Sepe, Romina (2013) Identification of genes regulated by CBX7 protein and characterization of the transcriptional regulation mechanism of the SPP1 gene. [Tesi di dottorato]
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| Tipologia del documento: | Tesi di dottorato |
|---|---|
| Lingua: | English |
| Titolo: | Identification of genes regulated by CBX7 protein and characterization of the transcriptional regulation mechanism of the SPP1 gene |
| Autori: | Autore Email Sepe, Romina romina.sepe@gmail.com |
| Data: | 29 Marzo 2013 |
| Numero di pagine: | 101 |
| Istituzione: | Università degli Studi di Napoli Federico II |
| Dipartimento: | Medicina Molecolare e Biotecnologie Mediche |
| Scuola di dottorato: | Medicina molecolare |
| Dottorato: | Oncologia ed endocrinologia molecolare |
| Ciclo di dottorato: | 25 |
| Coordinatore del Corso di dottorato: | nome email Santoro, Massimo masantor@unina.it |
| Tutor: | nome email Fusco, Alfredo alfusco@unina.it Pallante, Pierlorenzo pallante@unina.it |
| Data: | 29 Marzo 2013 |
| Numero di pagine: | 101 |
| Parole chiave: | CBX7, osteopontin, tumor |
| Settori scientifico-disciplinari del MIUR: | Area 06 - Scienze mediche > MED/04 - Patologia generale |
| Depositato il: | 11 Apr 2013 13:59 |
| Ultima modifica: | 22 Lug 2014 13:05 |
| URI: | http://www.fedoa.unina.it/id/eprint/9203 |
| DOI: | 10.6092/UNINA/FEDOA/9203 |
Abstract
CBX7 is a member of the Polycomb Repressive Complex 1 (PRC1) involved in the process of human and mouse tumorigenesis. Recently, we have demonstrated that CBX7 is drastically decreased in several human carcinomas and that CBX7 protein levels progressively decreased in relation with the malignant grade and the neoplastic stage. To characterize the mechanisms by which the loss of CBX7 contributes to the process of carcinogenesis, we analyzed the gene expression profiling of an anaplastic thyroid carcinoma cell line in which the expression of CBX7 was restored and found that CBX7 was able to negatively or positively regulate the expression of several genes (such as SPP1, SPINK1, STEAP1, and FOS, FOSB, EGR1, respectively) associated with cancer progression. By quantitative (q)RT-PCR, we confirmed these data in mouse and rat system in which the expression of Cbx7 was silenced. Then, we showed that CBX7 was able to physically interact with the promoter region of these genes, thus regulating their activity. qRT-PCR analysis performed on thyroid and lung carcinoma samples with different degree of malignancy, showed a negative correlation between CBX7 and its down-regulated genes, while a positive correlation was observed between CBX7 and its up-regulated genes. Recently, we have demonstrated that CBX7 protein is able to interact with the High Mobility Group A 1 (HMGA1) protein. Therefore, we asked whether this interaction could be involved in the transcriptional regulation of the SPP1 gene.qRT-PCR analysis demonstrated that HMGA1 protein is able to increase the SPP1 expression in several cellular systems. Moreover, by chromatin immunoprecipitation assays, we found that HMGA1 binds together with CBX7 protein to the SPP1 promoter and that the two proteins compete for the binding. Finally, functional assays showed that CBX7 is able to negatively regulate cellular migration by repressing transcriptional activation of the SPP1promoter. In conclusion, the loss of CBX7 expression might play a critical role in cancer progression by deregulating the expression of specific effector genes.
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