Senescence and immortality in hepatocellular carcinoma

Ozturk M., ARSLAN ERGÜL A., Bagislar S., ŞENTÜRK Ş., Yuzugullu H.

CANCER LETTERS, vol.286, no.1, pp.103-113, 2009 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Review
  • Volume: 286 Issue: 1
  • Publication Date: 2009
  • Doi Number: 10.1016/j.canlet.2008.10.048
  • Journal Name: CANCER LETTERS
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.103-113
  • Keywords: Liver cancer, Senescence, Telomeres, DNA damage, p53, p16(INK4a), p21(Cip1), Retinoblastoma, Cirrhosis, Hepatocytes, Telomerase reverse transcriptase, ONCOGENE-INDUCED SENESCENCE, IN-VITRO TRANSFECTION, HUMAN LIVER-TISSUES, HEPATITIS-C VIRUS, HUMAN TUMOR-CELLS, REPLICATIVE SENESCENCE, UP-REGULATION, CELLULAR SENESCENCE, DNA-DAMAGE, HUMAN TELOMERASE
  • Dokuz Eylül University Affiliated: No

Abstract

Cellular senescence is a process leading to terminal growth arrest with characteristic morphological features. This process is mediated by telomere-dependent, oncogene-induced and ROS-induced pathways, but persistent DNA damage is the most common cause. Senescence arrest is mediated by p16(INK4a)- and p21(Cip1)-dependent pathways both leading to retinoblastoma protein (pRb) activation. p53 plays a relay role between DNA damage sensing and p21(Cip1) activation. pRb arrests the cell cycle by recruiting proliferation genes to facultative heterochromatin for permanent silencing. Replicative senescence that occurs in hepatocytes in culture and in liver cirrhosis is associated with lack of telomerase activity and results in telomere shortening. Hepatocellular carcinoma (HCC) cells display inactivating mutations of p53 and epigenetic silencing of p16(INK4a). Moreover, they re-express telomerase reverse transcriptase required for telomere maintenance. Thus, senescence bypass and cellular immortality is likely to contribute significantly to HCC development. Oncogene-induced senescence in premalignant lesions and reversible immortality of cancer cells including HCC offer new potentials for tumor prevention and treatment. (C) 2008 Elsevier Ireland Ltd. All rights reserved.