Senescence and immortality genes as markers of hepatocellular carcinogenesis

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buir.advisorÖztürk, Mehmet
dc.contributor.authorArslan Ergül, Ayça
dc.date.accessioned2016-01-08T18:17:54Z
dc.date.available2016-01-08T18:17:54Z
dc.date.issued2009
dc.descriptionAnkara : The Department of Molecular Biology and Genetics and the Institute of Engineering and Science of Bilkent University, 2009.en_US
dc.descriptionThesis (Ph. D.) -- Bilkent University, 2009.en_US
dc.descriptionIncludes bibliographical references leaves 94-106.en_US
dc.description.abstractCellular senescence is a tumor-suppression mechanism, and immortalization facilitates neoplastic transformation. Both mechanisms may be highly relevant to hepatocellular carcinoma (HCC) development. We worked on two major aspects of cellular senescence and immortality in HCC. First, we analyzed the role of ZEB2 (Smad-interacting protein SIP1, ZFXH1B) gene for a senescence-related role in HCC. Then, we extended our work on the identification and analysis of a senescence and immortality gene network (SIGN) in relation to hepatocellular carcinogenesis. ZEB2 is a transcriptional repressor of E-cadherin, and induces epithelial-mesenchymal transition (EMT), a key process involved in tumor metastasis and progression. However, ZEB2 is also a repressor of telomerase reverse transcriptase (TERT) gene, which encodes a key enzyme required for telomere maintenance and tumor cell immortality. We performed in-vivo, in-silico and in-vitro studies to explore potential implications of ZEB2 in hepatocellular carcinoma (HCC). Tissue expression of ZEB2 transcripts displayed stepwise decreases in HCC lesions, as compared to liver cirrhosis. This inverse correlation suggested that sustained ZEB2 expression is not compatible with HCC progression. Next, vekt¨or¨u ile transfekte edilen Hep3B h¨ucrelerinin, ya¸slanma ili¸skili !-galaktozidaz aktivitesi ile, kalıcı h¨ucre d¨ong¨us¨u hapsine girdiklerini g¨ord¨uk. ZEB2 ile ind¨uklenen ya¸slanma hapsi, TERT ifadesinin baskılanması ve e¸slik eden siklin-ba˘gımlı kinaz engelleyici p21Cip1’in ifadesindeki artı¸s ile ba˘gıntılı idi. ZEB2’nin ge¸cici ifadesi, p21Cip1 ifadesindeki artı¸sı ind¨uklemedi. Son olarak, ZEB2’yi a¸sırı ifade eden Hep3B ve A431 klonlarının, in vitro k¨ult¨urde dereceli olarak azalması ile ZEB2 a¸sırı ifadesinin, kanser h¨ucrelerinin in vitro ya¸samı ile uyumlu olmadı˘gı sonucuna varıldı. Bu g¨ozlemler, ZEB2 geninin, EMT’deki rol¨un¨un dı¸sında, HCC h¨ucre b¨uy¨umesi ve ya¸samasında negatif rol oynadı˘gını d¨u¸s¨und¨urd¨u. Di˘ger ¸calı¸smamızda SIGN imzasını olu¸sturmak i¸cin, ya¸slanmaya programlanmı ¸s ve ¨ol¨ums¨uz HCC h¨ucrelerinden gelen gen ifade datasını, siroz ve HCC dokularından gelen data ile birle¸stirdik. SIGN imzası normal karaci˘ger, siroz, displazi ve HCC lezyonlarını do˘grulukla sınıflandırdı ve ya¸slanmadan ¨ol¨ums¨uzl¨u˘ge d¨on¨u¸s¨um¨un, ilk olarak displaziden erken HCC’ye ge¸ci¸ste ger¸cekle¸sti˘gini belirledi. Bu d¨on¨u¸s¨um, t¨um¨or ilerlemesine de katkıda bulunur. Ya¸slanmadan ¨ol¨ums¨uzl¨u˘ge d¨on¨u¸s¨ume, hepatik geri ba¸skala¸sım ile ve h¨ucre ¸co˘galması, kromozom de˘gi¸simi ve DNA hasar yanıtı genlerindeki ifade artı¸sı e¸slik etti. Bu nedenle, HCC ¨ol¨ums¨uzl¨u˘g¨u, k¨ok h¨ucre/¨onc¨u h¨ucre benzeri ¨ozellikler ile yakından ili¸skilidir. Son olarak, DNA hasar kontrol noktası ve DNA tamir genlerindeki artı¸s ile, t¨um¨or ba¸slangıcı ve ilerlemesi arasında ili¸ski bulduk. Bu genler, HCC’nin engellenmesinde ve terapisinde potansiyel hedefler olabilirler.en_US
dc.description.provenanceMade available in DSpace on 2016-01-08T18:17:54Z (GMT). No. of bitstreams: 1 0006134.pdf: 26405960 bytes, checksum: a56659a8132e0556246b752c02cf3c08 (MD5)en
dc.description.statementofresponsibilityErgül, Ayça Arslanen_US
dc.format.extentxvi, 123, [19] leaves, illustrationsen_US
dc.identifier.urihttp://hdl.handle.net/11693/15391
dc.language.isoEnglishen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subject.lccWI735 .E64 2009en_US
dc.subject.lcshLiver--Cancer.en_US
dc.subject.lcshLiver neoplasms.en_US
dc.subject.lcshCarcinoma, Hepatocellular.en_US
dc.subject.lcshCarcinogenesis.en_US
dc.subject.lcshGenetic regulation.en_US
dc.subject.lcshCancer cells.en_US
dc.subject.lcshCarcinoma.en_US
dc.subject.lcshHepatitis viruses.en_US
dc.titleSenescence and immortality genes as markers of hepatocellular carcinogenesisen_US
dc.typeThesisen_US
thesis.degree.disciplineMolecular Biology and Genetics
thesis.degree.grantorBilkent University
thesis.degree.levelDoctoral
thesis.degree.namePh.D. (Doctor of Philosophy)

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