1. The Epstein Barr-encoded BART-6-3p microRNA affects regulation of cell growth and immuno response in Burkitt lymphoma
- Author
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Lorenzo Leoncini, Stefano Lazzi, Cristina Ulivieri, Anna Onnis, Mohsen Navari, Lucia Mundo, Giulia De Falco, Lorena Di Lisio, Eduardo Andres Leon, Maria Raffaella Ambrosio, Gonzalo Gomez, Miguel A. Piris, and Sara Gazaneo
- Subjects
Cancer Research ,biology ,business.industry ,Epidemiology ,Burkitt lymphoma ,medicine.disease ,BCL10 ,Virus ,Lymphoma ,Malignant transformation ,MicroRNAs ,Infectious Diseases ,Oncology ,immune system diseases ,EBV ,hemic and lymphatic diseases ,microRNA ,Gene expression ,Immunology ,biology.protein ,Medicine ,PTEN ,business ,Gene ,Research Article - Abstract
Background: Burkitt lymphoma is an aggressive B-cell lymphoma presenting in three clinical forms: endemic, sporadic and immunodeficiency-associated. More than 90% of endemic Burkitt lymphoma carry latent Epstein-Barr virus, whereas only 20% of sporadic Burkitt lymphoma are associated with Epstein-Barr infection. Although the Epstein-Barr virus is highly related with the endemic form, how and whether the virus participates in its pathogenesis remains to be fully elucidated. In particular, the virus may impair cellular gene expression by its own encoded microRNAs. Methods: Using microRNA profiling we compared Epstein-Barr-positive and Epstein-Barr-negative Burkitt lymphoma cases for both cellular and viral microRNAs. The array results were validated by qRT-PCR, and potential targets of viral microRNAs were then searched by bioinformatic predictions, and classified in functional categories, according to the Gene Ontology. Our findings were validated by in vitro functional studies and by immunohistochemistry on a larger series of cases. Results: We showed that a few cellular microRNAs are differentially expressed between Epstein-Barr-positive and Epstein-Barr-negative Burkitt lymphoma cases, and identified a subset of viral microRNAs expressed in Epstein-Barrpositive Burkitt lymphomas. Of these, we characterized the effects of viral BART6-3p on regulation of cellular genes. In particular, we analyzed the IL-6 receptor genes (IL-6Rα and IL-6ST), PTEN and WT1 expression for their possible relevance to Burkitt lymphoma. By means of immunohistochemistry, we observed a down-regulation of the IL-6 receptor and PTEN specifically in Epstein-Barr-positive Burkitt lymphoma cases, which may result in the impairment of key cellular pathways and may contribute to malignant transformation. On the contrary, no differences were observed between Epstein-Barr-positive and Epstein-Barr-negative Burkitt lymphoma cases for WT1 expression. Conclusions: Our preliminary results point at an active role for the Epstein-Barr virus in Burkitt lymphomagenesis and suggest new possible mechanisms used by the virus in determining dysregulation of the host cell physiology.
- Published
- 2014