Dissertations / Theses on the topic 'Oncogenic transformations'
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Svingen, Terje, and n/a. "Hox Transcription Factors: Their Involvement in Human Cancer Cells and In Vitro Functional Specificity." Griffith University. School of Biomolecular and Biomedical Science, 2005. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20050830.135356.
Full textSvingen, Terje. "Hox Transcription Factors: Their Involvement in Human Cancer Cells and In Vitro Functional Specificity." Thesis, Griffith University, 2005. http://hdl.handle.net/10072/365774.
Full textThesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Physical Sciences
Full Text
CALVO, FERNANDA B. "Construcao e caracterizacao in vitro de um vetor retroviral bicistronico codificando endostatina e interleucina-2 para utilizacao em terapia genica." reponame:Repositório Institucional do IPEN, 2009. http://repositorio.ipen.br:8080/xmlui/handle/123456789/9487.
Full textMade available in DSpace on 2014-10-09T13:57:04Z (GMT). No. of bitstreams: 0
Dissertacao (Mestrado)
IPEN/D
Instituto de Pesquisas Energeticas e Nucleares - IPEN-CNEN/SP
Lehmann, Kerstin Elisabeth. "Regulation of epithelial cell transformation and survival by Raf activation." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248242.
Full textPierro, Cristina. "Remodelling of Ca2+ signalling mechanisms during K-RAS-driven oncogenic transformation." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610740.
Full textYe, Fang. "PPARγ and Smad2 Mediate Ski Induced Energy Metabolism Shift and Oncogenic Transformation." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1280930750.
Full textKabbout, Mohamed Nazih. "ETS1 AND ETS2 ROLE IN RAS ONCOGENIC TRANSFORMATION IN MOUSE EMBRYONIC FIBROBLASTS." The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1275408102.
Full textShima, Yasuko. "In vitro transformation of mesenchymal stem cells by oncogenic H-ras[Val12]." Kyoto University, 2007. http://hdl.handle.net/2433/135685.
Full textSumner, Evan T. "Characterizing the Oncogenic Properties of C-terminal Binding Protein." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4153.
Full textWebster, Marc A. "Mechanisms of polyomavirus transformation of the mouse mammary gland /." *McMaster only, 1996.
Find full textMacAuley, Iain Alasdair Somerled. "An analysis of the effects of oncogenes and growth factors on rat adrenal cortex cells." Thesis, University of British Columbia, 1987. http://hdl.handle.net/2429/27438.
Full textScience, Faculty of
Microbiology and Immunology, Department of
Graduate
Knarr, Matthew J. "The Monkey in the Wrench: MiR-181a's Role in Promoting Adipogenesis and Ovarian Cancer Transformation." Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1554481048956007.
Full textDhanraj, Karen Nalini. "The oncogenic transformation of T51B rat liver epithelial cells alters their sensitivity to apoptotic stimuli." Thesis, University of Ottawa (Canada), 1998. http://hdl.handle.net/10393/4372.
Full textAgochiya, Mahima. "Aspects of the regulation and role of focal adhesion kinase and Src in oncogenic transformation." Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312784.
Full textYoung, Nathan Price. "Tissue-specific interactions between oncogenic K-ras and the p19A̳r̳f̳_p53 pathway determine susceptibility to transformation." Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/58199.
Full textIn title on title page, doubled underscored "Arf" appears as superscript. Vita. Cataloged from PDF version of thesis.
Includes bibliographical references.
Tumor development is a multi-step process driven by the collective action of gain-of-function mutations in oncogenes and loss-of-function alterations in tumor suppressor genes. The particular spectrum of mutations in a given cancer is rarely the result of random chance but instead derives from the intimate connections between proliferative networks and those suppressing growth and transformation. Specifically, hyper-active oncogenes directly engage tumor suppressor programs, such that cells harboring oncogenic lesions frequently must acquire secondary mutations that disable these anti-proliferative responses before progressing to overt transformation. This tight coupling represents a critical checkpoint protecting against tumor formation. Whether different cell types exhibit variability in the extent and/or timing of this oncogene-induced tumor suppression is largely unknown. The ability of oncogenic Ras to induce the tumor suppressive p1 9 Arf-p5.3 pathway and cause irreversible cell cycle arrest typifies this phenomenon. Using this-well established interaction as model, we investigated the cell-type specificity of oncogene-induced tumor suppression. By combining K-rasL mice with a reporter for p19Arf expression (Ar FP), we identify a tissue-specific, onocogenic K-ras-dependent expression pattern of 19Arfin lung tumors and sarcomas that correlates with each tissue's genetic requirements for tumorigenesis. Lung tumors, which can arise in the presence of p19Arf and show modest increases in tumor progression in its absence, exhibit very minimal p19 Arf induction. Conversely, sarcomas, which depend on p19 f-p53 mutation for tumor formation, display robust p 1 9 Af up-regulation. While previous studies proposed oncogene levels as the main determinant of p19A induction, we find equivalent signaling levels and instead highlight tissue-specific differences in the epigenetic regulation of Ink4a/Arf Using in vivo RNAi, we implicate Polycomb group (PcG) proteinmediated repression in lung tumors and SWI/SNF-dependent activation in sarcomas as being critically important for each tissue's unique expression pattern of p1 9 Arf During normal tumor progression, mutations in oncogenes and tumor suppressors occur in a sequential fashion, although whether unique orders of mutations dictate distinct phenotypes is unknown. The requirement for complete p53 pathway abrogation during oncogenic K-rasdependent sarcomagenesis suggested that tumor development in the muscle critically depends on early p53 mutation. To test this we generated a Flp-inducible allele of K-rasG12D (K-rasFSF-G12D) that when combined with established reagents for Cre-dependent p53 deletion permits the separate regulation of K-ras activation and p53 loss. Strikingly, although simultaneous mutation results in robust tumor formation, delaying p53 deletion relative to oncogenic K-ras expression
(cont.) significantly diminishes tumor penetrance. This indicates that the tumorigenic capacity of KrasG12D mutant muscle cells is rapidly and severely compromised by a strong p53-dependent response, which is entirely different from the mode of action of p53 during lung tumorigenesis. Further genetic analysis implicates the p53 target gene p21 in this suppression, implying that p53 irreversibly constrains sarcoma development through cell cycle arrest mechanisms. Together, these results highlight tissue-specific variability in the relationship of oncogenic K-ras and the p53 pathway. Robust pathway up-regulation, as seen in muscle cells, affords potent inhibition of tumor initiation, while modest induction, such as in lung cells, permits tumor development and only hinders more advanced stages of progression. These differences might help explain the spectrum of tumors associated with K-Ras mutations as well as the overall frequency of difference cancer types.
by Nathan Price Young.
Ph.D.
Armitage, Mark. "Cytogenetic damage, oncogenic transformation and p53 induction in human epithelial cells in response to irradiation." Thesis, University of St Andrews, 1994. http://hdl.handle.net/10023/13910.
Full textWise-Draper, Trisha Michel. "The DEK proto-oncogene: roles in cellular death and transformation." Cincinnati, Ohio : University of Cincinnati, 2007. http://www.ohiolink.edu/etd/view.cgi?acc_num=ucin1201403348.
Full textAdvisor: Dr. Susanne Wells. Title from electronic thesis title page (viewed May 12, 2008). Includes abstract. Includes bibliographical references.
WISE-DRAPER, TRISHA MICHEL. "The DEK proto-oncogene: roles in cellular death and transformation." University of Cincinnati / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1201403348.
Full textFernandes, Tânia Patrícia Dias. "Role of SOX2 on RasV12-mediated transformation." Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22010.
Full textThe SRY (sex-determining region Y) - box 2 (SOX2) is a master factor in the maintenance of pluripotency and stemness. The transcription factor SOX2 allows the cells to maintain the unique characteristics of the embryonic stem cells (ESCs), such as clonogenicity, pluripotency, self-renewal ability, and conservation of the anti-apoptotic properties of cancer stem cells (CSCs). This factor has an important role in carcinogenesis of several tumors, including gastric, breast, pancreatic, and lung cancers. SOX2 overexpression can contribute to resistance of cancer cell to drug therapy and has been associated with tumor aggressiveness and worse prognosis. Ras GTPase is a proto-oncogene activated in several types of cancer with low success rate, including carcinomas of the pancreas, colon, lung, thyroid, and myeloid malignancies. This oncogene activates several signalling pathways, which includes the MAPK, PI3K, and RAL. It’s signalling is involved in many cellular functions, such as cell proliferation, apoptosis, migration, fate specification, and differentiation. This project aims to investigate the role of SOX2 on RasV12-mediated transformation and the genetic requirements for SOX2 induction mediated by Ras using immortalized mouse fibroblasts and primary mouse embryonic fibroblasts. We also study the effect of SOX2 overexpression on drug therapy using human lung carcinoma and human breast adenocarcinoma cell lines. We have demonstrated that RasV12 overexpression induced the expression of SOX2 and this induction is at level of transcription. We also determined that p53, Rb, and p19ARF factors are not essential for SOX2 induction and that MAPK pathway is required, but not sufficient for SOX2 induction by RasV12. Through a transformation assay we demonstrate that SOX2 overexpression increases the effect of RasV12 in cell transformation and SOX2 silencing mediated by siRNA decreases the transformation capacities of RasV12, so this factor is important in transformation mediated by RasV12. Several studies show that SOX2 not only influences tumor growth, but it also influences the response of tumor cells to therapeutic drugs. We observed that SOX2 overexpression increased the resistance of human breast adenocarcinoma cells to docetaxel. In conclusion, SOX2 is a key factor in cell transformation mediated by RasV12, as well as has an important role in chemoresistance of cancer cells. Looking at these results, this factor can be a novel target for anti-cancer therapy.
O fator de transcrição SOX2 (Sex-determining region Y (SRY)-Box2) é um fator importante na manutenção da pluripotência e “stemness”. Este fator permite que as células preservem as características únicas das células embrionárias estaminais (ESCs), como a clonogenicidade, pluripotência, capacidade de autorrenovação e a conservação das propriedades anti-apoptóticas de células estaminais cancerígenas (CSCs). O SOX2 tem um papel importante na carcinogénese de vários tumores, como no cancro gástrico, da mama, pancreático e do pulmão. A sobre-expressão de SOX2 pode contribuir para a resistência das células cancerígenas à terapia farmacológica e tem sido associada à agressividade tumoral e mau prognóstico. O proto-oncogene Ras GTPase está ativo em vários cancros com baixa taxa de sucesso, como os carcinomas do pâncreas, colón, pulmão, tiroide e mielomas malignos. Este oncogene ativa múltiplas vias de sinalização, incluindo a MAPK, PI3K e RAL e estas vias estão envolvidas em funções celulares como proliferação celular, apoptose, migração e diferenciação. Este projeto tem como objetivo investigar o papel de SOX2 na transformação mediada por RasV12 e os fatores genéticos importantes na indução de SOX2 usando fibroblastos imortalizados de rato e fibroblastos embrionários primários de rato e o efeito da sobre-expressão de SOX2 na terapia farmacológica usando células do carcinoma do pulmão humano e células do adenocarcinoma da mama humano. Foi possível demostrar que a sobre-expressão de RasV12 induz a expressão de SOX2 ao nível da transcrição. Os fatores p53, Rb e p19ARF não são essenciais na indução de SOX2 por RasV12, no entanto a via de sinalização MAPK é necessária neste processo. Através de ensaios de transformação foi possível demonstrar que a sobre-expressão de SOX2 incrementa o efeito de RasV12 na transformação celular e que o silenciamento de SOX2 usando siRNA diminui a capacidade transformante de RasV12, desta forma este fator é importante para a transformação celular mediada por RasV12. Vários estudos demonstram que o fator de transcrição SOX2 não só influencia o desenvolvimento tumoral, mas também a resposta das células tumorais à terapia farmacológica. Foi possível verificar que a sobre-expressão de SOX2 aumenta a resistência de células do adenocarcinoma da mama humano ao agente farmacológico docetaxel. Em conclusão, SOX2 é um fator essencial na transformação celular mediada por RasV12, assim como tem um papel importante na resistência das células cancerígenas à terapia. Olhando para estes resultados, este fator pode ser o novo alvo terapêutico na luta contra o cancro.
McGrath, Mark. "Studies on the transforming proteins of adenovirus 12 with regard to their functions in oncogenic transformation." Thesis, University of Leeds, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.328960.
Full textKabarowski, Janusz Henryk. "The mechanism of transformation by the BCR-ABL tyrosine kinase oncogene." Thesis, Institute of Cancer Research (University Of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266577.
Full textSteinbrück, Lisa. "The role of the herpesviral proteins LMP2A, K1, and K15 during oncogenic transformation of primary B cells." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-141298.
Full textDrayton, Sarah. "Neoplastic transformation of p16INK-deficient human fibroblasts by co-operating cellular oncogenes." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404410.
Full textQuattrochi, Brian J. "Subtle Controllers: MicroRNAs Drive Pancreatic Tumorigenesis and Progression: A Dissertation." eScholarship@UMMS, 2015. https://escholarship.umassmed.edu/gsbs_diss/776.
Full textQuattrochi, Brian J. "Subtle Controllers: MicroRNAs Drive Pancreatic Tumorigenesis and Progression: A Dissertation." eScholarship@UMMS, 2004. http://escholarship.umassmed.edu/gsbs_diss/776.
Full textChadee, Deborah Natalie. "Involvement of histone H1 and H3 phosphorylation in oncogene-mediated cellular transformation." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ41604.pdf.
Full textWang, Hsiao-Hsien. "Cytotoxic effects of a novel nitric oxide donor compound and oncogenic transformation of a human urothelial cell line." Thesis, University of St Andrews, 1995. http://hdl.handle.net/10023/14088.
Full textPalmer, Susan A. "The role of EVI-1 in cellular transformation and its biological activity in primary bone marrow cells." Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340250.
Full textSridhar, Joshi Pooja. "LOSS OF RAB25 COOPERATES WITH ONCOGENES IN THE TRANSFORMATION OF HUMAN MAMMARY EPITHELIAL CELLS (HMEC)." OpenSIUC, 2017. https://opensiuc.lib.siu.edu/theses/2150.
Full textLi, Xingnan. "Regulation of [beta]-catenin by Gli1 in epithelial transformation." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2006. http://www.mhsl.uab.edu/dt/2007p/li_xingnan.pdf.
Full textFonti, Claire. "Caractérisation des altérations génétiques et épigénétiques associées aux étapes précoces de la transformation tumorale mammaire." Thesis, Montpellier 1, 2013. http://www.theses.fr/2013MON1T024.
Full textThe genome of cancer cells undergoes profound changes at genetic and epigenetic level. Breast tumors exhibit in particular complex and heterogeneous genetic and epigenetic profiles. While a better understanding of the dynamics of these changes could allow a better understanding of tumor complexity, little information is available on this subject. In fact, most data have been, and are produced from primary tumors or established cancer cell lines and do not provide information on the sequence of events that accompany the transition from normal to cancerous state. Therefore, we have been interested in the early stages of carcinogenesis. To this aim, we have developed a stepwise transformation model of HMECs (human mammary epithelial cell) by sequential transduction of oncogenes and/or shRNA. Each cellular variant have been characterized at the cellular and molecular level (CGH, MeDIP, and Micro-array) in order to answer the following questions (1) what is the sequence of structural and epigenetic changes during malignant transformation? (2) The patterns of genetic and epigenetic abnormalities are they modulated according to the oncogenic pathway initially activated in the tumor? Contrary to the literature data, we have obtained transformed cells with the expression of only two defined genetic elements. Our results indicate that p53 inactivation promotes the acquisition of genomic alteration but mainly induces significant changes at the DNA methylation level. In addition, we have shown that the remodeling of genetic and epigenetic profiles depends on the oncogene initially activated. Finally, our results suggest that the nature of the oncogene initially activated and responible for the transformation affects the dynamics of production and selection of anomalies, and supports the hypothesis that the heterogeneity of breast cancer may be due to activation of different oncogenic pathways
Lucassen, Emy Marian. "The role of the neu oncogene in the transformation and differentiation of mammary epithelial cells." Thesis, Open University, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.276089.
Full textAntczak, Michael Richard. "Growth factor- and oncogene-induced transformation in chicken embryo fibroblasts and normal diploid human fibroblasts." Case Western Reserve University School of Graduate Studies / OhioLINK, 1993. http://rave.ohiolink.edu/etdc/view?acc_num=case1057173851.
Full textPavlova, Natalya Nickolayevna. "A Role for PVRL4-Driven Cell-Cell Interactions in Tumorigenesis." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10722.
Full textGu, Zhengming. "Studies on molecular mechanisms of transformation by human papillomavirus : the role of E6 and E5 oncogenes." Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=40133.
Full textKennah, Erin. "Identification of differentially expressed genes in AHI-1-mediated leukemic transformation in cutaneous t-cell lymphoma." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/962.
Full textSteinbrück, Lisa [Verfasser], and Dirk [Akademischer Betreuer] Eick. "The role of the herpesviral proteins LMP2A, K1, and K15 during oncogenic transformation of primary B cells / Lisa Steinbrück. Betreuer: Dirk Eick." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2012. http://d-nb.info/1020790709/34.
Full textMorton, Jennifer P. "The role of Fas signalling and the c-MYC oncogene in T cell apoptosis and transformation." Thesis, University of Glasgow, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390740.
Full textMcGarry, Lynn C. "Mediation of transformation by the v-fos oncogene : regulation of the invasive phenotype by histone deacetylases." Thesis, Open University, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.403835.
Full textPauker, Viktoria Isabella [Verfasser], Thomas C. [Gutachter] Mettenleiter, and Sonja [Gutachter] Härtle. "Proteome analysis of chicken lymphocytes after infection and transformation by the oncogenic Marek’s disease virus / Viktoria Isabella Pauker ; Gutachter: Thomas C. Mettenleiter, Sonja Härtle." Greifswald : Ernst-Moritz-Arndt-Universität, 2018. http://d-nb.info/1165227398/34.
Full textBaffet, Georges. "Expression des oncogenes et des cytokeratines au cours de la differenciation et de la transformation des cellules hepatiques." Rennes 1, 1989. http://www.theses.fr/1989REN10087.
Full textQuidute, Ana Rosa Pinto. "ExpressÃo dos genes GNAS e BTG2 e de um painel de microRNAs em somatotrofinomas esporÃdicos com e sem mutaÃÃo no gene GNAS." Universidade Federal do CearÃ, 2013. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=11346.
Full textIntroduÃÃo: MutaÃÃes nos genes GNAS e AIP estÃo presentes em 35% e 3%, respectivamente, dos somatotrofinomas esporÃdicos. Recentemente, observa-se importÃncia biolÃgica crescente dos microRNAs (miRNAs) na tumorigÃnese hipofisÃria. Entretanto, mecanismos moleculares envolvidos na patogÃnese de 60% desses tumores permanecem nÃo elucidados. Objetivos: Identificar a prevalÃncia de mutaÃÃes nos genes GNAS e AIP em um grupo de somatotrofinomas esporÃdicos. Comparar parÃmetros clÃnicos e bioquÃmicos ao diagnÃstico como idade, tamanho tumoral e agressividade (escore Hardy), hormÃnio do crescimento (GH), prolactina (PRL) e Fator de Crescimento Insulin-Like I (IGF-1) e resposta as terapÃuticas entre os grupos com (gsp+) e sem (gsp-) mutaÃÃo no GNAS. Analisar a expressÃo dos genes GNAS e BTG2 e miRNAs entre somatotrofinomas e hipÃfises normais (HN) e a associaÃÃo entre a expressÃo com agressividade, a resposta à cirurgia e a todas as terapÃuticas adjuvantes disponÃveis. Material e MÃtodos: 26 pacientes com diagnÃstico de acromegalia. Tamanho tumoral foi avaliado por RNM/CT e o grau de invasibilidade pelo escore de Hardy (I a IV). GH basal ≤2.5μg/L ou nadir de GH apÃs o GTT≤1μg/L e IGF-1 normal para idade e sexo foram utilizados como critÃrio de cura apÃs cirurgia transesfenoidal (CTE). Como controle com o anÃlogo da somatostatina (AS), adotamos a normalizaÃÃo dos nÃveis de IGF-1 para idade e sexo. As amostras tumorais (n=26) foram obtidas durante a CTE, realizado histopatolÃgico e armazenadas a -70 ÂC, para estudos moleculares. HN (07) foram obtidas durante autÃpsias. RNA e DNA total foram extraÃdos pelo TRIzolÂ. Os cÃdons 201 e 227 do gene GNAS e o AIP completo foram sequenciados. ExpressÃo relativa dos genes GNAS e BTG2 e dos miRNAs let-7a, miR-16a, miR-21, miR-141, miR-143, miR-15a, miR-145, miR-23a, miR-23b e miR-24-2 foi avaliada por qPCR (sondas TaqMan), pelo mÃtodo 2-ΔΔCt. Resultados: A frequÃncia de mutaÃÃes no GNAS foi de 35% e no AIP 3,8%. NÃo houve diferenÃa entre as mÃdias de idade (39,0Â11,5 vs 43,6Â9,0 anos; p=0,32), nas concentraÃÃes plasmÃticas basais de GH (62,4Â128,1 vs 39,9Â48,3Âg/L; p=0,39), IGF-1 (435,5Â230,8 vs 556,9 238,3 %ULNR; p=0,32), PRL (25,7Â29,8 vs 30,9Â32,8 ng/L; p=0,69) e agressividade tumoral entre os gsp+ e gsp-(p=1,00). Ao analisar o uso do AS como terapÃutica adjuvante à CTE, observamos que 04/05 (80%) dos indivÃduos com somatotrofinoma gsp+ obtiveram controle da doenÃa, enquanto que no grupo gsp- 02/06 (33%) obtiveram controle (p=0,08). Quando associamos ao AS, os agonistas dopaminÃrgicos e/ou radioterapia externa, observamos que 05/05 (100%) dos pacientes gsp+ tiveram critÃrio de controle da doenÃa, contra (04/09) 44% no grupo gsp- (p=0,09). NÃo houve diferenÃa na expressÃo de GNAS entre os somatotrofinomas e as HN (1,07Â0,55 vs 0,98Â0,28; p=0,97), e entre os gsp+ e gsp- (1,04Â0,59 vs 1,10Â0,55; p=0,97, respectivamente). Os tumores Hardy I / II apresentaram maior expressÃo do GNAS do que os tumores classificados como III / IV (p=0,02). NÃo houve associaÃÃo entre a expressÃo do GNAS e o controle da doenÃa com cirurgia isolada ou com o uso de todas as terapÃuticas adjuvantes. Observamos hipoexpressÃo do BTG2 e dos miR-16a e miR-141 em somatotrofinomas quando foram comparados com as HN (p=0,002, fold=-6,63; p=0,01, fold=-10,00; p=0,0003, fold=-50,00, respectivamente) sem diferenÃas entre os gsp+ e gsp-. Houve hiperexpressÃo do miR-21 (p=0,02;fold=10,18) em somatotrofinomas (20,16Â18,48) quando comparado com as HN (2,52 Â3,56), sem diferenÃa entre os gsp + e gsp-. NÃo houve diferenÃa na expressÃo entre os grupos gsp+ e gsp- para os miRNAs let-7a, miR-21, miR-143, miR-15a, miR-23a e miR-24-2. Entretanto, miR-145 e miR-23b foram mais hipoexpressos no grupo gsp+ quando comparados ao gsp- (p=0,03, fold=-4,83 e p=0,02, fold=-2,77, respectivamente). NÃo houve associaÃÃo entre a expressÃo do BTG2 e o painel de miRNAs com agressividade e com o controle da doenÃa. ConclusÃo: Na presente sÃrie de somatotrofinomas, assumidos como esporÃdicos, a frequÃncia de mutaÃÃes nos genes GNAS (35%) e AIP (3,8%) foram semelhantes aos relatados na literatura. NÃo houve diferenÃas nas caracterÃsticas clÃnicas e bioquÃmicas, agressividade, resposta Ãs terapÃuticas, e na expressÃo diferencial do GNAS entre os pacientes com tumores gsp+ e gsp-. HipoexpressÃo de BTG2 (gene supressor tumoral relacionado Ãs vias de sinalizaÃÃo do p53 e do Rb), baixa expressÃo de miRNAs (supressores tumorais) e alta expressÃo de oncomirs em somatotrofinomas sugerem um papel desses na tumorigÃnese somatotrÃfica.
Introduction: Mutations in GNAS and AIP genes are present in 35% and 3%, respectively, of the sporadic somatotropinomas. Recently, increased biological importance of microRNAs (miRNAs) has been observed in pituitary tumorigenesis. However, the molecular mechanisms involved in the pathogenesis of 60% of these tumors remain to be elucidated. Objectives: To identify the prevalence of mutations in GNAS and AIP genes in a series of sporadic somatotropinomas. Compare clinical, bioquimical parametrer at diagnosis as age, tumor size and theirs aggressiveness, pre-operative growth hormone (GH), prolactin (PRL) and insulin-like growth factor-I (IGF-1) levels and treatment responsiveness between somatotropinomas with (gsp+) and without (gsp-) GNAS mutation.To analyze the expression of GNAS and BTG2 genes and a panel of miRNAs between somatotrofinomas and normal pituitaries (NP) and the association between the expression of these genes and miRNAs with aggressiveness, as well as disease control with surgery or control with all adjuvant therapeutic approaches. Material and Methods: 26 patients with acromegaly. GH basal ≤2.5μg/L or nadir after OGTT ≤1μg/L and normal IGF-I matched for age and sex were used as diagnosis and for cure criteria after transsphenoidal surgery (TS). As control after somatostatin analogues (SA), we adopted the normalization of IGF-I matched for age and sex. Tumor size was evaluated by MRI/CT and the degree of invasiveness by Hardy score (I to IV).Tumor samples (26) were obtained during TS, processed for histopathology and stored at -70ÂC for molecular studies. NP (07) were obtained during autopsy. Total DNA and RNA were extracted by TRIzolÂ. Codons 201 and 227 of the GNAS gene and the whole AIP gene were sequenced. Relative expression of BTG2 and GNAS genes and miRNAs let-7a, miR-16a, miR-21, miR-141, miR-143, miR-15a, miR-145, miR-23a, miR-23b, and miR-24-2 was measured by qPCR (TaqMan probes) using 2-ΔΔCt method. Results: Frequencies of GNAS and AIP mutations were 35% and 3.8%, respectively. There was no difference between the mean age (39.0 Â 11.5 vs 43.6 Â 9.0 years, p=0.32), basal GH (62.4Â128.1 vs 39.9 Â 48.3 μg/L; p=0.39), IGF-I (435.5 Â 230.8 vs. 556.9 Â 238.3; p=0.32) and PRL (25.7 Â 29.8 vs. 30.9 Â 32.8 ng/L, p=0.69) in plasma concentration, and tumor aggressiveness (p=1.00) between (gsp+) and (gsp-) groups. We observed that 80% (04/05) of gsp+ whereas 33% (02/06) of the gsp- achieved control (p=0.07) after SA therapy adjuvant to TS. When SA, dopamine agonists and/or external radiotherapy were associated 100% (05/05) of gsp+ group and 44% (04/09) of gsp- group (p=0.08) showed disease control.There was no difference in GNAS expression between somatotropinomas and NP (1.07 Â 0.55 vs 0.98 Â 0.28, p=0.97) as well as between somatotropinomasgsp+ and gsp- (1.04 Â 0.59 vs 1.10 Â 0.55, p=0.97, respectively). Hardy I/II tumors showed higher GNAS expression than Hardy III/IV (p=0.02), but there was no association between GNAS expression and disease control with surgery alone or associated with other adjuvant therapies. We observed hypoexpression of BTG2 and miR-16a and miR-141 in somatotropinomas compared with NP (-6.6 fold, p=0.002; -10.0 fold, p=0.01; and -50.0 fold, p=0.0003, respectively) with no difference between gsp+ and gsp- somatotropinomas. There was miR-21 overexpression in somatotropinomas compared with NP (20.2 Â 18.5 vs 2.5 Â 3.6; 10.2 fold, p=0.02), with no difference between gsp+ and gsp- somatotropinomas. However, miR-145 and miR-23b were more hipoexpressed in gsp+ compared to gsp- (-4.8fold, p=0.03 and-2.7 fold, p=0.02). There was no association between the expression of BTG2 and a panel of miRNAs with aggressiveness or disease control. Conclusion: In this series of assumed sporadic somatotopinomas, the frequencies of mutations in GNAS (35%) and AIP (3.8%) were similar to the literature. There were no differences in clinical and biochemical characteristics, aggressiveness, response to therapy, and GNAS expression in patients with gsp+ and gsp- somatotropinomas. Hypoexpression of BTG2, a tumor suppressor gene related to p53 and Rb signaling pathways, low expression of tumor suppressor miRNAs and high expression of oncomirs in somatotropinomas suggest a role in the somatotrophic tumorigenesis.
Chaix, Amandine. "Les spécificités de la signalisation oncogénique par rapport à la signalisation physiologique : le modèle de KIT, un récepteur à activité tyrosine kinase." Thesis, Aix-Marseille 2, 2010. http://www.theses.fr/2010AIX22079/document.
Full textThe receptor tyrosine kinase KIT and its ligand, the stem cell factor (SCF), are implicated both in the development and the homeostasis of multiple cell lineages. Dysfunctions in the KIT/SCF pathway are involved in several pathologies affecting these compartments. In particular, gain-of-function mutations that lead to constitutive activation of the receptor KIT are found in human neoplasia.The purpose of this thesis project was to investigate some differences between normal and oncogenic signalling of KIT receptor using mast cells transformed by the KIT-D816 oncogene as a model. This question was analysed at aproximal level on the oncogenic receptor itself and at a more distal level on the STAT signal transduction pathway, which is specifically and constitutively activated by theKIT-D816 mutant.At the proximal level, we show that the juxtamembrane dityrosine motif Y568-Y570 of KIT is the major platform of recruitment of intracellular signalling partnerswith more than 15 interactors found in mast cells. Furthermore, the analysis ofcellular models in both in vitro and in vivo assays related to KIT physiological functions has revealed the negative role of the motif in KIT-D816-mediated cell transformation. At the distal level, we have analysed the mechanisms of phosphorylation ofSTAT1, -3 and -5 proteins and the functional relevance of their activation in KITD816-mediated transformation. We describe the contribution of different kinases inthe phosphorylation of STATs on both serine and tyrosine residues. Our results suggest that only STAT5 is transcriptionaly active whereas STAT1 and STAT3 are not, suggesting a non conventional implication of their activation in celltransformation. Our work contributes to a better understanding of the mechanisms of KITD816-mediated oncogenesis and could be used to improve the rational developmentof new targeted cancer therapies
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