Data di Pubblicazione:
2021
Citazione:
POTENTIAL ROLE OF LIN28/LET-7 AXIS IN SEZARY SYNDROME / D. Fanoni ; tutor: E. Berti ; coordinatore: E. Berti. Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 2021 Mar 26. 33. ciclo, Anno Accademico 2020. [10.13130/fanoni-daniele_phd2021-03-26].
Abstract:
Sézary Syndrome (SS) is a rare leukemic cutaneous T-cell lymphoma (CTCL) with an aggressive clinical course and a survival of 1-5 years. It is characterized by erythroderma, generalized lymphadenopathy and the presence of neoplastic CD4+ lymphocytes (Sézary cells) in the skin, lymph nodes and peripheral blood. It is well known that deregulation in STAT3 signaling is one of the molecular mechanism involved in CTCL pathogenesis and cancer progression and many studies demonstrated the efficacy of JAK/STAT inhibitors to induce apoptosis in Sézary cells. However the cause of SS is still unknown and until now, no specific therapy is available for this disease. Recently, microRNA (miRNA) profiling analysis in SS revealed a possible role of miRNAs in the pathogenesis of the disease and identified specific miRNAs as possible new targets in SS treatment. Particularly miR-21, miR-486 and miR-214 were found upregulated in SS while let-7 family members were found downregulated. miRNAs are small non-coding RNAs that regulate gene expression via post transcriptional silencing of target genes. They have important roles in fundamental biological processes such as cell development, differentiation, proliferation and apoptosis.
Let-7 family members are widely viewed as tumor suppressor miRNAs and they are strongly downregulated in many cancers. Particularly let-7a is known to target many oncogenes including c-Myc and its upregulation inhibits cell proliferation by reducing the expression of c-Myc. Another target of let-7a is c-MET and its downstream signaling pathways such as RAS, PI3K, STAT3 and β-catenin pathways. Let-7b has several oncogenes as targets such as HMGA1, HMGA2, CCND2 and KRAS, and loss of expression of let-7b has been demonstrated in many cancers comprising acute lymphoblastic leukemia. Many studies demonstrated that downregulation of let-7 is due to its direct interaction with LIN28A or LIN28B. LIN28 depletion resulted in specific increases in all let-7 family members. On contrast Nishi et al demonstrated that let-7b is downregulated in leukemic cells via DNA hypermethylation of its regulatory region. Moreover in pancreatic cancer cell lines let-7 downregulation has been reported to be linked to a constitutively-active STAT3.
In two independent studies (Narducci et al. and Corti et al.) a downregulation of some members of let-7 family, particularly let-7a and let-7b, was demonstrated in SS by using microRNA microarrays.
Particularly, in a previous unpublished study from our group we found a clear split in miRNA expression between SS patients and controls. Of particular interest let-7b was the most downregulated in our patients series and comparison of miRNA profile and CGH data showed that all patients with gains in 8q (MYC) have also let-7b downregulation. We found 24 miRNA differentially expressed between SS patients and healthy controls, including miR-214, miR-486 and miR-21 yet described and validated by Narducci et al. and Qin et al. Expression of let-7 members is controlled by MYC binding to their promoters and levels of let-7 have been reported to decrease in models of MYC-mediated tumorigenesis. Amplification of 8q (MYC) found on the same patients with let-7b downregulation and LIN28/let-7b link with STAT3/miR21 activation suggest a possible key role of let-7 family members (particularly let-7b) in SS. Finally, let-7 family members expression lead to apoptosis by Bcl-XL repression. In a recent study, Adams et al demonstrates that, in a wide group of haematologic malignancies, Let-7b downregulation lead to apoptosis blockage and that restoring let-7 normal expression downregulates Bcl-XL with a consequent upregulation of caspase-3 and apoptotic activity in neoplastic cells.
26 patients affected by SS and 15 healthy
Tipologia IRIS:
Tesi di dottorato
Keywords:
Sézary syndrome; let-7; apoptosis;
Elenco autori:
D. Fanoni
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