Ó 2012 John Wiley & Sons A/S Immunological Reviews 246/2012 379 Joseph A. DiDonato Frank Mercurio Michael Karin NF-jB and the link between inflammation and cancer Authors’ addresses Joseph A. DiDonato 1 , Frank Mercurio 2 , Michael Karin 3 1 Cleveland Clinic Foundation, Department of Cell Biology, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, USA. 2 BioTheryx Inc., San Diego, CA, USA. 3 Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California at San Diego, USA. Correspondence to: Michael Karin Laboratory of Gene Regulation and Signal Transduction Department of Pharmacology, School of Medicine University of California at San Diego, USA Tel.: +1 858 534 1361 Fax: +1 858 534 8158 e-mail: karinoffice@ucsd.edu Acknowledgements The authors declare no conflicts of interest. This article is part of a series of reviews covering NF-jB appearing in Volume 246 of Immunological Reviews. Video podcast available Go to www.immunologicalreviews.com to watch interview with Guest Editor Sankar Ghosh Immunological Reviews 2012 Vol. 246: 379–400 Printed in Singapore. All rights reserved Ó 2012 John Wiley & Sons A/S Immunological Reviews 0105-2896 Summary: The nuclear factor-jB (NF-jB) transcription factor family has been considered the central mediator of the inflammatory process and a key participant in innate and adaptive immune responses. Coinci- dent with the molecular cloning of NF-jB ⁄ RelA and identification of its kinship to the v-Rel oncogene, it was anticipated that NF-jB itself would be involved in cancer development. Oncogenic activating mutations in NF-jB genes are rare and have been identified only in some lymphoid malignancies, while most NF-jB activating mutations in lymphoid malignancies occur in upstream signaling components that feed into NF- jB. NF-jB activation is also prevalent in carcinomas, in which NF-jB activation is mainly driven by inflammatory cytokines within the tumor microenvironment. Importantly, however, in all malignancies, NF-jB acts in a cell type-specific manner: activating survival genes within cancer cells and inflammation-promoting genes in components of the tumor microenvironment. Yet, the complex biological functions of NF-jB have made its therapeutic targeting a challenge. Keywords: cancer, inflammation, NF-jB Introduction Upon the discovery that the RelA ⁄ p65 component of nuclear factor jB (NF-jB) was related to c-Rel and its oncogenic avian derivative v-Rel (1), NF-jB’s role as a lynchpin linking immu- nity, inflammation, and cancer became highly anticipated (2, 3). However, oncogenic mutations that provide RelA, c-Rel, or other NF-jB proteins with transforming potential were found to be relatively rare and mainly occur in malignancies of lymphoid cells (2). Most tumors, lymphoid or solid, exhi- bit activated NF-jB (3). Interestingly for the most part, no loss-of-function inhibitor of NF-jB (IjB) mutations or gain- of-function IjB kinase (IKK) mutations has been detected. We have suggested that NF-jB activation in cancer may be the result of either exposure to proinflammatory stimuli in the tumor microenvironment or mutational activation of upstream components of IKK–NF-jB signaling pathways (3–5). Normal functions for NF-jB demonstrate include inhi- bition of apoptosis (6–9), stimulation of cell proliferation (10), and promotion of migratory and invasive cell behaviors that are associated with tumor progression (11). These find- ings supported the hypothesis that events leading to ‘normal’