5 research outputs found
Epigenetic deregulation of micrornas in rhabdomyosarcoma and neuroblastoma and translational perspectives
Gene expression control mediated by microRNAs and epigenetic remodeling of
chromatin are interconnected processes often involved in feedback regulatory loops, which
strictly guide proper tissue differentiation during embryonal development. Altered
expression of microRNAs is one of the mechanisms leading to pathologic conditions, such
as cancer. Several lines of evidence pointed to epigenetic alterations as responsible for
aberrant microRNA expression in human cancers. Rhabdomyosarcoma and neuroblastoma
are pediatric cancers derived from cells presenting features of skeletal muscle and neuronal
precursors, respectively, blocked at different stages of differentiation. Consistently, tumor
cells express tissue markers of origin but are unable to terminally differentiate. Several
microRNAs playing a key role during tissue differentiation are often epigenetically
downregulated in rhabdomyosarcoma and neuroblastoma and behave as tumor suppressors
when re-expressed. Recently, inhibition of epigenetic modulators in adult tumors has
provided encouraging results causing re-expression of anti-tumor master gene pathways.
Thus, a similar approach could be used to correct the aberrant epigenetic regulation of
microRNAs in rhabdomyosarcoma and neuroblastoma. The present review highlights the
current insights on epigenetically deregulated microRNAs in rhabdomyosarcoma and
neuroblastoma and their role in tumorigenesis and developmental pathways. The
translational clinical implications and challenges regarding modulation of epigenetic
chromatin remodeling/microRNAs interconnections are also discusse
Drug transporters and multiple drug resistance in the most common pediatric solid tumors
Solid tumors account for approximately 30% of all pediatric cancers. Although chemotherapy has
largely contributed to strongly improve patient outcome, multidrug resistance (MDR) remains one of the major
mechanisms limiting the overall survival. The enhanced efflux rate of chemotherapeutic drugs from tumor cells
through drug transporters is one of the most important mechanisms of MDR. Drug transporters play a pivotal role
in preserving the balance between sensitivity and resistance of tumor cells to anti-neoplastic drugs. Their functional
activities have been barely investigated in pediatric solid malignancies. Here, we provide evidence from the current
literatures on drug transporters and MDR in the most common types of pediatric solid tumors, including neuroblastoma, Wilms’ tumor, rhabdomyosarcoma, retinoblastoma, medulloblastoma and hepatoblastoma
Epigenetic deregulation of microRNAs in rhabdomyosarcoma and neuroblastoma and translational perspectives
Gene expression control mediated by microRNAs and epigenetic remodeling of chromatin are interconnected processes often involved in feedback regulatory loops, which strictly guide proper tissue differentiation during embryonal development. Altered expression of microRNAs is one of the mechanisms leading to pathologic conditions, such as cancer. Several lines of evidence pointed to epigenetic alterations as responsible for aberrant microRNA expression in human cancers. Rhabdomyosarcoma and neuroblastoma are pediatric cancers derived from cells presenting features of skeletal muscle and neuronal precursors, respectively, blocked at different stages of differentiation. Consistently, tumor cells express tissue markers of origin but are unable to terminally differentiate. Several microRNAs playing a key role during tissue differentiation are often epigenetically downregulated in rhabdomyosarcoma and neuroblastoma and behave as tumor suppressors when re-expressed. Recently, inhibition of epigenetic modulators in adult tumors has provided encouraging results causing re-expression of anti-tumor master gene pathways. Thus, a similar approach could be used to correct the aberrant epigenetic regulation of microRNAs in rhabdomyosarcoma and neuroblastoma. The present review highlights the current insights on epigenetically deregulated microRNAs in rhabdomyosarcoma and neuroblastoma and their role in tumorigenesis and developmental pathways. The translational clinical implications and challenges regarding modulation of epigenetic chromatin remodeling/microRNAs interconnections are also discussed
Redundancy and Complementarity between ERAP1 and ERAP2 revealed by their effects on the behcet’s disease-associated HLA-B*51 peptidome
The endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 trim peptides to be loaded onto HLA molecules, including the main risk factor for Behçet's disease HLA-B*51. ERAP1 is also a risk factor among HLA-B*51-positive individuals, whereas no association is known with ERAP2. This study addressed the mutual relationships between both enzymes in the processing of an HLA-bound peptidome, interrogating their differential association with Behçet's disease. CRISPR/Cas9 was used to generate knock outs of ERAP1, ERAP2 or both from transfectant 721.221-HLA-B*51:01 cells. The surface expression of HLA-B*51 was reduced in all cases. The effects of depleting each or both enzymes on the B*51:01 peptidome were analyzed by quantitative label-free mass spectrometry. Substantial quantitative alterations of peptide length, subpeptidome balance, N-terminal residue usage, affinity and presentation of noncanonical ligands were observed. These effects were often different in the presence or absence of the other enzyme, revealing their mutual dependence. In the absence of ERAP1, ERAP2 showed similar and significant processing of B*51:01 ligands, indicating functional redundancy. The high overlap between the peptidomes of wildtype and double KO cells indicates that a large majority of B*51:01 ligands are present in the ER even in the absence of ERAP1/ERAP2. These results indicate that both enzymes have distinct, but complementary and partially redundant effects on the B*51:01 peptidome, leading to its optimization and maximal surface expression. The distinct effects of both enzymes on the HLA-B*51 peptidome provide a basis for their differential association with Behçet's disease and suggest a pathogenetic role of the B*51:01 peptidome
High-Resolution Array CGH Profiling Identifies Na/K Transporting ATPase Interacting 2 (NKAIN2) as a Predisposing Candidate Gene in Neuroblastoma
Neuroblastoma (NB), the most common solid cancer in early childhood, usually occurs sporadically but also its familial
occurance is known in 1-2% of NB patients. Germline mutations in the ALK and PHOX2B genes have been found in a subset
of familial NBs. However, because some individuals harbouring mutations in these genes do not develop this tumor,
additional genetic alterations appear to be required for NB pathogenesis. Herein, we studied an Italian family with three NB
patients, two siblings and a first cousin, carrying an ALK germline-activating mutation R1192P, that was inherited from their
unaffected mothers and with no mutations in the PHOX2B gene. A comparison between somatic and germline DNA copy
number changes in the two affected siblings by a high resolution array-based Comparative Genomic Hybridization (CGH)
analysis revealed a germline gain at NKAIN2 (Na/K transporting ATPase interacting 2) locus in one of the sibling, that was
inherited from the parent who does not carry the ALK mutation. Surprisingly, NKAIN2 was expressed at high levels also in
the affected sibling that lacks the genomic gain at this locus, clearly suggesting the existance of other regulatory
mechanisms. High levels of NKAIN2 were detected in the MYCN-amplified NB cell lines and in the most aggressive NB
lesions as well as in the peripheral blood of a large cohort of NB patients. Consistent with a role of NKAIN2 in NB
development, NKAIN2 was down-regulated during all-trans retinoic acid differentiation in two NB cell lines. Taken together,
these data indicate a potential role of NKAIN2 gene in NB growth and differentiation