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Epigenetic modifications as therapeutic targets in hepatocellular carcinoma

The field of epigenetics studies the heritable changes in gene expression (genes can be switched on or off) that affect the phenotype by allowing the fine-tuning of gene transcription without altering the primary DNA sequence. The most studied epigenetic marks are DNA methylation within CpG dinucleotides and post-translational histone modifications (acetylation, methylation, phosphorylation, ubiquitination, ribosylation and biotinylation of histone tails). These are dynamic mechanisms responsive to environment and capable of intervening in all of life stages. Extensive studies have demonstrated that epigenetics play a key role in regulating various physiological and pathological processes. During the past decade, cancer development and its progression have been most extensively connected with epigenetic dysregulation of critical gene expression. This is the field of my thesis proposal, which has the purpose of investigating the methylation profile in hepatocellular carcinoma (HCC).
Initially, in this study we evaluated cell proliferation levels in transgenic HCC cell lines treated with a chemotherapeutic agent, analogous of 5-aza-2’-deoxycytidine (5-aza-dC, Decitabine), called Guadecitabine. This novel next-generation hypomethylating agent is currently being evaluated in a large global Phase 3 study in the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MSD). However, its use has been recently expanding also for the treatment of solid tumors such as HCC.
Then, we also investigated the relationship between macroH2A1 isoforms, macroH2A1.1 and macroH2A1.2, and HCC development.
Finally, on the same transgenic HCC cell lines, we studied the methylation status of the genes which are under the epigenetic control of macroH2A1 and Guadecitabine treatment during liver cancer, using techniques such as bisulfite conversion and methyl-specific real time PCR (MSP). These experiments have been performed on DNA extracted from cell cultures.

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3 Abstract The field of epigenetics studies the heritable changes in gene expression (genes can be switched on or off) that affect the phenotype by allowing the fine-tuning of gene transcription without altering the primary DNA sequence. The most studied epigenetic marks are DNA methylation within CpG dinucleotides and post-translational histone modifications (acetylation, methylation, phosphorylation, ubiquitination, ribosylation and biotinylation of histone tails). These are dynamic mechanisms responsive to environment and capable of intervening in all of life stages. Extensive studies have demonstrated that epigenetics play a key role in regulating various physiological and pathological processes. During the past decade, cancer development and its progression have been most extensively connected with epigenetic dysregulation of critical gene expression. This is the field of my thesis proposal, which has the purpose of investigating the methylation profile in hepatocellular carcinoma (HCC). Initially, in this study we evaluated cell proliferation levels in transgenic HCC cell lines treated with a chemotherapeutic agent, analogous of 5-aza-2’-deoxycytidine (5-aza-dC, Decitabine), called Guadecitabine. This novel next-generation hypomethylating agent is currently being evaluated in a large global Phase 3 study in the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MSD). However, its use has been recently expanding also for the treatment of solid tumors such as HCC. Then, we also investigated the relationship between macroH2A1 isoforms, macroH2A1.1 and macroH2A1.2, and HCC development. Finally, on the same transgenic HCC cell lines, we studied the methylation status of the genes which are under the epigenetic control of macroH2A1 and Guadecitabine treatment during liver cancer, using techniques such as bisulfite conversion and methyl-specific real time PCR (MSP). These experiments have been performed on DNA extracted from cell cultures.

Tesi di Laurea Magistrale

Facoltà: Scienze della Vita

Autore: Sara Cannito Contatta »

Composta da 37 pagine.

 

Questa tesi ha raggiunto 161 click dal 23/02/2017.

Disponibile in PDF, la consultazione è esclusivamente in formato digitale.