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Telomere length, TERT and shelterin complex proteins in hepatocellular carcinomas expressing ‘‘stemness’’-related markers

Authors
 Haeryoung Kim  ;  Jeong Eun Yoo  ;  Jai Young Cho  ;  Bong-Kyeong Oh  ;  Yoo-Seok Yoon  ;  Ho-Seong Han  ;  Hye Seung Lee  ;  Ja June Jang  ;  Sook Hyang Jeong  ;  Jin Wook Kim  ;  Young Nyun Park 
Citation
 JOURNAL OF HEPATOLOGY, Vol.59(4) : 746-752, 2013 
Journal Title
JOURNAL OF HEPATOLOGY
ISSN
 0168-8278 
Issue Date
2013
MeSH
Adult ; Aged ; Antigens, Neoplasm/metabolism ; Apoptosis ; Biomarkers, Tumor/metabolism* ; Carcinoma, Hepatocellular/genetics* ; Carcinoma, Hepatocellular/metabolism* ; Carcinoma, Hepatocellular/pathology ; Cell Adhesion Molecules/metabolism ; Cell Proliferation ; Chromosomal Instability ; Epithelial Cell Adhesion Molecule ; Female ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Keratin-19/metabolism ; Liver Neoplasms/genetics* ; Liver Neoplasms/metabolism* ; Liver Neoplasms/pathology ; Male ; Middle Aged ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Prognosis ; Telomerase/metabolism* ; Telomere Homeostasis/genetics ; Telomere Homeostasis/physiology* ; Telomere-Binding Proteins/metabolism* ; Telomeric Repeat Binding Protein 2/metabolism
Keywords
Hepatocellular carcinoma ; Stemness ; Telomere ; TERT ; Shelterin
Abstract
BACKGROUND & AIMS:
Hepatocellular carcinomas (HCCs) expressing "stemness"-related markers have been associated with aggressive biological behavior and poor prognosis. We examined the relationship between "stemness"-related protein expression and telomere length, hTERT and shelterin complex protein expression and chromosomal instability.
METHODS:
Quantitative fluorescent in situ hybridization for telomere length, immunohistochemistry for K19, EpCAM, CD133, c-kit, HepPar1, hTERT, TRF1, TRF2, POT1, RAP1 and TPP1, and TUNEL assay were performed in 137 HCCs, and array comparative genomic hybridization was performed with 24 HCCs.
RESULTS:
Telomeres were significantly longer in HCCs expressing "stemness"-related proteins (K19: p < 0.001, EpCAM: p = 0.002, CD133: p = 0.002). On analyzing different tumor cells within EpCAM-expressing HCCs, EpCAM-positive tumor cells showed longer telomeres (1.329 ± 0.246) compared to EpCAM-negative tumor cells (0.996 ± 0.381) within the same HCCs (p = 0.031). Telomeres were significantly longer in HCCs expressing hTERT (p = 0.048) and RAP1 proteins (p = 0.031). K19-expressing HCCs expressed hTERT (p = 0.002), TRF2 (p = 0.001) and TPP1 (p = 0.013) more frequently compared to K19-negative HCCs. EpCAM-positivity was associated with more frequent hTERT (p = 0.028), TPP1 (p = 0.017), TRF2 (p = 0.027) and POT1 (p = 0.004) expression. Copy number alterations were more frequent in K19 and EpCAM-expressing HCCs compared to HCCs without these markers (K19: p = 0.038, EpCAM: p = 0.009). HCCs with longer telomeres were associated with a shorter overall (p = 0.019) and disease-free survivals (p = 0.049), and decreased disease-free survivals were seen in TRF2-positive HCCs (p = 0.018).
CONCLUSIONS:
HCCs expressing "stemness"-related proteins are characterized by increased telomere length, increased expression of hTERT and shelterin complex proteins, and increased chromosomal instability compared to conventional HCCs. Longer telomeres and TRF2 expression in HCCs are associated with poor patient outcomes.
Full Text
http://www.sciencedirect.com/science/article/pii/S0168827813003371
DOI
10.1016/j.jhep.2013.05.011
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Park, Young Nyun(박영년) ORCID logo https://orcid.org/0000-0003-0357-7967
Yoo, Jeong Eun(유정은) ORCID logo https://orcid.org/0000-0001-9990-279X
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/87584
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