Genome-Wide Transcriptional Reorganization Associated with Senescence-to-Immortality Switch during Human Hepatocellular Carcinogenesis

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dc.contributor.authorÖzdag, Hilal
dc.contributor.authorIDhttp://orcid.org/0000-0001-7940-2499tr_TR
dc.contributor.departmentBiyoteknoloji Enstitüsütr_TR
dc.contributor.otherBozkaya, Hakan
dc.contributor.otherİlk, Hakkı Gökhan
dc.date.accessioned2020-05-06T06:54:52Z
dc.date.available2020-05-06T06:54:52Z
dc.date.issued2013
dc.description.abstractSenescence 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.tr_TR
dc.description.indexwos
dc.description.indexScopus
dc.identifier.endpage14tr_TR
dc.identifier.issue5tr_TR
dc.identifier.othere64016tr_TR
dc.identifier.startpage01tr_TR
dc.identifier.urihttps://doi.org/10.1371/journal.pone.0064016tr_TR
dc.identifier.urihttp://hdl.handle.net/20.500.12575/71212
dc.identifier.volume8tr_TR
dc.language.isoentr_TR
dc.relation.isversionof10.1371/journal.pone.0064016tr_TR
dc.relation.journalPLoS ONEtr_TR
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıtr_TR
dc.subjectGenome-Widetr_TR
dc.titleGenome-Wide Transcriptional Reorganization Associated with Senescence-to-Immortality Switch during Human Hepatocellular Carcinogenesistr_TR
dc.typeArticletr_TR

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