CD99 triggers upregulation of miR-9-modulated PRDM1/BLIMP1 in Hodgkin/Reed-Sternberg cells and induces redifferentiation.
CD99 is a 32-kDa transmembrane glycoprotein that is encoded by the MIC2 gene. Our study was carried out to examine the role of CD99 in tumor progression of classical Hodgkin lymphoma (cHL). Here, we showed that lowly expressed CD99 protein in cHL cell lines and primary cHL cases correlates with the deficient expression of the positive regulatory domain 1 (PRDM1/BLIMP1). In addition, cHL cell lines showed high levels of miR-9 expression. We determined that the upregulation of CD99 induced expression of transcription factor PRDM1, a master regulator of plasma-cell differentiation, which is also a target for miR-9-mediated downregulation. Indeed, inhibition of miR-9 also triggered upregulation of PRDM1 expression. Furthermore, overexpression of CD99 resulted in changed growth features and reorganization of actin cytoskeleton. As upregulation of CD99 led to a decrease in cHL diagnosis marker CD30 and CD15 and an increase in plasma-cell differentiation marker CD38 and the restoration of B-cell makers PAX5, CD79α and CD19, we suggest that downregulated CD99 leads to the prevention of plasma-cell differentiation in Hodgkin/Reed-Sternberg (H/RS) cells. Furthermore, these data indicate that CD99 may control miR-9 expression, which directly targets PRDM1. Altogether, these results reveal a CD99-miR-9-PRDM1 molecule axis in lymphomagenesis of cHL and suggest that upregulation of CD99 in H/RS cells induces terminal B-cell differentiation, which may provide a novel therapeutic strategies for cHL.
Department of Pathology, Nanfang Hospital affiliated to Southern Medical University, Guangzhou, China.
Xueping
X
Huang
Xinhua
X
Zhou
Zhiqiang
Z
Wang
Feng
F
Li
Fanrong
F
Liu
Lin
L
Zhong
Xiangzhao
X
Li
Xiqun
X
Han
Ziqing
Z
Wu
Shaohong
S
Chen
Tong
T
Zhao
D000071443:12E7 Antigen; D015703:Antigens, CD / Q000502:physiology*; D001483:Base Sequence; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D017931:DNA Primers; D005434:Flow Cytometry; D006689:Hodgkin Disease / Q000473:pathology*; D006801:Humans; D018189:Immunomagnetic Separation; D017403:In Situ Hybridization; D035683:MicroRNAs / Q000502:physiology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D016539:Reed-Sternberg Cells / Q000166:cytology / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000502:physiology*
D000071443:12E7 Antigen; D015703:Antigens, CD; C061828:CD99 protein, human; D015815:Cell Adhesion Molecules; D017931:DNA Primers; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1