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

Download

index.pdf

Date

2013-05-15

Author

Yildiz, Gokhan
ARSLAN ERGÜL, AYÇA
Bagislar, Sevgi
KONU KARAKAYALI, ÖZLEN
Yuzugullu, Haluk
Gursoy-Yuzugullu, Ozge
Ozturk, Nuri
Özen, Çiğdem
ÖZDAĞ, Hilal
Erdal, Esra
KARADEMİR, SEDAT
SAĞOL, ÖZGÜL
Mizrak, Dilsa
BOZKAYA, HAKAN
İLK, HAKKI GÖKHAN
İlk Dağ, Özlem
Bilen, Biter
Atalay, Rengül
Akar, Nejat
Ozturk, Mehmet

Metadata

Show full item record

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Item Usage Stats

188
views

88
downloads

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.

Subject Keywords

General Biochemistry, Genetics and Molecular Biology, General Agricultural and Biological Sciences, General Medicine

URI

https://hdl.handle.net/11511/37426

Journal

PLOS ONE

DOI

https://doi.org/10.1371/journal.pone.0064016

Collections

Department of Statistics, Article

Suggestions

OpenMETU
Core

Genome-wide analysis of gene expression profiling revealed that COP9 signalosome is essential for correct expression of Fe homeostasis genes in Arabidopsis Eroğlu, Seçkin (Springer Science and Business Media LLC, 2017-10-01) In plant cells, either excess or insufficient iron (Fe) concentration triggers stress responses, therefore it is strictly controlled. Proteasome-mediated degradation through ubiquitination of Fe homeostasis proteins has just become the focus of research in recent years. Deactivating ubiquitin ligases, COP9 signalosome has a central importance in the translational control of various stress responses. The aim of the study was to investigate COP9 signalosome in Fe deficiency response of Strategy I plants. In s...
Epigenetic Mechanisms Underlying the Dynamic Expression of Cancer-Testis Genes, PAGE2, -2B and SPANX-B, during Mesenchymal-to-Epithelial Transition Yilmaz-Ozcan, Sinem; Sade, Asli; Kucukkaraduman, Baris; Kaygusuz, Yasemin; Senses, Kerem Mert; Banerjee, Sreeparna; GÜRE, ALİ OSMAY (Public Library of Science (PLoS), 2014-09-17) Cancer-testis (CT) genes are expressed in various cancers but not in normal tissues other than in cells of the germline. Although DNA demethylation of promoter-proximal CpGs of CT genes is linked to their expression in cancer, the mechanisms leading to demethylation are unknown. To elucidate such mechanisms we chose to study the Caco-2 colorectal cancer cell line during the course of its spontaneous differentiation in vitro, as we found CT genes, in particular PAGE2, -2B and SPANX-B, to be up-regulated duri...
GOPred: GO Molecular Function Prediction by Combined Classifiers Sarac, Oemer Sinan; Atalay, Mehmet Volkan; Atalay, Rengül (Public Library of Science (PLoS), 2010-08-31) Functional protein annotation is an important matter for in vivo and in silico biology. Several computational methods have been proposed that make use of a wide range of features such as motifs, domains, homology, structure and physicochemical properties. There is no single method that performs best in all functional classification problems because information obtained using any of these features depends on the function to be assigned to the protein. In this study, we portray a novel approach that combines ...
Evidence for uteroplacental malperfusion in fetuses with major congenital heart defects Binder, Julia; Carta, Silvia; Carvalho, Julene S.; Kalafat, Erkan; Khalil, Asma; Thilaganathan, Basky (Public Library of Science (PLoS), 2020-2-5) Aims Fetuses affected by congenital heart defects (CHD) are considered to be at increased risk of fetal growth restriction and intrauterine demise. Whether these risks are a direct consequence of fetal CHD or a result of associated uteroplacental dysfunction is not evident from the data of recent studies. The aim of this study was to investigate the prevalence of uteroplacental dysfunction reflected by abnormal uterine artery Doppler indices and reduced fetal growth in CHD pregnancies. Methods This...
Target-specific delivery of doxorubicin to human glioblastoma cell line via ssDNA aptamer BAYRAÇ, TAHİR; Akca, Oya Ercan; Eyidogan, Fusun Inci; Öktem, Hüseyin Avni (Springer Science and Business Media LLC, 2018-03-01) Targeted drug delivery approaches have been implementing significant therapeutic gain for cancer treatment since last decades. Aptamers are one of the mostly used and highly selective targeting agents for cancer cells. Herein, we address a nano-sized targeted drug delivery approach adorned with A-172 glioblastoma cell-line-specific single stranded DNA (ssDNA) aptamer in which the chemotherapeutic agent Doxorubicin (DOX) had been conjugated. DNA aptamer, GMT-3, was previously selected for specific recognitio...

Citation Formats

G. Yildiz et al., “Genome-Wide Transcriptional Reorganization Associated with Senescence-to-Immortality Switch during Human Hepatocellular Carcinogenesis,” PLOS ONE, pp. 0–0, 2013, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/37426.