Metastasis suppressor genes and proteins in non-melanoma skin cancers

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buir.advisorYuluğ, Işık G.
dc.contributor.authorBozdoğan, Önder
dc.date.accessioned2016-04-20T10:46:48Z
dc.date.available2016-04-20T10:46:48Z
dc.date.copyright2014-09
dc.date.issued2014-09
dc.date.submitted04-09-2014
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.descriptionCataloged from PDF version of thesisen_US
dc.descriptionIncludes bibliographical references (leaves 89-107).en_US
dc.descriptionThesis (Ph. D.): Bilkent University, Department of Molecular Biology and Genetics, İhsan Doğramacı Bilkent University, 2014.en_US
dc.description.abstractSkin cancers are the most common cancer in human population. They are practically divided into two major group; melanoma and non-melanoma skin cancer (NMSC). NMSC often refers to two common neoplasms; cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC). BCCs are slow growing, malignant, significantly invasive but rarely metastasizing carcinomas. cSCCs are the malignant tumor of keratinocytes with significant squamous differentiation. In contrast to BCCs, SCCs have significant metastatic capacity. Metastasis is a complex multistep process and strictly positively or negatively controlled by tens of genes or proteins. Besides supporting genes, a group of gene, called metastasis suppressor genes (MSG), slow or inhibit metastasis without significantly affecting tumorigenicity. The aim of this study was to find out distribution and importance of the seven selected metastasis suppressor gene/proteins including NM23-H1, NDRG1, Ecadherin, RHOGDI2 (ARHGDIB), CD82/KAI1, MKK4, and AKAP12 in NMSC. Ninety six BCCs, 32 cSCCs, 6 in-situ SCCs, two cell lines (HaCaT, A-431) were included for immunohistochemistry study. Eleven BCCs, 8 normal skin adjacent to the BCCs, 3 normal skin frozen tissue, and, two cell lines were inserted for qRT-PCR studies. Promoter methylations of CD82/KAI1 and MKK4 genes were analyzed in 7 tumors and 5 normal tissue samples by bisulfite sequencing method. In immunohistochemistry study, NM23-H1 was protected in NMSC. Similarly, relatively preserved cytoplasmic expressions of NDRG1 were also detected. AKAP12 and RHOGDI2 were decreased in both tumor groups. However, CD82/KAI1 downregulation was only detected in BCCs. E-Cadherin was relatively protected in BCCs but significant lost was seen in cSCCs. Cytoplasmic positivity of MKK4 was more pronounced in cSCC when compared to BCCs. Immunohistochemical study of cell lines showed similar finding as in seen cSCC. In qRT-PCR study, we found significant upregulation of NM23-H1 (1.4 fold; p=0.032) and downregulation of AKAP12 (-1.2 fold; p=0.006) when BCC was compared to normal skin. NDRG1 showed significantly higher levels (2.2 fold, p=0.001) in BCC when compared to the skin adjacent to the BCC. MKK4 (-2.1-fold, P=0.001), ARHGDIB (RHOGDI2) (-4.7-fold, P=0.001), CD82/KAI1 (-2.4-fold, P=0.001) and AKAP12 (-9.7-fold, P=0.001) were downregulated but NDRG1 (34.4-fold, p=0.001) was upregulated in A-431 cell line when compared to HaCaT. CD82/KAI and MKK4 promoters were heavily unmethylated in BCCs and normal skin. In conclusion, we have demonstrated differential expression patterns for the seven MSPs in NMSCs. In SCCs, the MSG expression signature is similar but not identical to BCCs. The preserved levels of NM23-H1 and NDRG1 may contribute to the nonmetastatic features of NMSC.en_US
dc.description.degreePh.D.en_US
dc.description.statementofresponsibilityby Önder Bozdoğanen_US
dc.embargo.release2016-09-04
dc.format.extentxiii, 118 leaves : charts, plates, illustrations.en_US
dc.identifier.itemidB148313
dc.identifier.urihttp://hdl.handle.net/11693/28950
dc.language.isoEnglishen_US
dc.publisherBilkent Universityen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectMetastasis suppressor geneen_US
dc.subjectSkin canceren_US
dc.subjectMetastasisen_US
dc.subjectNM23-H1en_US
dc.subjectNDRG1en_US
dc.subjectE-cadherinen_US
dc.subjectE-cadherinen_US
dc.subjectRHOGDI2en_US
dc.subjectRHOGDI2en_US
dc.subjectCD82/KAI1en_US
dc.subjectMKK4en_US
dc.subjectAKAP12Sen_US
dc.titleMetastasis suppressor genes and proteins in non-melanoma skin cancersen_US
dc.title.alternativeMelanom dışı deri kanserlerinde metastaz baskılayıcı genler ve proteinleren_US
dc.typeThesisen_US

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