The Unit will investigate role and function of miRNAs over-expressed in Sezary syndrome and other cutaneous T-cell lymphoma (CTCL). In particular, the Unit will provide the facilities (Agilent microarray platform and analytical bioinformatic expertise) for investigating: (i) expression of miRNA during disease progression; (ii) expression of miRNA modulated by treatment with Vorinostat, a histone deacetylase inhibitor for the treatment of cutaneous T cell lymphoma. In addition, since preliminary studies have already indicated the over-expression of various miRNAs, such as miR-18a, miR-106b and miR-21 among others, in comparison with the normal cellular counterpart, we plan to investigate their role in disease progression and drug responsiveness using cellular models. In fact, several studies have indicated that the identified upregulated miRNAs have a role in suppressing apoptosis and, at least for miR-21, its inhibition by anti-miRNA oligonucleotides (AMOs) increases sensitivity to the chemotherapeutic agent gemcitabine (Meng et al Gastroenterology,2006,130:2113). Thus, it is possible that the identified over-expressed miRNA might be involved in resistance to drug treatment and may therefore represent important targets for treatment. The effectiveness and safety of the in vivo use of AMOs has been proven in primates (Elmen et al., 2008), suggesting that AMOs may potentially represent a new form of anti-cancer agents, either as a single agent or through the potentiation of conventional anti-cancer drugs. In summary, specific aims of the unit are: (i) expression of miRNA during cutaneous lymphoma disease progression; (ii) expression of miRNA modulated by treatment with the histone deacetylase inhibitor Vorinostat; (iii) assessment of cellular and molecular changes by modulation of miR-21 and/or miR-18/miR-106. Achievement of the objectives will improve our understanding on the molecular basis of cutaneous lymphoma. In particular, the contribution of aberrant miRNA expression will be clarified. This understanding could be translated into diagnostic approaches important for choosing the most appropriate therapy and, since efficacy and safety of anti-microRNA oligonucleotides has already been proved, it may open the way to the development of novel unconventional therapeutic approaches.
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|Titolo:||Ministero della Salute Progetti Finalizzati 2009: New pathogenetic and therapeutic targets in Cutaneous Lymphoma|
|Data di pubblicazione:||2010|
|Appare nelle tipologie:||08.1 Coordinamento Prog.Ricerca Naz. ed Internaz.|