EARLY DETECTION
the possible role of EBV in inducing lymphomagenesis in
Figure 2: Flow chart illustrating how alterations in molecular pathways
can be identified starting from a miRNA profiling collaboration with African colleagues. Results from our
miRNA profiling studies have shown that the expression of some microRNAs is
deregulated in samples of Burkitt lymphoma due to the
presence of EBV18, 27. In EBV-positive cases, microRNA
Identification of target
genes imbalance seems to specifically rely on the expression
Gene Ontology of of EBV-encoded proteins which deregulate microRNA
Target genes
expression28,29. Furthermore, we have performed both Gene
Cell Cycle
Expression Profiles (GEP) and microRNA profiling, since the
Nucleic Acid Metabolism
Identification of molecular
latter has permitted even more discriminative than GEP in
Proliferation pathways
identifying tiny differences among subtypes. In particular, we
Transcription
focused on the possible role of miRNA dysregulation. Figure 2
illustrates the steps that lead to the identification of altered
molecular pathways starting from a miRNA profiling. Our GEP
studies have demonstrated that the molecular signatures of
BL cases associated with EBV differ from those lacking EBV,
suggesting a direct role for the virus in dysregulating cellular
gene expression30. In addition, a microRNA profiling of BL
cases, in collaboration with the African institutions and with
MicroRNAs are able to regulate gene expression by mRNA the Charité University of Berlin, has demonstrated that a few
cleavage or translational inhibition20. They are usually microRNAs are differentially expressed between sBL and
expressed in a tissue specific manner and play important roles eBL31. To evaluate the extent to which the expression of EBV-
21
in apoptosis, differentiation and cell proliferation . coded miRNAs may affect host gene expression, we have more
MicroRNAs are transcribed by RNA Pol II as capped and recently performed a study taking into consideration also the
polyadenylated transcripts, either mono- or polycystronic, of EBV-coded miRNAs, in collaboration with the CNIO of
several kilobases in length. Pre-miRNA are precessed in the Madrid, Spain. In this study, endemic BL cases collected at
nucleus, by RNase III Drosha to produce pre-miRNAs that Lacor Hospital, were compared with sporadic BL cases with
migrate into the cytoplasm. Here, a protein called Dicer cuts respect to miRNA expression. This study further confirmed
them at specific sites to produce mature miRNAs22. that differences in the expression of cellular microRNAs exist
Experimental evidence has reported miRNA involvement in between sBL and eBL cases (Leoncini, unpublished results),
cancer and their association with fragile sites in the genome23-25, and identified viRNAs of EBV that may affect the expression of
suggesting that these molecules could act as tumor cellular genes involved in key physiological processes, such as
suppressors or oncogenes26. Even though increasing evidence signalling and cell control (Leoncini, unpublished results). This
highlights a possible role in malignant transformation, little is finding suggests that EBV may actively interfere with the
known about their expression and their deregulation in mechanisms of control of the host cells, through its encoded
malignant lymphomas. We recently performed a miRNA proteins and/or miRNAs.
profiling comparing MYC translocation-negative BL cases with The role of Human Immunodeficiency Virus (HIV) in the
classical BL cases, to identify whether a differential expression pathogenesis of AIDS-related lymphomas is still not completely
of specific miRNAs could be detected between these two understood. HIV infection is associated with strong polyclonal
groups. This study identified several differentially expressed B-cell/plasma cell activation/expansion. To date, the mechanism
miRNAs which could be related to the absence of MYC whereby HIV leads to malignant transformation remains
translocation (Leoncini, unpublished). unknown, although several events have been proposed as co-
factors in HIV-related tumorigenesis.
Exploring the role of infectious agents and In our collaborative studies, we have previously
environmental factors demonstrated that Tat is able to interfere with the control of
A strong association between EBV and the onset of specific cell proliferation, through physical interaction with members
types of lymphomas has been observed, especially in the so- of the retinoblastoma family15,16. In addition, we have
called “lymphoma belt” in Africa. To unravel the molecular demonstrated that Tat diminishes the promoter activity of
mechanisms underlying such a condition, we have investigated VEGF promoter in vitro, suggesting that Tat may modulate the
CANCER CONTROL 2013 79