title: Genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis.
abstract: Senescence is a permanent proliferation arrest in response to cell stress such as DNA damage. It contributes strongly to tissue aging and serves as a major barrier against tumor development. Most tumor cells are believed to bypass the senescence barrier (become "immortal") by inactivating growth control genes such as TP53 and CDKN2A. They also reactivate telomerase reverse transcriptase. Senescence-to-immortality transition is accompanied by major phenotypic and biochemical changes mediated by genome-wide transcriptional modifications. This appears to happen during hepatocellular carcinoma (HCC) development in patients with liver cirrhosis, however, the accompanying transcriptional changes are virtually unknown. We investigated genome-wide transcriptional changes related to the senescence-to-immortality switch during hepatocellular carcinogenesis. Initially, we performed transcriptome analysis of senescent and immortal clones of Huh7 HCC cell line, and identified genes with significant differential expression to establish a senescence-related gene list. Through the analysis of senescence-related gene expression in different liver tissues we showed that cirrhosis and HCC display expression patterns compatible with senescent and immortal phenotypes, respectively; dysplasia being a transitional state. Gene set enrichment analysis revealed that cirrhosis/senescence-associated genes were preferentially expressed in non-tumor tissues, less malignant tumors, and differentiated or senescent cells. In contrast, HCC/immortality genes were up-regulated in tumor tissues, or more malignant tumors and progenitor cells. In HCC tumors and immortal cells genes involved in DNA repair, cell cycle, telomere extension and branched chain amino acid metabolism were up-regulated, whereas genes involved in cell signaling, as well as in drug, lipid, retinoid and glycolytic metabolism were down-regulated. Based on these distinctive gene expression features we developed a 15-gene hepatocellular immortality signature test that discriminated HCC from cirrhosis with high accuracy. Our findings demonstrate that senescence bypass plays a central role in hepatocellular carcinogenesis engendering systematic changes in the transcription of genes regulating DNA repair, proliferation, differentiation and metabolism.
authors.affiliation: BilGen Genetics and Biotechnology Center, Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.
authors.forename: Gokhan
authors.initials: G
authors.lastname: Yildiz
authors.forename: Ayca
authors.initials: A
authors.lastname: Arslan-Ergul
authors.forename: Sevgi
authors.initials: S
authors.lastname: Bagislar
authors.forename: Ozlen
authors.initials: O
authors.lastname: Konu
authors.forename: Haluk
authors.initials: H
authors.lastname: Yuzugullu
authors.forename: Ozge
authors.initials: O
authors.lastname: Gursoy-Yuzugullu
authors.forename: Nuri
authors.initials: N
authors.lastname: Ozturk
authors.forename: Cigdem
authors.initials: C
authors.lastname: Ozen
authors.forename: Hilal
authors.initials: H
authors.lastname: Ozdag
authors.forename: Esra
authors.initials: E
authors.lastname: Erdal
authors.forename: Sedat
authors.initials: S
authors.lastname: Karademir
authors.forename: Ozgul
authors.initials: O
authors.lastname: Sagol
authors.forename: Dilsa
authors.initials: D
authors.lastname: Mizrak
authors.forename: Hakan
authors.initials: H
authors.lastname: Bozkaya
authors.forename: Hakki Gokhan
authors.initials: HG
authors.lastname: Ilk
authors.forename: Ozlem
authors.initials: O
authors.lastname: Ilk
authors.forename: Biter
authors.initials: B
authors.lastname: Bilen
authors.forename: Rengul
authors.initials: R
authors.lastname: Cetin-Atalay
authors.forename: Nejat
authors.initials: N
authors.lastname: Akar
authors.forename: Mehmet
authors.initials: M
authors.lastname: Ozturk
mesh_terms: D001483:Base Sequence; D063646:Carcinogenesis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology*; D016922:Cellular Senescence / Q000235:genetics*; D017931:DNA Primers; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D016133:Polymerase Chain Reaction; D014158:Transcription, Genetic
chemical_list: D017931:DNA Primers