Browsing by Subject "Gene-expression"

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    Genome-Wide Transcriptional Reorganization Associated with Senescence-to-Immortality Switch during Human Hepatocellular Carcinogenesis
    (PLOS ONE, 2013) Yildiz, G.; Arslan Ergul, A.; Bagislar, S.; Konu, O.; Yuzugullu, H.; Gursoy Yuzugullu, O.; Ozturk, N.; Ozen, C.; Ozdag, H.; Erdal, E.; Karademir, S.; Sagol, O.; Mizrak, D.; Bozkaya, H.; Ilk, H. G.; Ilk, O.; Bilen, B.; Cetin Atalay, R.; Akar, N.; Ozturk, M.
    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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    Induction of ROS, p53, p21 in DEHP-and MEHP-exposed LNCaP cells-protection by selenium compunds
    (Elsevier, 2011-07) Erkekoglu, P.; Rachidi, W.; Yazgullu, O. G.; Giray, B.; Ozturk, M.; Favier, A.; Hincal, F.
    This study was designed to investigate the hypothesis that the toxic effects of di(2-ethylhexyl)phthalate (DEHP), the most abundantly used plasticizer and ubiquitous environmental contaminant that cause alterations in endocrine and spermatogenic functions in animals is mediated through the induction of reactive oxygen species (ROS) and activation of nuclear p53 and p21 proteins in LNCaP human prostate adenocarcinoma cell line. Protective effects of two selenocompounds, sodium selenite (SS) and selenomethionine (SM) were also examined. It was demonstrated that 24. h exposure of the cells to 3. mM DEHP or its main metabolite, mono(2-ethylhexyl)phthalate (MEHP, 3 μM) caused strongly amplified production of ROS. Both SS (30. nM) and SM (10 μM) supplementations reduced ROS production, and p53 and p21 activation that induced significantly only by MEHP-exposure. The overall results of this study indicated that the induction of oxidative stress is one of the important mechanisms underlying the toxicity of DEHP and this is mainly through the effects of the metabolite, MEHP. Generated data also emphasized the critical role of Se in modulation of intracellular redox status, implicating the importance of the appropriate Se status in cellular response against testicular toxicity of phthalates. © 2011 Elsevier Ltd.