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

被引:58
作者
Kim, Haeryoung [1 ]
Yoo, Jeong Eun [2 ]
Cho, Jai Young [3 ]
Oh, Bong-Kyeong [4 ]
Yoon, Yoo-Seok [3 ]
Han, Ho-Seong [3 ]
Lee, Hye Seung [1 ]
Jang, Ja June [5 ]
Jeong, Sook Hyang [6 ]
Kim, Jin Wook [6 ]
Park, Young Nyun [2 ]
机构
[1] Seoul Natl Univ, Bundang Hosp, Dept Pathol, Songnam, South Korea
[2] Yonsei Univ, Coll Med, Dept Pathol, Grad Sch Med Sci,Integrated Genom Res Ctr Metab R, Seoul, South Korea
[3] Seoul Natl Univ, Dept Surg, Bundang Hosp, Songnam, South Korea
[4] Hanyang Univ, Coll Med, Inst Med Sci, Dept Obstet & Gynecol, Seoul 133791, South Korea
[5] Seoul Natl Univ, Coll Med, Dept Pathol, Seoul 151, South Korea
[6] Seoul Natl Univ, Dept Internal Med, Bundang Hosp, Songnam, South Korea
关键词
Hepatocellular carcinoma; Stemness; Telomere; TERT; Shelterin; ABERRATIONS; CELLS; TPP1;
D O I
10.1016/j.jhep.2013.05.011
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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 inK19and EpCAM-expressingHCCscomparedto HCCswithout 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. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
引用
收藏
页码:746 / 752
页数:7
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