Research Paper Volume 8, Issue 12 pp 3321—3340
RelA NF-κB subunit activation as a therapeutic target in diffuse large B-cell lymphoma
- 1 Department of Oncology, The First Affiliated Hospital Zhengzhou University, Zhengzhou, Henan, China
- 2 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- 3 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- 4 San Bortolo Hospital, Vicenza, Italy
- 5 University Hospital, Basel, Switzerland
- 6 Hospital Universitario Marques de Valdecilla, Santander, Spain
- 7 Aalborg University Hospital, Aalborg, Denmark
- 8 Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
- 9 Weill Medical College of Cornell University, New York, NY 10065, USA
- 10 The Methodist Hospital, Houston, TX 77030, USA
- 11 Columbia University Medical Center and New York Presbyterian Hospital, New York, NY 10032, USA
- 12 University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA
- 13 Cleveland Clinic, Cleveland, OH 44195, USA
- 14 University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China
- 15 Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands
- 16 Asan Medical Center, Ulsan University College of Medicine, Seoul, Korea
- 17 San Raffaele H. Scientific Institute, Milan, Italy
- 18 Odense University Hospital, Odense, Denmark
- 19 Gundersen Medical Foundation, La Crosse, WI 54601, USA
- 20 Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- 21 The University of Texas School of Medicine, Graduate School of Biomedical Sciences, Houston, TX 77030, USA
Received: October 29, 2016 Accepted: November 11, 2016 Published: December 8, 2016
https://doi.org/10.18632/aging.101121How to Cite
Abstract
It has been well established that nuclear factor kappa-B (NF-κB) activation is important for tumor cell growth and survival. RelA/p65 and p50 are the most common NF-kB subunits and involved in the classical NF-kB pathway. However, the prognostic and biological significance of RelA/p65 is equivocal in the field. In this study, we assessed RelA/p65 nuclear expression by immunohistochemistry in 487 patients with de novo diffuse large B-cell lymphoma (DLBCL), and studied the effects of molecular and pharmacological inhibition of NF-kB on cell viability. We found RelA/p65 nuclear expression, without associations with other apparent genetic or phenotypic abnormalities, had unfavorable prognostic impact in patients with stage I/II DLBCL. Gene expression profiling analysis suggested immune dysregulation and antiapoptosis may be relevant for the poorer prognosis associated with p65 hyperactivation in germinal center B-cell–like (GCB) DLBCL and in activated B-cell–like (ABC) DLBCL, respectively. We knocked down individual NF-κB subunits in representative DLBCL cells in vitro, and found targeting p65 was more effective than targeting other NF-κB subunits in inhibiting cell growth and survival. In summary, RelA/p65 nuclear overexpression correlates with significant poor survival in early-stage DLBCL patients, and therapeutic targeting RelA/p65 is effective in inhibiting proliferation and survival of DLBCL with NF-κB hyperactivation.