NF-kappaB down-regulates expression of the B-lymphoma marker CD10 through a miR-155/PU.1 pathway.
Cell-surface protein CD10 is a prognostic marker for diffuse large B-cell lymphoma (DLBCL), where high expression of CD10 is found in the germinal center B-cell (GCB) subtype and CD10 expression is low or absent in the activated B-cell (ABC) subtype. As compared with the GCB subtype, patients with ABC DLBCL have a poorer prognosis after standard treatment, and ABC tumor cells have higher NF-κB activity. Herein, we show that increased expression of the NF-κB target micro-RNA miR-155 is correlated with reduced expression of transcription factor PU.1 and CD10 in several B-lymphoma cell lines. Moreover, electromobility shift assays and luciferase reporter assays indicate that PU.1 can directly activate expression from the CD10 promoter. Expression of a DLBCL-derived mutant of the adaptor CARD11 (a constitutive activator of NF-κB) in the GCB-like human BJAB cell line or v-Rel in the chicken DT40 B-lymphoma cell line causes reduced expression of PU.1. The CARD11 mutant also causes a decrease in CD10 levels in BJAB cells. Similarly, overexpression of miR-155, which is known to down-regulate PU.1, leads to reduced expression of CD10 in BJAB cells. Finally, we show that CD10 expression is reduced in BJAB cells after treatment with the NF-κB inducer lipopolysaccharide (LPS). Additionally, miR-155 is induced by LPS treatment or expression of the CARD11 mutant in BJAB cells. These results point to an NF-κB-dependent mechanism for down-regulation of CD10 in B-cell lymphoma: namely, that increased NF-κB activity leads to increased miR-155, which results in decreased PU.1, and consequently reduced CD10 mRNA and protein.
Department of Biology, Boston University, Boston, Massachusetts 02215, USA.
Ryan C
RC
Thompson
Melanie
M
Herscovitch
Ian
I
Zhao
Tyler J
TJ
Ford
Thomas D
TD
Gilmore
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D053468:CARD Signaling Adaptor Proteins; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002645:Chickens; D015972:Gene Expression Regulation, Neoplastic; D018858:Germinal Center / Q000378:metabolism; D006162:Guanylate Cyclase; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D015260:Neprilysin / Q000096:biosynthesis* / Q000235:genetics; D020572:Oncogene Proteins v-rel / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics; D000099232:Proto-Oncogene Protein Spi-1
D014408:Biomarkers, Tumor; D053468:CARD Signaling Adaptor Proteins; D006162:Guanylate Cyclase; D008070:Lipopolysaccharides; D035683:MicroRNAs; D016328:NF-kappa B; D015260:Neprilysin; D020572:Oncogene Proteins v-rel; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C524942:MIRN155 microRNA, human; C426242:CARD11 protein, human