To be an ally or an adversary in bladder cancer: the NF-κB story has not unfolded

Abstract

Signaling and regulation of transcription factor nuclear factor-kappaB (NF-κB) has been an area of extensive research since its first discovery nearly three decades ago. Members of the NF-κB family have been reported to critically mediate a multitude of responses in normal cells. Therefore, it is not surprising that NF-κB function can go awry and result in pathological conditions including cancer. Despite its critical importance, the functional role of NF-κB has not received the same attention in cancers of all tissue types. In the case of cancer of the urinary bladder, which is the second most common urologic cancer, the involvement of NF-κB in the development of superficial or muscle invasive disease and during cancer recurrence is rudimentary at best. Nuclear expression of p65/RelA is seen in bladder cancer patients and has been found to negatively affect survival of patients with superficial and muscle invasive disease. Despite these observations, the exact mechanism of NF-κB upregulation and function remains unknown. Furthermore, the emergence of a tumor suppressive role for NF-κB in recent years suggests that the family may play the role of a double-edged sword in cancer, which remains unexplored in bladder cancer. The challenge now is to delineate the increasing complexity of this pathway in the development and progression of bladder cancer. Here, we review key aspects of the current knowledge of signaling and regulation by the NF-κB family focusing on its controversial role in cancer and highlight the importance of studying NF-κB in bladder cancer in particular.

Regorefenib induces extrinsic/intrinsic apoptosis and inhibits MAPK/NF‐κB‐modulated tumor progression in bladder cancer in vitro and in vivo

“…NF‐κB p50/p65 heterodimer is critical mediator for tumorigenesis and cancer progression. A number of tumor progression‐associated proteins which modulate proliferation, anti‐apoptosis, angiogenesis, and metastasis are encoded by NF‐κB target genes and upregulated with active NF‐κB signaling in bladder cancer . Constitutive NF‐κB activation was observed in high grade bladder cancer .…”

“…A number of tumor progression-associated proteins which modulate proliferation, antiapoptosis, angiogenesis, and metastasis are encoded by NF-κB target genes and upregulated with active NF-κB signaling in bladder cancer. 29,30 Constitutive NF-κB activation was observed in high grade bladder cancer. 31 Many studies indicated inhibition of NF-κB activation suppresses tumor growth, anti-apoptosis, angiogenesis, and metastatic potential in bladder cancer in vitro and in vivo.…”

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

“…Other functions of NF-kB, without the involvement of inflammation, are also thought to associate with the promotion of tumorigenesis. These include stimulation of cell proliferation, prevention of apoptosis, regulation of angiogenesis, and immortalization via regulating the expression/function of oncogenes, antiapoptotic genes, angiogenic factors, and telomerases, respectively (35). In urothelial cancer, associations between polymorphisms in the NF-kB1/ p50 gene, which could form a heterodimer with p65 as the NF-kB activator, and the risk of tumor development or recurrence have been reported (36,37).…”

The role of ZBTB38 in promoting migration and invasive growth of bladder cancer cells

“…Furthermore, deletion of chromosome 9 is detected in the majority of cases of non-muscle invasive bladder cancer (7). In addition, factors associated with bladder cancer include the phosphatidylinositol-3-kinase/protein kinase B/mechanistic target of rapamycin pathway, RAS, cell cycle progression and receptor tyrosine kinases (8)(9)(10). Two bladder cancer cell lines, 253J B-V and 253J, were used in the present study.…”