REVIEW Bladder neoplasms and NF-κB: an unfathomed association Charles Emmanuel Jebaraj Walter a *, Sankari Durairajan a *, Kalaiselvi Periyandavan b , George Priya Doss C c , Dicky John Davis G a , Hannah Rachel Vasanthi A d , Thanka Johnson a and Hatem Zayed e a Department of Biotechnology, Faculty of Biomedical Sciences, Technology and Research, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Chennai, India; b Department of Medical Biochemistry, Dr. ALM PG Institute of Basic Medical Science, University of Madras, Chennai, India; c Department of Integrative Biology, School of Biosciences and Technology, VIT University, Vellore, India; d Department of Biotechnology, School of Life Sciences, Pondicherry University, Pondicherry, India; e Department of Biomedical Sciences, College of Health Sciences, Qatar University, Doha, Qatar ABSTRACT Introduction: Bladder cancer is the second most common genitourinary tract cancer and is often recurrent and/or chemoresistant after tumor resection. Cigarette smoking, exposure to aromatic amines, and chronic infection/inflammation are bladder cancer risk factors. NF-κB is a transcription factor that plays a critical role in normal physiology and bladder cancer. Bladder cancer patients have constitutively active NF-κB triggered by pro-inflammatory cytokines, chemokines, and hypoxia, aug- menting carcinogenesis and progression. Areas covered: NF-κB orchestrates protein interactions (PTEN, survivin, VEGF), regulation (CYLD, USP13) and gene expression (Trp 53) resulting in bladder cancer progression, recurrence and resistance to therapy. This review focuses on NF-κB in bladder inflammation, cancer and resistance to therapy. Expert opinion: NF-κB and bladder cancer necessitate further research to develop better diagnostic and treatment regimens that address progression, recurrence and resistance to therapy. NF-κB is a master regulator that can act with or on minimally one cancer hallmark gene or protein, leading to bladder cancer progression (Tp53, PTEN, VEGF, HMGB1, CYLD, USP13), recurrence (PCNA, BcL-2, JUN) and resistance to therapy (P-gp, twist, SETD6). Thus, an understanding of bladder cancer in relation to NF-κB will offer improved strategies and efficacious targeted therapies resulting in minimal progression, recurrence and resistance to therapy. ARTICLE HISTORY Received 20 September 2019 Accepted 13 March 2020 KEYWORDS Bladder cancer; chemoresistance; inflammation; NF-κB; signal transduction 1. Introduction Bladder cancer is the second most common genitourinary tract malignancy and the ninth most common cancer worldwide. It is the third leading cause of death related to genitourinary tumors. There is a male predominance of bladder cancer, where men are at higher risk than women in industrialized nations. Over the past few decades, a high prevalence of bladder cancer has been detected in the western world, particularly in North American and European countries. At present, lifestyle changes and increas- ing awareness of the risks related to bladder cancer have insti- gated a declining trend in the prevalence rates in these countries. Conversely, industrialization and lifestyle changes in developing countries have increased the prevalence of bladder cancer over the years in Asian countries like India [1,2]. In India, the risk of older males presenting with bladder cancer is more prominent (8.6 males:1 female) [3] than that in western countries (3 males:1 female) [4]. Although comparatively fewer female patients are diagnosed with bladder cancer, their stage at diagnosis is much higher and they have poorer prognoses compared with their male counterparts [5]. Epidemiological studies have stated that intrinsic sex-related differences are a cause for the higher inci- dence of bladder cancer in men than in women [6,7]. There are many risk factors associated with bladder cancer incidence that can be broadly categorized into environ- mental, infection/inflammation and/or molecular determinants. Environmental/lifestyle/occupational exposure to compounds, like tobacco or cigarette smoking, aromatic amines, polycyclic hydrocarbons, anilines, nitrates/nitrites, acrolein, coal and arsenic, can trigger bladder carcinogenesis. Tobacco or cigarette smoking is a major risk factor associated with bladder cancer, among others, due to the oxidative stress caused by the exposure leading to inflammation and proliferation [8]. Thus, smoking increases the chance of bladder cancer in men, with an average age at the time of diagnosis of ~ 65 years or older [9]. Chronic inflammation due to pelvic irradiation, indwelling catheters or infection of the bladder lining by Schistosoma haematobium causing schistosoma also trig- gers bladder cancer. Apart from the above, the genetic make-up of some of the population predisposes them to a higher risk of bladder cancer. The molecular determinants are mutations, poly- morphisms in oncogenes (TP63, EGFR, Ras, p21), tumor suppressor genes (TP53, Rb1, histidine triad gene) and others (CABLES, Ki67, cyclin D1) [6]. These mutations that occur in certain populations not only increase the risk of bladder cancer but also determine the treatment response of some bladder cancer patients [2]. CONTACT Charles Emmanuel Jebaraj Walter cejwalter@sriramachandra.edu.in Department of Biotechnology, Faculty of Biomedical Sciences, Technology and Research, Sri Ramachandra Institute of Higher Education and Research (Deemed to be University), Chennai 600116, India * Share first authorship EXPERT REVIEW OF MOLECULAR DIAGNOSTICS 2020, VOL. 20, NO. 5, 497–508 https://doi.org/10.1080/14737159.2020.1743688 © 2020 Informa UK Limited, trading as Taylor & Francis Group