1. Academic Validation
  2. Nuclear Factor-κB Promotes Urothelial Tumorigenesis and Cancer Progression via Cooperation with Androgen Receptor Signaling

Nuclear Factor-κB Promotes Urothelial Tumorigenesis and Cancer Progression via Cooperation with Androgen Receptor Signaling

  • Mol Cancer Ther. 2018 Jun;17(6):1303-1314. doi: 10.1158/1535-7163.MCT-17-0786.
Satoshi Inoue  # 1 2 3 4 5 Hiroki Ide  # 3 4 6 Taichi Mizushima 1 2 3 4 Guiyang Jiang 1 2 George J Netto 3 4 7 Momokazu Gotoh 5 Hiroshi Miyamoto 8 2 3 4 9
Affiliations

Affiliations

  • 1 Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.
  • 2 James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York.
  • 3 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • 4 James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • 5 Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • 6 Department of Urology, Keio University School of Medicine, Tokyo, Japan.
  • 7 Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
  • 8 Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York. hiroshi_miyamoto@urmc.rochester.edu.
  • 9 Department of Urology, University of Rochester Medical Center, Rochester, New York.
  • # Contributed equally.
Abstract

We investigated the role of NF-κB in the development and progression of urothelial Cancer as well as cross-talk between NF-κB and Androgen Receptor (AR) signals in urothelial cells. Immunohistochemistry in surgical specimens showed that the expression levels of NF-κB/p65 (P = 0.015)/phospho-NF-κB/p65 (P < 0.001) were significantly elevated in bladder tumors, compared with those in nonneoplastic urothelial tissues. The rates of phospho-NF-κB/p65 positivity were also significantly higher in high-grade (P = 0.015)/muscle-invasive (P = 0.033) tumors than in lower grade/non-muscle-invasive tumors. Additionally, patients with phospho-NF-κB/p65-positive muscle-invasive bladder Cancer had significantly higher risks of disease progression (P < 0.001) and cancer-specific mortality (P = 0.002). In immortalized human normal urothelial SVHUC cells stably expressing AR, NF-κB activators and inhibitors accelerated and prevented, respectively, their neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene. Bladder tumors were identified in 56% (mock), 89% (betulinic acid), and 22% (parthenolide) of N-butyl-N-(4-hydroxybutyl)nitrosamine-treated male C57BL/6 mice at 22 weeks of age. NF-κB activators and inhibitors also significantly induced and reduced, respectively, cell proliferation/migration/invasion of AR-positive bladder Cancer lines, but not AR-knockdown or AR-negative lines, and their growth in xenograft-bearing mice. In both nonneoplastic and neoplastic urothelial cells, NF-κB activators/inhibitors upregulated/downregulated, respectively, AR expression, whereas AR overexpression was associated with increases in the expression levels of NF-κB/p65 and phospho-NF-κB/p65. Thus, NF-κB appeared to be activated in bladder Cancer, which was associated with tumor progression. NF-κB activators/inhibitors were also found to modulate tumorigenesis and tumor outgrowth in AR-activated urothelial cells. Accordingly, NF-κB inhibition, together with AR inactivation, has the potential of being an effective chemopreventive and/or therapeutic approach for urothelial carcinoma. Mol Cancer Ther; 17(6); 1303-14. ©2018 AACR.

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