MicroRNA 28 controls cell proliferation and is down-regulated in B-cell lymphomas.
Burkitt lymphoma (BL) is a highly aggressive B-cell non-Hodgkin lymphoma (B-NHL), which originates from germinal center (GC) B cells and harbors translocations deregulating v-myc avian myelocytomatosis viral oncogene homolog (MYC). A comparative analysis of microRNAs expressed in normal and malignant GC B cells identified microRNA 28 (miR-28) as significantly down-regulated in BL, as well as in other GC-derived B-NHL. We show that reexpression of miR-28 impairs cell proliferation and clonogenic properties of BL cells by modulating several targets including MAD2 mitotic arrest deficient-like 1, MAD2L1, a component of the spindle checkpoint whose down-regulation is essential in mediating miR-28-induced proliferation arrest, and BCL2-associated athanogene, BAG1, an activator of the ERK pathway. We identify the oncogene MYC as a negative regulator of miR-28 expression, suggesting that its deregulation by chromosomal translocation in BL leads to miR-28 suppression. In addition, we show that miR-28 can inhibit MYC-induced transformation by directly targeting genes up-regulated by MYC. Overall, our data suggest that miR-28 acts as a tumor suppressor in BL and that its repression by MYC contributes to B-cell lymphomagenesis.
Institute for Cancer Genetics.
Christof
C
Schneider
Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
Manu
M
Setty
Institute for Cancer Genetics.
Antony B
AB
Holmes
Institute for Cancer Genetics.
Roy L
RL
Maute
Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
Christina S
CS
Leslie
Clinica di Oncoematologia Pediatrica, Azienda Ospedaliera-Università di Padova, 35128 Padua, Italy; andIstituto di Ricerca Pediatrico Fondazione Città della Speranza, 35127 Padua, Italy.
Lara
L
Mussolin
Clinica di Oncoematologia Pediatrica, Azienda Ospedaliera-Università di Padova, 35128 Padua, Italy; and.
Angelo
A
Rosolen
Institute for Cancer Genetics,Herbert Irving Comprehensive Cancer Center, andDepartments of Pathology and Cell Biology,Genetics and Development, andMicrobiology and Immunology, Columbia University, New York, NY 10032;
Riccardo
R
Dalla-Favera
Institute for Cancer Genetics,Departments of Pathology and Cell Biology, kb451@columbia.edu.
Katia
K
Basso
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001402:B-Lymphocytes / Q000502:physiology; D002051:Burkitt Lymphoma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D063646:Carcinogenesis; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D016259:Genes, myc / Q000502:physiology; D018858:Germinal Center; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D035683:MicroRNAs / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome
D048868:Adaptor Proteins, Signal Transducing; C091732:BCL2-associated athanogene 1 protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C470309:MAD2L1BP protein, human; C570628:MIRN28 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D014157:Transcription Factors