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

被引:52
作者
Yildiz, Gokhan [1 ,2 ]
Arslan-Ergul, Ayca [1 ]
Bagislar, Sevgi [1 ,2 ]
Konu, Ozlen [1 ]
Yuzugullu, Haluk [1 ,2 ]
Gursoy-Yuzugullu, Ozge [1 ,2 ]
Ozturk, Nuri [1 ]
Ozen, Cigdem [1 ]
Ozdag, Hilal [3 ]
Erdal, Esra [4 ]
Karademir, Sedat [5 ]
Sagol, Ozgul [6 ]
Mizrak, Dilsa [7 ]
Bozkaya, Hakan [7 ]
Ilk, Hakki Gokhan [8 ]
Ilk, Ozlem [9 ]
Bilen, Biter [1 ]
Cetin-Atalay, Rengul [1 ]
Akar, Nejat [3 ]
Ozturk, Mehmet [1 ,2 ]
机构
[1] Bilkent Univ, Dept Mol Biol & Genet, BilGen Genet & Biotechnol Ctr, Ankara, Turkey
[2] Univ Grenoble 1, INSERM, CRI U823, Grenoble, France
[3] Ankara Univ, Inst Biotechnol, TR-06100 Ankara, Turkey
[4] Dokuz Eylul Univ, Sch Med, Dept Med Biol, Izmir, Turkey
[5] Dokuz Eylul Univ, Sch Med, Dept Surg, Izmir, Turkey
[6] Dokuz Eylul Univ, Sch Med, Dept Pathol, Izmir, Turkey
[7] Ankara Univ, Dept Gastroenterol, TR-06100 Ankara, Turkey
[8] Ankara Univ, Dept Elect Engn, TR-06100 Ankara, Turkey
[9] Middle E Tech Univ, Dept Stat, TR-06531 Ankara, Turkey
来源
PLOS ONE | 2013年 / 8卷 / 05期
关键词
CELLULAR SENESCENCE; REPLICATIVE SENESCENCE; MOLECULAR SIGNATURE; MICROARRAY ANALYSIS; TELOMERE LENGTH; HEPATITIS-C; CARCINOMA; LIVER; GENE; EXPRESSION;
D O I
10.1371/journal.pone.0064016
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:14
相关论文
共 68 条
[1]   REDUCED RETINOID CONTENT IN HEPATOCELLULAR-CARCINOMA WITH SPECIAL REFERENCE TO ALCOHOL-CONSUMPTION [J].
ADACHI, S ;
MORIWAKI, H ;
MUTO, Y ;
YAMADA, Y ;
FUKUTOMI, Y ;
SHIMAZAKI, M ;
OKUNO, M ;
NINOMIYA, M .
HEPATOLOGY, 1991, 14 (05) :776-780
[2]   Healing and Hurting: Molecular Mechanisms, Functions, and Pathologies of Cellular Senescence [J].
Adams, Peter D. .
MOLECULAR CELL, 2009, 36 (01) :2-14
[3]   The landscape of somatic copy-number alteration across human cancers [J].
Beroukhim, Rameen ;
Mermel, Craig H. ;
Porter, Dale ;
Wei, Guo ;
Raychaudhuri, Soumya ;
Donovan, Jerry ;
Barretina, Jordi ;
Boehm, Jesse S. ;
Dobson, Jennifer ;
Urashima, Mitsuyoshi ;
Mc Henry, Kevin T. ;
Pinchback, Reid M. ;
Ligon, Azra H. ;
Cho, Yoon-Jae ;
Haery, Leila ;
Greulich, Heidi ;
Reich, Michael ;
Winckler, Wendy ;
Lawrence, Michael S. ;
Weir, Barbara A. ;
Tanaka, Kumiko E. ;
Chiang, Derek Y. ;
Bass, Adam J. ;
Loo, Alice ;
Hoffman, Carter ;
Prensner, John ;
Liefeld, Ted ;
Gao, Qing ;
Yecies, Derek ;
Signoretti, Sabina ;
Maher, Elizabeth ;
Kaye, Frederic J. ;
Sasaki, Hidefumi ;
Tepper, Joel E. ;
Fletcher, Jonathan A. ;
Tabernero, Josep ;
Baselga, Jose ;
Tsao, Ming-Sound ;
Demichelis, Francesca ;
Rubin, Mark A. ;
Janne, Pasi A. ;
Daly, Mark J. ;
Nucera, Carmelo ;
Levine, Ross L. ;
Ebert, Benjamin L. ;
Gabriel, Stacey ;
Rustgi, Anil K. ;
Antonescu, Cristina R. ;
Ladanyi, Marc ;
Letai, Anthony .
NATURE, 2010, 463 (7283) :899-905
[4]   WNT16B Is a New Marker of Cellular Senescence That Regulates p53 Activity and the Phosphoinositide 3-Kinase/AKT Pathway [J].
Binet, Romuald ;
Ythier, Damien ;
Robles, Ana I. ;
Collado, Manuel ;
Larrieu, Delphine ;
Fonti, Claire ;
Brambilla, Elisabeth ;
Brambilla, Christian ;
Serrano, Manuel ;
Harris, Curtis C. ;
Pedeux, Remy .
CANCER RESEARCH, 2009, 69 (24) :9183-9191
[5]   Hepatocyte senescence in end-stage chronic liver disease: a study of cyclin-dependent kinase inhibitor p21 in liver biopsies as a marker for progression to hepatocellular carcinoma [J].
Brunt, Elizabeth M. ;
Walsh, Sarah N. ;
Hayashi, Paul H. ;
LaBundy, Jennifer ;
Di Bisceglie, Adrian M. .
LIVER INTERNATIONAL, 2007, 27 (05) :662-671
[6]   Retinoid pathway and cancer therapeutics [J].
Bushue, Nathan ;
Wan, Yu-Jui Yvonne .
ADVANCED DRUG DELIVERY REVIEWS, 2010, 62 (13) :1285-1298
[7]   Constitutional Telomerase Mutations Are Genetic Risk Factors for Cirrhosis [J].
Calado, Rodrigo T. ;
Brudno, Jennifer ;
Mehta, Paulomi ;
Kovacs, Joseph J. ;
Wu, Colin ;
Zago, Marco A. ;
Chanock, Stephen J. ;
Boyer, Thomas D. ;
Young, Neal S. .
HEPATOLOGY, 2011, 53 (05) :1600-1607
[8]   Functional characterization of ATAD2 as a new cancer/testis factor and a predictor of poor prognosis in breast and lung cancers [J].
Caron, C. ;
Lestrat, C. ;
Marsal, S. ;
Escoffier, E. ;
Curtet, S. ;
Virolle, V. ;
Barbry, P. ;
Debernardi, A. ;
Brambilla, C. ;
Brambilla, E. ;
Rousseaux, S. ;
Khochbin, S. .
ONCOGENE, 2010, 29 (37) :5171-5181
[9]   Microarray analysis identifies interferon-inducible genes and Stat-1 as major transcriptional targets of human papillomavirus type 31 [J].
Chang, YJE ;
Laimins, LA .
JOURNAL OF VIROLOGY, 2000, 74 (09) :4174-4182
[10]   ATAD2 Is a Novel Cofactor for MYC, Overexpressed and Amplified in Aggressive Tumors [J].
Ciro, Marco ;
Prosperini, Elena ;
Quarto, Micaela ;
Grazini, Ursula ;
Walfridsson, Julian ;
McBlane, Fraser ;
Nucifero, Paolo ;
Pacchiana, Giovanni ;
Capra, Maria ;
Christensen, Jesper ;
Helin, Kristian .
CANCER RESEARCH, 2009, 69 (21) :8491-8498