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

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.