Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis

Ruben Raphael Plentz, Young Nyun Park, André Lechel, Haeryoung Kim, Friederike Nellessen, Britta Heike Eva Langkopf, Ludwig Wilkens, Annarita Destro, Barbara Fiamengo, Michael Peter Manns, Massimo Roncalli, Karl Lenhard Rudolph

Research output: Contribution to journalArticle

99 Citations (Scopus)

Abstract

Telomere shortening and inactivation of cell cycle checkpoints characterize carcinogenesis. Whether these molecular features coincide at specific stages of human hepatocarcinogenesis is unknown. The preneoplasia-carcinoma sequence of human HCC is not well defined. Small cell changes (SCC) and large cell changes (LCC) are potential precursor lesions. We analyzed hepatocellular telomere length, the prevalence of DNA damage, and the expression of p21 and p16 in biopsy specimens of patients with chronic liver disease (n = 27) that showed different precursor lesions and/or HCC: liver cirrhosis (n = 25), LCC (n = 26), SCC (n = 13), and HCC (n = 13). The study shows a decrease in telomere length in nondysplastic cirrhotic liver compared with normal liver and a further significant shortening of telomeres in LCC, SCC, and HCC. HCC had the shortest telomeres, followed by SCC and LCC. Hepatocytes showed an increased p21 labeling index (p21-LI) at the cirrhosis stage, which remained elevated in most LCC. In contrast, most SCC and HCC showed a strongly reduced p21-LI. Similarly, p16 was strongly expressed in LCC but reduced in SCC and not detectable in HCC. γH2AX-DNA-damage-foci were not detected in LCC but were present in SCC and more frequently in HCC. These data indicate that LCC and SCC represent clonal expansions of hepatocytes with shortened telomeres. Conclusion: The inactivation of cell cycle checkpoints coincides with further telomere shortening and an accumulation of DNA damage in SCC and HCC, suggesting that SCC represent more advanced precursor lesions compared with LCC.

Original languageEnglish
Pages (from-to)968-976
Number of pages9
JournalHepatology
Volume45
Issue number4
DOIs
Publication statusPublished - Apr 2007

Fingerprint

Telomere Shortening
Cell Cycle Checkpoints
Telomere
DNA Damage
Hepatocytes

ASJC Scopus subject areas

  • Hepatology

Cite this

Plentz, R. R., Park, Y. N., Lechel, A., Kim, H., Nellessen, F., Langkopf, B. H. E., ... Rudolph, K. L. (2007). Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis. Hepatology, 45(4), 968-976. https://doi.org/10.1002/hep.21552

Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis. / Plentz, Ruben Raphael; Park, Young Nyun; Lechel, André; Kim, Haeryoung; Nellessen, Friederike; Langkopf, Britta Heike Eva; Wilkens, Ludwig; Destro, Annarita; Fiamengo, Barbara; Manns, Michael Peter; Roncalli, Massimo; Rudolph, Karl Lenhard.

In: Hepatology, Vol. 45, No. 4, 04.2007, p. 968-976.

Research output: Contribution to journalArticle

Plentz, RR, Park, YN, Lechel, A, Kim, H, Nellessen, F, Langkopf, BHE, Wilkens, L, Destro, A, Fiamengo, B, Manns, MP, Roncalli, M & Rudolph, KL 2007, 'Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis', Hepatology, vol. 45, no. 4, pp. 968-976. https://doi.org/10.1002/hep.21552
Plentz RR, Park YN, Lechel A, Kim H, Nellessen F, Langkopf BHE et al. Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis. Hepatology. 2007 Apr;45(4):968-976. https://doi.org/10.1002/hep.21552
Plentz, Ruben Raphael ; Park, Young Nyun ; Lechel, André ; Kim, Haeryoung ; Nellessen, Friederike ; Langkopf, Britta Heike Eva ; Wilkens, Ludwig ; Destro, Annarita ; Fiamengo, Barbara ; Manns, Michael Peter ; Roncalli, Massimo ; Rudolph, Karl Lenhard. / Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis. In: Hepatology. 2007 ; Vol. 45, No. 4. pp. 968-976.
@article{962aac369d15414cab81a9a339cc25a1,
title = "Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis",
abstract = "Telomere shortening and inactivation of cell cycle checkpoints characterize carcinogenesis. Whether these molecular features coincide at specific stages of human hepatocarcinogenesis is unknown. The preneoplasia-carcinoma sequence of human HCC is not well defined. Small cell changes (SCC) and large cell changes (LCC) are potential precursor lesions. We analyzed hepatocellular telomere length, the prevalence of DNA damage, and the expression of p21 and p16 in biopsy specimens of patients with chronic liver disease (n = 27) that showed different precursor lesions and/or HCC: liver cirrhosis (n = 25), LCC (n = 26), SCC (n = 13), and HCC (n = 13). The study shows a decrease in telomere length in nondysplastic cirrhotic liver compared with normal liver and a further significant shortening of telomeres in LCC, SCC, and HCC. HCC had the shortest telomeres, followed by SCC and LCC. Hepatocytes showed an increased p21 labeling index (p21-LI) at the cirrhosis stage, which remained elevated in most LCC. In contrast, most SCC and HCC showed a strongly reduced p21-LI. Similarly, p16 was strongly expressed in LCC but reduced in SCC and not detectable in HCC. γH2AX-DNA-damage-foci were not detected in LCC but were present in SCC and more frequently in HCC. These data indicate that LCC and SCC represent clonal expansions of hepatocytes with shortened telomeres. Conclusion: The inactivation of cell cycle checkpoints coincides with further telomere shortening and an accumulation of DNA damage in SCC and HCC, suggesting that SCC represent more advanced precursor lesions compared with LCC.",
author = "Plentz, {Ruben Raphael} and Park, {Young Nyun} and Andr{\'e} Lechel and Haeryoung Kim and Friederike Nellessen and Langkopf, {Britta Heike Eva} and Ludwig Wilkens and Annarita Destro and Barbara Fiamengo and Manns, {Michael Peter} and Massimo Roncalli and Rudolph, {Karl Lenhard}",
year = "2007",
month = "4",
doi = "10.1002/hep.21552",
language = "English",
volume = "45",
pages = "968--976",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Inc.",
number = "4",

}

TY - JOUR

T1 - Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis

AU - Plentz, Ruben Raphael

AU - Park, Young Nyun

AU - Lechel, André

AU - Kim, Haeryoung

AU - Nellessen, Friederike

AU - Langkopf, Britta Heike Eva

AU - Wilkens, Ludwig

AU - Destro, Annarita

AU - Fiamengo, Barbara

AU - Manns, Michael Peter

AU - Roncalli, Massimo

AU - Rudolph, Karl Lenhard

PY - 2007/4

Y1 - 2007/4

N2 - Telomere shortening and inactivation of cell cycle checkpoints characterize carcinogenesis. Whether these molecular features coincide at specific stages of human hepatocarcinogenesis is unknown. The preneoplasia-carcinoma sequence of human HCC is not well defined. Small cell changes (SCC) and large cell changes (LCC) are potential precursor lesions. We analyzed hepatocellular telomere length, the prevalence of DNA damage, and the expression of p21 and p16 in biopsy specimens of patients with chronic liver disease (n = 27) that showed different precursor lesions and/or HCC: liver cirrhosis (n = 25), LCC (n = 26), SCC (n = 13), and HCC (n = 13). The study shows a decrease in telomere length in nondysplastic cirrhotic liver compared with normal liver and a further significant shortening of telomeres in LCC, SCC, and HCC. HCC had the shortest telomeres, followed by SCC and LCC. Hepatocytes showed an increased p21 labeling index (p21-LI) at the cirrhosis stage, which remained elevated in most LCC. In contrast, most SCC and HCC showed a strongly reduced p21-LI. Similarly, p16 was strongly expressed in LCC but reduced in SCC and not detectable in HCC. γH2AX-DNA-damage-foci were not detected in LCC but were present in SCC and more frequently in HCC. These data indicate that LCC and SCC represent clonal expansions of hepatocytes with shortened telomeres. Conclusion: The inactivation of cell cycle checkpoints coincides with further telomere shortening and an accumulation of DNA damage in SCC and HCC, suggesting that SCC represent more advanced precursor lesions compared with LCC.

AB - Telomere shortening and inactivation of cell cycle checkpoints characterize carcinogenesis. Whether these molecular features coincide at specific stages of human hepatocarcinogenesis is unknown. The preneoplasia-carcinoma sequence of human HCC is not well defined. Small cell changes (SCC) and large cell changes (LCC) are potential precursor lesions. We analyzed hepatocellular telomere length, the prevalence of DNA damage, and the expression of p21 and p16 in biopsy specimens of patients with chronic liver disease (n = 27) that showed different precursor lesions and/or HCC: liver cirrhosis (n = 25), LCC (n = 26), SCC (n = 13), and HCC (n = 13). The study shows a decrease in telomere length in nondysplastic cirrhotic liver compared with normal liver and a further significant shortening of telomeres in LCC, SCC, and HCC. HCC had the shortest telomeres, followed by SCC and LCC. Hepatocytes showed an increased p21 labeling index (p21-LI) at the cirrhosis stage, which remained elevated in most LCC. In contrast, most SCC and HCC showed a strongly reduced p21-LI. Similarly, p16 was strongly expressed in LCC but reduced in SCC and not detectable in HCC. γH2AX-DNA-damage-foci were not detected in LCC but were present in SCC and more frequently in HCC. These data indicate that LCC and SCC represent clonal expansions of hepatocytes with shortened telomeres. Conclusion: The inactivation of cell cycle checkpoints coincides with further telomere shortening and an accumulation of DNA damage in SCC and HCC, suggesting that SCC represent more advanced precursor lesions compared with LCC.

UR - http://www.scopus.com/inward/record.url?scp=34247400156&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34247400156&partnerID=8YFLogxK

U2 - 10.1002/hep.21552

DO - 10.1002/hep.21552

M3 - Article

VL - 45

SP - 968

EP - 976

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 4

ER -