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

Simple item page
dc.citation.epage64016-13en_US
dc.citation.issueNumber5en_US
dc.citation.spage64016-1en_US
dc.citation.volumeNumber8en_US
dc.contributor.authorYildiz, G.en_US
dc.contributor.authorArslan Ergul, A.en_US
dc.contributor.authorBagislar, S.en_US
dc.contributor.authorKonu, O.en_US
dc.contributor.authorYuzugullu, H.en_US
dc.contributor.authorGursoy Yuzugullu, O.en_US
dc.contributor.authorOzturk, N.en_US
dc.contributor.authorOzen, C.en_US
dc.contributor.authorOzdag, H.en_US
dc.contributor.authorErdal, E.en_US
dc.contributor.authorKarademir, S.en_US
dc.contributor.authorSagol, O.en_US
dc.contributor.authorMizrak, D.en_US
dc.contributor.authorBozkaya, H.en_US
dc.contributor.authorIlk, H. G.en_US
dc.contributor.authorIlk, O.en_US
dc.contributor.authorBilen, B.en_US
dc.contributor.authorCetin Atalay, R.en_US
dc.contributor.authorAkar, N.en_US
dc.contributor.authorOzturk, M.en_US
dc.date.accessioned2015-07-28T12:01:51Z
dc.date.available2015-07-28T12:01:51Z
dc.date.issued2013en_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
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.en_US
dc.identifier.doi10.1371/journal.pone.0064016en_US
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/11693/12541
dc.language.isoEnglishen_US
dc.publisherPLOS ONEen_US
dc.relation.isversionofhttp://dx.doi.org/10.1371/journal.pone.0064016en_US
dc.source.titlePLoS ONEen_US
dc.subjectChronic Liver-diseaseen_US
dc.subjectCellular Senescenceen_US
dc.subjectGene-expressionen_US
dc.subjectReplicative Senescenceen_US
dc.subjectMolecular Signatureen_US
dc.subjectMicroarray Analysisen_US
dc.subjectTelomere Lengthen_US
dc.subjectCarcinoma Cellsen_US
dc.subjectHepatitis-cen_US
dc.subjectCanceren_US
dc.titleGenome-Wide Transcriptional Reorganization Associated with Senescence-to-Immortality Switch during Human Hepatocellular Carcinogenesisen_US
dc.typeArticleen_US

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
10.1371-journal.pone.0064016.g007.pdf
Size:
4.84 MB
Format:
Adobe Portable Document Format
Download

Collections

Department of Molecular Biology and Genetics