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

By S. Grivennikov, M. Karin. Cytokine & growth factor reviews, 2009

1,169 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Epidemiology, Oncology

View Paper: https://www.semanticscholar.org/paper/c1910ac640a51c8ec73ce1e7892d488244aee186

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In Cancer Research

1. T. Hirano
2. J. Hong
3. M. Park
4. Johannes A. Schmid
5. Gautam Sethi
6. Bastian Hoesel

In Epidemiology

1. T. Hirano
2. Y. Belkaid
3. T. Hand

In Oncology

1. T. Hirano
2. J. Hong
3. M. Park
4. Neeraj Kumari
5. Johannes A. Schmid
6. A. Bhatt
7. Bastian Hoesel
8. B. Dwarakanath

Citations in the corpus

• Immunity, Inflammation, and Cancer (2010, neutral): “NF-κB and STAT3 activate genes that control cell survival, proliferation, and growth, as well as angiogenesis, invasiveness, motility, chemokine, and cytokine production (Grivennikov and Karin, 2009; Yu et al., 2009).”
• Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. (2014, background): “attributed to autocrine and paracrine factors that are produced within the tumor microenvironment, STAT3 is constitutively phosphorylated in neoplastic cells [36].”
• Roles of NF-κB in Cancer and Inflammatory Diseases and Their Therapeutic Approaches (2016, background): “This is often evident in severely compromised regulation of NF-κB activity, which allows cancer cells to express abnormal cohorts of NF-κB target genes [68].”
• Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer (2017, neutral): “Furthermore, STAT3 and NFκB, which can be activated by IRE1α and PERK, transcriptionally upregulate multiple anti-apoptotic proteins, including BCL2 family members, the caspase-8 inhibitor c-FLIP, MCL1, and inhibitor of apoptosis proteins (IAPs)(Grivennikov and Karin, 2010).”
• Role of the Microbiota in Immunity and inflammation (2014, background): “Intestinal cancer is inextricably linked to inflammation in the GI tract, and commensal-driven immune activation is an important contributing factor to the etiology of these diseases (Grivennikov and Karin, 2010).”
• The complexity of NF-κB signaling in inflammation and cancer (2013, background): “Several of these links have been studied and characterized in more detail, in particular those with STAT family members (signal transducers and activators of transcription) and with the p53 tumor suppressor [107,108].”
• Role of interleukin-6 in cancer progression and therapeutic resistance (2016, background): “Since NF-kB and STAT-3 are regulated by IL-6, it appears that the NF-kB/STAT-3/IL-6 signalling cascade plays an important role in oncogenesis [134].”
• IL-6 in inflammation, autoimmunity and cancer (2020, background): “Furthermore, NF-κ B and STAT3 play crucial roles in cancer development and progression (19, 25, 67, 279).”