.ResultsIn 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.ConclusionsGiving 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.

Immunohistochemical expression and clinical significance of suggested stem cell markers in hepatocellular carcinoma

“…15,21 The proportion of tissues expressing EpCAM in this study was a little higher than in earlier series, which reported EpCAM in 15.9%-48.7% of HCCs. [15][16][17][20][21][22][23] Kimura et al 23 have demonstrated that EpCAM expression was observed more often in HCC patients with HBV than in those with other etiologies, and the immunoreactivity of EpCAM has been found in up to 78% of HCC patients with HBV. The high proportion of HCC patients with HBV (74%) examined in this study might be a possible explanation for the higher EpCAMpositive rate.…”

“…These findings are in agreement with previous studies showing that expression level of EpCAM correlates with de-differentiation 11 and vascular invasion and is associated with the high AFP level in HCC. 20,21 The prognosis of patients with EpCAM-negative HCC is considered to be better than that of those with EpCAM-positive HCC. 11,[14][15][16]20,21 Although EpCAM expression was not found to be an independent predictor of survival in patients with HCC in this study, EpCAM expression was found to be associated with well-known unfavorable prognostic factors in HCC.…”

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

“…In addition, the phenotypic and genotypic profiles are similar to cholangiolo cellular carcinoma, thought to originate from hepatic progenitor cells 17,50,51 . A number of observations suggest that bile ductular (mixed)-type iCCAs together with cholangiolocellular carcinoma and CK19 + HCC represent a group of primitive liver cancers originating from hepatic progenitor cells, the different phenotype depending on the step of hepatic progenitor cell differentiation toward cholangiocytes or hepatocytes, in which neoplastic transformation occurs 17,20,[52][53][54] .…”

Keratin 19, a Cancer Stem Cell Marker in Human Hepatocellular Carcinoma

“…K19 is known to be a marker of poor prognosis in HCC in several studies (19)(20)(21). Especially, K19 is reported as a key player in tumor invasion in HCC (22). However, the relationship between K19 and HCCCSCs is not fully understood.…”