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Human hepatocellular carcinomas with "Stemness"-related marker expression: keratin 19 expression and a poor prognosis

Authors
 Haeryoung Kim  ;  Gi Hong Choi  ;  Deuk Chae Na  ;  Ei Young Ahn  ;  Gwang Il Kim  ;  Jae Eun Lee  ;  Jai Young Cho  ;  Jeong Eun Yoo  ;  Jin Sub Choi  ;  Young Nyun Park 
Citation
 HEPATOLOGY, Vol.54(5) : 1707-1717, 2011 
Journal Title
HEPATOLOGY
ISSN
 0270-9139 
Issue Date
2011
MeSH
AC133 Antigen ; Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antigens, CD/metabolism ; Antigens, Neoplasm/metabolism ; Biomarkers/metabolism ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism* ; Carcinoma, Hepatocellular/diagnosis* ; Carcinoma, Hepatocellular/metabolism* ; Cell Adhesion Molecules/metabolism ; Cohort Studies ; Epithelial Cell Adhesion Molecule ; Epithelial-Mesenchymal Transition/physiology ; Female ; Glycoproteins/metabolism ; Humans ; Keratin-19/genetics ; Keratin-19/metabolism* ; Liver Neoplasms/diagnosis* ; Liver Neoplasms/metabolism* ; Male ; Middle Aged ; Peptides/metabolism ; Prognosis ; Proto-Oncogene Proteins c-kit/metabolism ; Stem Cells/metabolism ; Young Adult
Abstract
There is a recently proposed subtype of hepatocellular carcinoma (HCC) that is histologically similar to usual HCC, but characterized by the expression of "stemness"-related markers. A large-scale study on two different cohorts of HCCs was performed to investigate the clinicopathologic features and epithelial-mesenchymal transition (EMT)-related protein expression status of this subtype of HCCs. The expression status of stemness-related (e.g., keratin 19 [K19], cluster of differentiation [CD]133, epithelial cell adhesion molecule [EpCAM], and c-kit) and EMT-related markers (e.g., snail, S100A4, urokinase plasminogen activator receptor [uPAR], ezrin, vimentin, E-cadherin, and matrix metalloproteinase [MMP]2) were examined using tissue microarrays from cohort 1 HCCs (n = 137). K19 protein expression in cohort 2 HCCs (n = 237) was correlated with the clinicopathologic parameters and messenger RNA (mRNA) levels of K19, uPAR, VIL2, Snail, Slug, and Twist. K19, EpCAM, c-kit, and CD133 positivity were observed in 18.2%, 35.0%, 34.3%, and 24.8%, respectively. K19 was most frequently expressed in combination with at least one other stemness-related marker (92.0%). K19-positive HCCs demonstrated more frequent major vessel invasion and increased tumor size, compared to K19-negative HCCs (P < 0.05). K19 was most significantly associated with EMT-related protein expression (e.g., vimentin, S100A4, uPAR, and ezrin) (P < 0.05) and a poor prognosis (overall survival: P = 0.018; disease-free survival: P = 0.007) in cohort 1. In cohort 2, HCCs with high K19 mRNA levels demonstrated higher mRNA levels of Snail, uPAR, and MMP2 (P < 0.05). K19-positive HCCs demonstrated more frequent microvascular invasion, fibrous stroma, and less tumor-capsule formation, compared to K19-negative HCCs (P < 0.05). K19 expression was a significant independent predictive factor of poor disease-free survival (P = 0.032).

CONCLUSION: K19 was well correlated with clinicopathologic features of tumor aggressiveness, compared to other stemness-related proteins. K19-positive HCCs showed significantly increased EMT-related protein and mRNA expression, suggesting that they may acquire more invasive characteristics, compared to K19-negative HCCs through the up-regulation of EMT-associated genes.
Full Text
http://onlinelibrary.wiley.com/doi/10.1002/hep.24559/abstract
DOI
10.1002/hep.24559
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Park, Young Nyun(박영년) ORCID logo https://orcid.org/0000-0003-0357-7967
Choi, Gi Hong(최기홍) ORCID logo https://orcid.org/0000-0002-1593-3773
Choi, Jin Sub(최진섭)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/94594
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