6533b829fe1ef96bd1289b3e
RESEARCH PRODUCT
The abrogation of the HOXB7/PBX2 complex induces apoptosis in melanoma through the miR-221&222-c-FOS pathway.
Alessandra BoeGianfranco MattiaHardev PandhaLisabianca BotteroMario P. ColomboClaudio TripodoMarina PetriniM. Cristina ErricoRichard MorganMaria BellenghiMarco CalvarusoAlessandra CarèNadia FelliFederica Felicettisubject
Programmed cell deathCancer ResearchSkin NeoplasmsTranscription GeneticApoptosisSmall Interferingc-FosPolymerase Chain ReactionCell LineGeneticCell Line TumorProto-Oncogene ProteinsHOXB7/PBX2 complexmicroRNATranscriptional regulationmedicinemelanomaHumansPBXRNA Small InterferingDNA PrimersHomeodomain Proteinsc-FOS pathwayTumorbiologymicroRNABase SequenceMelanomaHOXB7; HXR9 peptide; melanoma; microRNA; PBX; Apoptosis; Base Sequence; Cell Line Tumor; DNA Primers; Dimerization; Homeodomain Proteins; Humans; Melanoma; MicroRNAs; Polymerase Chain Reaction; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-fos; RNA Small Interfering; Skin Neoplasms; Transcription Genetic; Cancer Research; Oncologymedicine.diseaseMicroRNAsHXR9 peptideOncologyApoptosisCell cultureCutaneous melanomaHOXB7/PBX2 complex ;melanoma ;c-FOS pathwayCancer researchbiology.proteinHOXB7RNATranscriptionDimerizationProto-Oncogene Proteins c-fosCancer Cell Biologydescription
Cutaneous melanoma is the fastest increasing cancer worldwide. Although several molecular abnormalities have been associated with melanoma progression, the underlying mechanisms are still largely unknown and few targeted therapies are under evaluation. Here we show that the HOXB7/PBX2 dimer acts as a positive transcriptional regulator of the oncogenic microRNA-221 and -222. In addition, demonstrating c-FOS as a direct target of miR-221&222, we identify a HOXB7/PBX2→miR-221&222 →c-FOS regulatory link, whereby the abrogation of functional HOXB7/PBX2 dimers leads to reduced miR-221&222 transcription and elevated c-FOS expression with consequent cell death. Taking advantage of the treatment with the peptide HXR9, an antagonist of HOX/PBX dimerization, we recognize miR-221&222 as effectors of its action, in turn confirming the HXR9 efficacy in the treatment of human melanoma malignancy, whilst sparing normal human melanocytes. Our findings, besides suggesting the potential therapeutic of HXR9 or its derivatives in malignant melanoma, suggest the disruption of the HOXB7/PBX2 complexes, miR-221&222 inhibition or even better their combination, as innovative therapeutic approaches.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2013-01-01 |