title: Human hepatocellular carcinomas with "Stemness"-related marker expression: keratin 19 expression and a poor prognosis.
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).
  
  
  CONCLUSIONS
  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.
authors: Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea.
authors: Haeryoung
authors: H
authors: Kim
authors: Gi Hong
authors: GH
authors: Choi
authors: Deuk Chae
authors: DC
authors: Na
authors: Ei Young
authors: EY
authors: Ahn
authors: Gwang Il
authors: GI
authors: Kim
authors: Jae Eun
authors: JE
authors: Lee
authors: Jai Young
authors: JY
authors: Cho
authors: Jeong Eun
authors: JE
authors: Yoo
authors: Jin Sub
authors: JS
authors: Choi
authors: Young Nyun
authors: YN
authors: Park
mesh_terms: D000071916:AC133 Antigen; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D015331:Cohort Studies; D000071858:Epithelial Cell Adhesion Molecule; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D053539:Keratin-19 / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000378:metabolism; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D055815:Young Adult
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D015415:Biomarkers; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D006023:Glycoproteins; D053539:Keratin-19; C000606023:PROM1 protein, human; D010455:Peptides; D019009:Proto-Oncogene Proteins c-kit