Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalk in cancer

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Abstract

Transcriptional factors of the NF-κB family and STAT3 are ubiquitously expressed and control numerous physiological processes including development, differentiation, immunity, metabolism and cancer. Both NF-κB and STAT3 are rapidly activated in response to various stimuli including stresses and cytokines, although they are regulated by entirely different signaling mechanisms. Once activated, NF-κB and STAT3 control the expression of anti-apoptotic, pro-proliferative and immune response genes. Some of these genes overlap and require transcriptional cooperation between the two factors. The activation of and interaction between STAT3 and NF-κB plays a key role in controlling the dialog between the malignant cell and its microenvironment, especially with inflammatory/immune cells that infiltrate tumors. Quite often, cytokines whose expression is induced in response to NF-κB in immune cells of the tumor microenvironment lead to STAT3 activation in both malignant and immune cells. While within malignant and pre-malignant cells STAT3 exerts important oncogenic functions, within inflammatory cells it may also suppress tumor promotion through its anti-inflammatory effects. Other interactions and forms of crosstalk between NF-κB and STAT3 include physical interaction between the two, cooperation of these factors at gene promoters/enhancers, the NF-κB dependent expression of inhibitors of STAT3 activation and the participation of STAT3 in inflammatory cells in the negative regulation NF-κB. Despite these versatile and occasionally antagonistic interactions, NF-κB and STAT3 cooperate to promote the development and progression of colon, gastric and liver cancers. In addition to explaining the molecular pathogenesis of cancer, these interactions also offer opportunities for the design of new therapeutic interventions.

Introduction

The search for genes that control tumor growth and progression has resulted in the discovery of oncogenes, which are subject to mutational activation in cancer cells, as well as tumor suppressors [1]. However, not all oncogenes are targets for mutational activation. Notable examples are the NF-κB and STAT3 transcriptional factors which were found to play pivotal roles in various aspects of the tumorigenic process in a number of malignancies [2], [3]. Most often, NF-κB and STAT3 are constitutively activated in neoplastic cells due to upregulation of upstream signaling pathways in response to autocrine and paracrine factors that are produced within the tumor microenvironment [4]. Although NF-κB and STAT3 do not match the classical oncogene definition, they are powerful activators of the malignant state and control expression of target genes important for cell proliferation, survival, angiogenesis and tissue repair [5], [6], [7], [8]. However, the functions of NF-κB and STAT3 extend far beyond the cancer cell and both transcriptional factors are important regulators of immune and inflammatory functions [9], [10]. While being activated by cytokines and growth factors, both NF-κB and STAT3 control the expression of other cytokines and inflammatory/immune mediators, thus serving as a regulatory hub that coordinates immune and inflammatory responses. Therefore, NF-κB and STAT3 also affect cancer cell physiology through their effects on immune and inflammatory cells in the tumor microenvironment [11], [12], [13].

Section snippets

NF-κB

The NF-κB term refers to a family of signal-responsive transcription factors that includes RelA/p65, c-Rel, RelB, NF-κB1/p50 and NF-κB2/p52 [14]. A potential link between NF-κB and cancer first became obvious when the RelA gene, encoding its p65 subunit, was cloned and identified to be homologous to the viral oncogene v-Rel [15]. While most solid and lymphoid tumors show constitutive NF-κB activity [7], mutations in genes encoding NF-κB family members are rare. In most cases NF-κB is maintained

STAT3

STAT3 belongs to the signal transducer and activator of transcription (STAT) family of signal responsive transcription factors, which like NF-κB are kept in an inactive form in the cytoplasm of non-stimulated cells [10], [32]. However, STAT3 activation, like other members of its family, does not require inducible degradation of an inhibitor. Instead, it is mediated by phosphorylation of a critical tyrosine residue (Tyr 705) that induces STAT3 dimerization through phosphotyrosine-SH2 domain

Interactions between STAT3 and NF-κB

Global chromatin binding surveys revealed that STAT3 binds at least 3,000 different gene promoters and the number of genes targeted by NF-κB family members is even larger. Importantly, NF-κB and STAT3 control both distinct and overlapping groups of genes during tumorigenesis. This can be explained in part by the distribution of NF-κB and STAT3 binding sites in the regulatory regions of such genes. For instance, a gene that contains only NF-κB sites may be NF-κB, but not STAT3, responsive,

NF-κB and STAT3 control a protumorigenic gene expression

Amongst the many genes controlled by NF-κB and STAT3, either synergistically or individually, one can identify groups whose products play important roles in tumor development. One of the key hallmarks of cancer is the ability of malignant cells to execute an anti-apoptotic prosurvival program that prevents intrinsically-programmed or exogenously-induced cell death [69]. Anti-apoptotic genes are prominent targets for NF-κB and STAT3, and genes such as Bcl-xL, Bcl-2, c-IAP2 are activated by both

NF-κB and STAT3 in immune and inflammatory cells

STAT3 and NF-κB are often activated in tumor associated immune and inflammatory cells, including myeloid cells and T lymphocytes [9], [79], [96], [97]. Importantly, many of the protumorigenic signals generated by STAT3 and NF-κB are exerted within immune and inflammatory cells [4], [5]. In some cells, NF-κB and STAT3 are critical for cell survival, for instance NF-κB in developing B cells or thymocytes [16], and STAT3 in activated T cells, subjected to activation-induced cell death [5]. As

The interplay between NF-κB and STAT3 in colitis associated cancer: malignant cooperation between immune and cancer cells matter

CAC was the first cancer model in which a role of NF-κB or any defined molecular entity in providing a critical link between inflammatory cells and premalignant epithelial cells in tumor development was demonstrated [99]. Using a conditional disruption of the IKKβ gene in mice, we found that NF-κB activation in enterocytes is essential for the development of colonic adenomas [99]. The oncogenic role of NF-κB in neoplastic epithelial cells is mediated through induction of anti-apoptotic

Conclusions and future directions

It has become clear that NF-κB and STAT3, a highly interactive duo are key regulators of epithelial tumorigenesis. Pro-inflammatory cytokines that are produced by immune and inflammatory cells and signal in on cancer cells functionally link NF-κB and STAT3 within the two cell types. NF-κB and STAT3 control the expression of proliferative and survival genes in premalignant cells and their neoplastic progeny. In addition, STAT3 in immune/inflammatory cells modulates the effect of NF-κB on

Acknowledgements

We thank E. Koltsova for help with figure preparation. This work was supported in part by Research Fellowship Award from Crohn‘s and Colitis Foundation of America (CCFA #1762) to S.G. and grants from the NIH and a Jeannik M. Littlefield-AACR grant in metastatic colon cancer to M.K., who is an American Cancer Society Research Professor.

Authors declare no competing financial interests.

Sergei Grivennikov is a Postdoctoral Fellow in Dr. Michael Karin Lab, University of California, San Diego. He received the PhD degree from the Engelhardt Institute of Molecular Biology under the supervision of Prof. Sergei Nedospasov in 2004. He is interested in molecular mechanisms of tumor promotion by pro-inflammatory cytokines.

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    Sergei Grivennikov is a Postdoctoral Fellow in Dr. Michael Karin Lab, University of California, San Diego. He received the PhD degree from the Engelhardt Institute of Molecular Biology under the supervision of Prof. Sergei Nedospasov in 2004. He is interested in molecular mechanisms of tumor promotion by pro-inflammatory cytokines.

    Michael Karin is a Professor of pharmacology at the School of Medicine, University of California, San Diego, where he has been since 1986. He is a leading world authority on signal transduction pathways that regulate gene expression in response to extracellular stimuli and their role in inflammatory diseases, cancer and Type II diabetes. He received the PhD degree in molecular biology from the University of California, Los Angeles, and completed the postdoctoral training at the Fox Chase Institute for Cancer Research and the Departments of Medicine and Biochemistry, University of California, San Francisco.

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