296P - miR-17 ∼ 92 activates the canonical NF-κB signaling by targeting TNFAIP3, CYLD and Rnf11 in ABC-DLBCL lymphoma

Date 19 December 2015
Event ESMO Asia 2015 Congress
Session Poster presentation 1
Topics Lymphomas
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter Xianhuo Wang
Citation Annals of Oncology (2015) 26 (suppl_9): 85-92. 10.1093/annonc/mdv526
Authors X. Wang1, H. Wang2, C. Bi3, X. Zhang4, X. Huang3, X. Zhang3, J. Iqbal3, G.W. Wright5, L.M. Staudt6, W.C. Chan7, T.W. McKeithan7, P. Wang2, H. Zhang2, K. Fu3
  • 1Department Of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, 300060 - Tianjin/CN
  • 2Department Of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Tianjin/CN
  • 3Department Of Pathology And Microbiology And Internal Medicine, University of Nebraska Medical Center, Omaha/US
  • 4Department Of Pediatrics, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin/CN
  • 5Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethlehem/US
  • 6Lymphoid Malignancies Branch, Center for Cancer Research-National Cancer Institute, Bethesda/US
  • 7Department Of Pathology, City of Hope, Duarte/US



ABC-DLBCL is a aggressive lymphoma characterized by constitutive NF-κB activation, but whether miRNAs dysfunction contributes to this event remains unclear. The purpose of this study is to reveal the correlations between miR-17 ∼ 92 and NF-κB signaling in ABC-DLBCL


MiRNA array platform was used for informatics and statistical interrelations. Potential miR-17 ∼ 92 targets were identified and validated using computational prediction and reporter gene assays. The activity of NF-κB signaling was determined by reporter assays. The expression and regulation of miR-17 ∼ 92 were studied using real-time quantitative PCR and Western blotting. Cell proliferation, cycle and apoptosis were detected by MTS and flow cytometry. Ubiquitination was studied by co-immunoprecipitation.


The interactions between NF-κB signaling and miR-17 ∼ 92 existed in ABC-DLBCL patients. Several important NF-κB negative regulators including TNFAIP3, CYLD and Rnf11 were predicted and validated to be targets of miR-17 ∼ 92. Knock-down of miR-17 ∼ 92 could suppress NF-κB activity and elevate targets protein expression in 293T cells. Furthermore, overexpression of miR-17 ∼ 92 could also decrease targets protein level in ABC-DLBCL cells. Conditional overexpression of miR-17 ∼ 92 could promote cells growth, accelerate G1/G0 phase to S phase transition, and suppress NF-κB inhibitor-induced apoptosis. Conversely, knock-down of miR-17 ∼ 92 could inhibit cells growth and sensitize cells to NF-κB inhibitor-induced apoptosis. MiR-17 ∼ 92 could induce IκB-α and NF-κB p65 phosphorylation and aberrant expression of NF-κB transcriptional target genes. However, miR-17 ∼ 92 did not regulate NF-κB p52/p100 phosphorylation. Overexpression of miR-17 ∼ 92 enhanced K63-linked ubiquitination and reduced K48-linked ubiquitination of RIP1. High expression level of miR-17 ∼ 92 was associated with poorer survival in ABC-DLBCL patients.


Our results uncovered a novel mechanism for canonical but not non-canonical NF-κB pathway by modulation of miR-17 ∼ 92 in ABC-DLBCL, and suggested that targeting miR-17 ∼ 92 might be novel bio-therapeutic strategies for ABC-DLBCL patients.

Clinical trial identification

The study was approved by the Institutional Review Board of the University of Nebraska Medical Center.


All authors have declared no conflicts of interest.