MIR152, MIR200B, and MIR338, human positional and functional neuroblastoma candidates, are involved in neuroblast differentiation and apoptosis.
MicroRNAs (MIRs) perform critical regulatory functions within cell networks, both in physiology as well as in pathology. Through the positional gene candidate approach, we have identified three MIRs (MIR152, MIR200B, and MIR338) that are located in regions frequently altered in neuroblastoma (NB) and target mRNAs encoding proteins involved in cell proliferation, neuroblast differentiation, neuroblast migration, and apoptosis. Expression analysis in NB biopsies and NB cell lines showed that these MIRs are dysregulated. We have characterized a CpG island, close to the gene encoding MIR200B and hypermethylated in NB samples, that explains its negative regulation. Expression of MIR152, MIR200B, and MIR338 is specifically modulated in NB cell lines during differentiation and apoptosis. Functional genomic experiments through enforced expression of MIR200B and knockdown of MIR152 resulted in a significant decrease of the invasion activity of SH-SY5Y cells. Reconstruction of a NB network comprising MIR152, MIR200B, and MIR338 allowed us to confirm their role in the control of NB cell stemness and apoptosis: This suggests that altered regulation of these MIRs could have a role in NB pathogenesis by interfering with the molecular mechanisms, which physiologically control differentiation and death of neuroblasts. Accordingly, they could be considered as new NB biomarkers and potential targets of antagomirs or epigenetic therapies.
Ragusa
Marco
M
Unità di BioMedicina Molecolare Genomica e dei Sistemi Complessi, Genetica, Biologia Computazionale G Sichel, Dipartimento di Scienze BioMediche, Sezione di Biologia Generale, Biologia Cellulare, Genetica Molecolare, Università degli Studi di Catania, 95123, Catania, Italy.
Majorana
Alessandra
A
Banelli
Barbara
B
Barbagallo
Davide
D
Statello
Luisa
L
Casciano
Ida
I
Guglielmino
Maria Rosa
MR
Duro
Laura Rita
LR
Scalia
Marina
M
Magro
Gaetano
G
Di Pietro
Cinzia
C
Romani
Massimo
M
Purrello
Michele
M
D017209:Apoptosis / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
D018398:Homeodomain Proteins; C550856:MIRN152 microRNA, human; C533896:MIRN200 microRNA, human; C532050:MIRN338 microRNA, human; D035683:MicroRNAs; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1