Abstract
Primary liver cancer comprises a diverse group of liver tumors. The heterogeneity of these tumors is seen as one of the obstacles to finding an effective therapy. The Hippo pathway, with its downstream transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), has a decisive role in the carcinogenesis of primary liver cancer. Therefore, we examined the expression pattern of YAP and TAZ in 141 patients with hepatocellular carcinoma keratin 19 positive (HCC K19⁺), hepatocellular carcinoma keratin 19 negative (HCC K19-), combined hepatocellular⁻cholangiocarcinoma carcinoma (cHCC-CCA), or cholangiocarcinoma (CCA). All cHCC-CCA and CCA patients showed high expression levels for YAP and TAZ, while only some patients of the HCC group were positive. Notably, we found that a histoscore of both markers is useful in the challenging diagnosis of cHCC-CCA. In addition, positivity for YAP and TAZ was observed in the hepatocellular and cholangiocellular components of cHCC-CCA, which suggests a single cell origin in cHCC-CCA. Within the K19- HCC group, our results demonstrate that the expression of YAP is a statistically significant predictor of poor prognosis when observed in the cytoplasm. Nuclear expression of TAZ is an even more specific and independent predictor of poor disease-free survival and overall survival of K19- HCC patients. Our results thus identify different levels of YAP/TAZ expression in various liver cancers that can be used for diagnostics.
Keywords:
CCA; HCC; Hepatic progenitor cells; Keratin 19; TAZ; YAP; cHCC-CCA.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Aged
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Bile Duct Neoplasms / diagnosis
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Bile Duct Neoplasms / genetics*
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Bile Duct Neoplasms / mortality
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Bile Duct Neoplasms / pathology
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Biomarkers, Tumor / genetics*
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Biomarkers, Tumor / metabolism
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Carcinogenesis / genetics
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Carcinogenesis / metabolism
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Carcinogenesis / pathology
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Carcinoma, Hepatocellular / diagnosis
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Carcinoma, Hepatocellular / genetics*
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Carcinoma, Hepatocellular / mortality
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Carcinoma, Hepatocellular / pathology
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Cell Nucleus / metabolism
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Cell Nucleus / pathology
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Cholangiocarcinoma / diagnosis
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Cholangiocarcinoma / genetics*
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Cholangiocarcinoma / mortality
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Cholangiocarcinoma / pathology
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Cytosol / metabolism
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Cytosol / pathology
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Female
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Gene Expression Regulation, Neoplastic*
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Genetic Heterogeneity
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Humans
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Intracellular Signaling Peptides and Proteins / genetics*
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Intracellular Signaling Peptides and Proteins / metabolism
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Kaplan-Meier Estimate
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Keratin-19 / deficiency
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Keratin-19 / genetics
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Ki-67 Antigen / genetics
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Ki-67 Antigen / metabolism
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Liver Neoplasms / diagnosis
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Liver Neoplasms / genetics*
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Liver Neoplasms / mortality
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Liver Neoplasms / pathology
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Male
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Middle Aged
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Phosphoproteins / genetics*
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Phosphoproteins / metabolism
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Prognosis
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Proportional Hazards Models
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Retrospective Studies
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Signal Transduction
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Trans-Activators
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Transcription Factors
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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YAP-Signaling Proteins
Substances
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Adaptor Proteins, Signal Transducing
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Biomarkers, Tumor
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Intracellular Signaling Peptides and Proteins
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KRT19 protein, human
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Keratin-19
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Ki-67 Antigen
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Phosphoproteins
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Trans-Activators
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Transcription Factors
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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WWTR1 protein, human
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YAP-Signaling Proteins
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YAP1 protein, human