Primary mediastinal large B-cell lymphoma: transcriptional regulation by miR-92a through FOXP1 targeting.
BACKGROUND
Primary mediastinal large B-cell lymphoma (PMBL) shares pathological features with diffuse large B-cell lymphoma (DLBCL), and molecular features with classical Hodgkin lymphoma (cHL). The miR-17~92 oncogenic cluster, located at chromosome 13q31, is a region that is amplified in DLBCL.


METHODS
Here we compared the expression of each member of the miR-17~92 oncogenic cluster in samples from 40 PMBL patients versus 20 DLBCL and 20 cHL patients, and studied the target genes linked to deregulated miRNA in PMBL.


RESULTS
We found a higher level of miR-92a in PMBL than in DLBCL, but not in cHL. A combination of in silico prediction and transcriptomic analyses enabled us to identify FOXP1 as a main miR-92a target gene in PMBL, a result so far not established. This was confirmed by 3'UTR, and RNA and protein expressions in transduced cell lines. In vivo studies using the transduced cell lines in mice enabled us to demonstrate a tumor suppressor effect of miR-92a and an oncogenic effect of FOXP1.A higher expression of miR-92a and the down-regulation of FOXP1 mRNA and protein expression were also found in human samples of PMBL, while miR-92a expression was low and FOXP1 was high in DLBCL.


CONCLUSIONS
We concluded to a post-transcriptional regulation by miR-92a through FOXP1 targeting in PMBL, with a clinico-pathological relevance for better characterisation of PMBL.
Université-Paris-Diderot, Sorbonne-Paris-Cité, Laboratoire de Pathologie, UMR-S-1165, Paris, France.|INSERM, U1165-Paris, Paris, France.|Hospital-Universitario-Fundación-Santa-Fe-de-Bogotá, Pathology-Department, Bogotá, Colombia.
Martha
M
Romero
Université-Paris-Diderot, Sorbonne-Paris-Cité, Laboratoire de Pathologie, UMR-S-1165, Paris, France.|INSERM, U1165-Paris, Paris, France.
Guillaume
G
Gapihan
INSERM, UMR970, Paris-Cardiovascular Research Center, Paris, France.
Luis Jaime
LJ
Castro-Vega
Hospital-Universitario-Fundación-Santa-Fe-de-Bogotá, Pathology-Department, Bogotá, Colombia.
Andrés
A
Acevedo
Université-Paris-Diderot, Sorbonne-Paris-Cité, Laboratoire de Pathologie, UMR-S-1165, Paris, France.|Pôle-Recherches Sino-Français en Science du Vivant Génomique, Molecular-Pathology, Shanghai, China.
Li
L
Wang
Université-Paris-Diderot, Sorbonne-Paris-Cité, Laboratoire de Pathologie, UMR-S-1165, Paris, France.|Pôle-Recherches Sino-Français en Science du Vivant Génomique, Molecular-Pathology, Shanghai, China.
Zhao Wei
ZW
Li
Université-Paris-Diderot, Sorbonne-Paris-Cité, Laboratoire de Pathologie, UMR-S-1165, Paris, France.
Morad
M
El Bouchtaoui
Université-Paris-Diderot, Sorbonne-Paris-Cité, Laboratoire de Pathologie, UMR-S-1165, Paris, France.
Mélanie
M
Di Benedetto
Université-Paris-Diderot, Sorbonne-Paris-Cité, Laboratoire de Pathologie, UMR-S-1165, Paris, France.|INSERM, U1165-Paris, Paris, France.
Philippe
P
Ratajczak
Université-Paris-Diderot, Sorbonne-Paris-Cité, Laboratoire de Pathologie, UMR-S-1165, Paris, France.|INSERM, U1137, Paris, France.
Jean-Paul
JP
Feugeas
AP-HP-Hôpital Saint-Louis, Hemato-oncology-Department -Paris, Paris, France.
Catherine
C
Thieblemont
Hospital-Universitario-Fundación-Santa-Fe-de-Bogotá, Pathology-Department, Bogotá, Colombia.
Carlos
C
Saavedra
Université-Paris-Diderot, Sorbonne-Paris-Cité, Laboratoire de Pathologie, UMR-S-1165, Paris, France.|INSERM, U1165-Paris, Paris, France.|AP-HP-Hôpital Saint-Louis, Pathology-Department-Paris, Paris, France.
Anne
A
Janin
D020413:3' Untranslated Regions / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008479:Mediastinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D055815:Young Adult
D020413:3' Untranslated Regions; C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins
FOXP1; bioinformatics approach; diffuse large B-cell lymphoma; miR-17-92 oncogenic cluster; primary mediastinal large B-cell lymphoma