title: Senescence and immortality in hepatocellular carcinoma.
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.
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, 06800 Ankara, Turkey. ozturkm@ujf-grenoble.fr
authors.forename: Mehmet
authors.initials: M
authors.lastname: Ozturk
authors.forename: Ayca
authors.initials: A
authors.lastname: Arslan-Ergul
authors.forename: Sevgi
authors.initials: S
authors.lastname: Bagislar
authors.forename: Serif
authors.initials: S
authors.lastname: Senturk
authors.forename: Haluk
authors.initials: H
authors.lastname: Yuzugullu
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016922:Cellular Senescence; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004789:Enzyme Activation; D022781:Hepatocytes / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D047428:Protein Kinase Inhibitors; D019098:Telomerase / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D018844:Cyclin-Dependent Kinases; D019098:Telomerase