Follicular dendritic cell-dependent drug resistance of non-Hodgkin lymphoma involves cell adhesion-mediated Bim down-regulation through induction of microRNA-181a.
Follicular dendritic cells (FDCs), an essential component of the lymph node microenvironment, regulate and support B-lymphocyte differentiation, survival, and lymphoma progression. Here, we demonstrate that adhesion of mantle cell lymphoma and other non-Hodgkin lymphoma cells to FDCs reduces cell apoptosis and is associated with decreased levels of the proapoptotic protein, Bim. Bim down-regulation is posttranscriptionally regulated via up-regulation of microRNA-181a (miR-181a). miR-181a overexpression decreases, whereas miR-181a inhibition increases Bim levels by directly targeting Bim. Furthermore, we found that cell adhesion-up-regulated miR-181a contributes to FDC-mediated cell survival through Bim down-regulation, implicating miR-181a as an upstream effector of the Bim-apoptosis signaling pathway. miR-181a inhibition and Bim upregulation significantly suppressed FDC-mediated protection against apoptosis in lymphoma cell lines and primary lymphoma cells. Thus, FDCs protect B-cell lymphoma cells against apoptosis, in part through activation of a miR-181a-dependent mechanism involving down-regulation of Bim expression. We demonstrate, for the first time, that cell-cell contact controls tumor cell survival and apoptosis via microRNA in mantle cell and other non-Hodgkin lymphomas. Regulation of microRNAs by B-cell-FDC interaction may support B-cell survival, representing a novel molecular mechanism for cell adhesion-mediated drug resistance and a potential therapeutic target in B-cell lymphomas.
Lwin
Tint
T
Department of Malignant Hematology, Molecular Oncology and Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA.
Lin
Jianhong
J
Choi
Yong Sung
YS
Zhang
Xinwei
X
Moscinski
Lynn C
LC
Wright
Kenneth L
KL
Sotomayor
Eduardo M
EM
Dalton
William S
WS
Tao
Jianguo
J
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000072224:Bcl-2-Like Protein 11; D002448:Cell Adhesion; D020566:Dendritic Cells, Follicular / Q000473:pathology*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D008228:Lymphoma, Non-Hodgkin / Q000473:pathology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D035683:MicroRNAs / Q000096:biosynthesis*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015533:Transcriptional Activation
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C540193:MIrn181 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins