Genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis.
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...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2013
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/8e1281cde73745e7a1c2cc9e38f3e9db |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:8e1281cde73745e7a1c2cc9e38f3e9db |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:8e1281cde73745e7a1c2cc9e38f3e9db2021-11-18T07:45:37ZGenome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis.1932-620310.1371/journal.pone.0064016https://doaj.org/article/8e1281cde73745e7a1c2cc9e38f3e9db2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23691139/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Senescence 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.Gokhan YildizAyca Arslan-ErgulSevgi BagislarOzlen KonuHaluk YuzugulluOzge Gursoy-YuzugulluNuri OzturkCigdem OzenHilal OzdagEsra ErdalSedat KarademirOzgul SagolDilsa MizrakHakan BozkayaHakki Gokhan IlkOzlem IlkBiter BilenRengul Cetin-AtalayNejat AkarMehmet OzturkPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 5, p e64016 (2013) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Gokhan Yildiz Ayca Arslan-Ergul Sevgi Bagislar Ozlen Konu Haluk Yuzugullu Ozge Gursoy-Yuzugullu Nuri Ozturk Cigdem Ozen Hilal Ozdag Esra Erdal Sedat Karademir Ozgul Sagol Dilsa Mizrak Hakan Bozkaya Hakki Gokhan Ilk Ozlem Ilk Biter Bilen Rengul Cetin-Atalay Nejat Akar Mehmet Ozturk Genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis. |
| description |
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. |
| format |
article |
| author |
Gokhan Yildiz Ayca Arslan-Ergul Sevgi Bagislar Ozlen Konu Haluk Yuzugullu Ozge Gursoy-Yuzugullu Nuri Ozturk Cigdem Ozen Hilal Ozdag Esra Erdal Sedat Karademir Ozgul Sagol Dilsa Mizrak Hakan Bozkaya Hakki Gokhan Ilk Ozlem Ilk Biter Bilen Rengul Cetin-Atalay Nejat Akar Mehmet Ozturk |
| author_facet |
Gokhan Yildiz Ayca Arslan-Ergul Sevgi Bagislar Ozlen Konu Haluk Yuzugullu Ozge Gursoy-Yuzugullu Nuri Ozturk Cigdem Ozen Hilal Ozdag Esra Erdal Sedat Karademir Ozgul Sagol Dilsa Mizrak Hakan Bozkaya Hakki Gokhan Ilk Ozlem Ilk Biter Bilen Rengul Cetin-Atalay Nejat Akar Mehmet Ozturk |
| author_sort |
Gokhan Yildiz |
| title |
Genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis. |
| title_short |
Genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis. |
| title_full |
Genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis. |
| title_fullStr |
Genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis. |
| title_full_unstemmed |
Genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis. |
| title_sort |
genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/8e1281cde73745e7a1c2cc9e38f3e9db |
| work_keys_str_mv |
AT gokhanyildiz genomewidetranscriptionalreorganizationassociatedwithsenescencetoimmortalityswitchduringhumanhepatocellularcarcinogenesis AT aycaarslanergul genomewidetranscriptionalreorganizationassociatedwithsenescencetoimmortalityswitchduringhumanhepatocellularcarcinogenesis AT sevgibagislar genomewidetranscriptionalreorganizationassociatedwithsenescencetoimmortalityswitchduringhumanhepatocellularcarcinogenesis AT ozlenkonu genomewidetranscriptionalreorganizationassociatedwithsenescencetoimmortalityswitchduringhumanhepatocellularcarcinogenesis AT halukyuzugullu genomewidetranscriptionalreorganizationassociatedwithsenescencetoimmortalityswitchduringhumanhepatocellularcarcinogenesis AT ozgegursoyyuzugullu genomewidetranscriptionalreorganizationassociatedwithsenescencetoimmortalityswitchduringhumanhepatocellularcarcinogenesis AT nuriozturk genomewidetranscriptionalreorganizationassociatedwithsenescencetoimmortalityswitchduringhumanhepatocellularcarcinogenesis AT cigdemozen genomewidetranscriptionalreorganizationassociatedwithsenescencetoimmortalityswitchduringhumanhepatocellularcarcinogenesis AT hilalozdag genomewidetranscriptionalreorganizationassociatedwithsenescencetoimmortalityswitchduringhumanhepatocellularcarcinogenesis AT esraerdal genomewidetranscriptionalreorganizationassociatedwithsenescencetoimmortalityswitchduringhumanhepatocellularcarcinogenesis AT sedatkarademir genomewidetranscriptionalreorganizationassociatedwithsenescencetoimmortalityswitchduringhumanhepatocellularcarcinogenesis AT ozgulsagol genomewidetranscriptionalreorganizationassociatedwithsenescencetoimmortalityswitchduringhumanhepatocellularcarcinogenesis AT dilsamizrak genomewidetranscriptionalreorganizationassociatedwithsenescencetoimmortalityswitchduringhumanhepatocellularcarcinogenesis AT hakanbozkaya genomewidetranscriptionalreorganizationassociatedwithsenescencetoimmortalityswitchduringhumanhepatocellularcarcinogenesis AT hakkigokhanilk genomewidetranscriptionalreorganizationassociatedwithsenescencetoimmortalityswitchduringhumanhepatocellularcarcinogenesis AT ozlemilk genomewidetranscriptionalreorganizationassociatedwithsenescencetoimmortalityswitchduringhumanhepatocellularcarcinogenesis AT biterbilen genomewidetranscriptionalreorganizationassociatedwithsenescencetoimmortalityswitchduringhumanhepatocellularcarcinogenesis AT rengulcetinatalay genomewidetranscriptionalreorganizationassociatedwithsenescencetoimmortalityswitchduringhumanhepatocellularcarcinogenesis AT nejatakar genomewidetranscriptionalreorganizationassociatedwithsenescencetoimmortalityswitchduringhumanhepatocellularcarcinogenesis AT mehmetozturk genomewidetranscriptionalreorganizationassociatedwithsenescencetoimmortalityswitchduringhumanhepatocellularcarcinogenesis |
| _version_ |
1718422986876256256 |