Abstract
Although links between cancer and inflammation were firstly proposed in the nineteenth century, the molecular mechanism has not yet been clearly understood. Epidemiological studies have identified chronic infections and inflammation as major risk factors for various types of cancer. NF-κB transcription factors and the signaling pathways are central coordinators in innate and adaptive immune responses. STAT3 regulates the expression of a variety of genes in response to cellular stimuli, and thus plays a key role in cell growth and apoptosis. Recently, roles of NF-κB and STAT3 in colon, gastric and liver cancers have been extensively investigated. The activation and interaction between STAT3 and NF-κB play vital roles in control of the communication between cancer cells and inflammatory cells. NF-κB and STAT3 are two major factors controlling the ability of pre-neoplastic and malignant cells to resist apoptosis-based tumor-surveillance and regulating tumor angiogenesis and invasiveness. Understanding the molecular mechanisms of NF-κB and STAT3 cooperation in cancer will offer opportunities for the design of new chemo-preventive and chemotherapeutic approaches.
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Aaronson, D.S., and Horvath, C.M. (2002). A road map for those who don’t know JAK-STAT. Science 296, 1653–1655.
Akaishi, H., Takeda, K., Kaisho, T., Shineha, R., Satomi, S., Takeda, J., and Akira, S. (1998). Defective IL-2-mediated IL-2 receptor alpha chain expression in Stat3-deficient T lymphocytes. Int Immunol 10, 1747–1751.
Atkinson, G.P., Nozell, S.E., and Benveniste, E.T. (2010). NF-kappaB and STAT3 signaling in glioma: targets for future therapies. Expert Rev Neurother 10, 575–586.
Baby, J., Pickering, B.F., Vashisht Gopal, Y.N., and Van Dyke, M.W. (2007). Constitutive and inducible nuclear factor-kappaB in immortalized normal human bronchial epithelial and non-small cell lung cancer cell lines. Cancer Lett 255, 85–94.
Balkwill, F., and Mantovani, A. (2001). Inflammation and cancer: back to Virchow? Lancet 357, 539–545.
Basu, S., Rosenzweig, K.R., Youmell, M., and Price, B.D. (1998). The DNA-dependent protein kinase participates in the activation of NF kappa B following DNA damage. Biochem Biophys Res Commun 247, 79–83.
Beg, A.A., Sha, W.C., Bronson, R.T., Ghosh, S., and Baltimore, D. (1995). Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature 376, 167–170.
Bhoj, V.G., and Chen, Z.J. (2009). Ubiquitylation in innate and adaptive immunity. Nature 458, 430–437.
Bollrath, J., and Greten, F.R. (2009). IKK/NF-kappaB and STAT3 pathways: central signalling hubs in inflammation-mediated tumour promotion and metastasis. EMBO Rep 10, 1314–1319.
Bonizzi, G., Bebien, M., Otero, D.C., Johnson-Vroom, K.E., Cao, Y., Vu, D., Jegga, A.G., Aronow, B.J., Ghosh, G., Rickert, R.C., et al. (2004). Activation of IKKalpha target genes depends on recognition of specific kappaB binding sites by RelB:p52 dimers. Embo J 23, 4202–4210.
Bowman, T., Broome, M.A., Sinibaldi, D., Wharton, W., Pledger, W.J., Sedivy, J.M., Irby, R., Yeatman, T., Courtneidge, S.A., and Jove, R. (2001). Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc Natl Acad Sci U S A 98, 7319–7324.
Caamano, J.H., Rizzo, C.A., Durham, S.K., Barton, D.S., Raventos-Suarez, C., Snapper, C.M., and Bravo, R. (1998). Nuclear factor (NF)-kappa B2 (p100/p52) is required for normal splenic microarchitecture and B cell-mediated immune responses. J Exp Med 187, 185–196.
Colotta, F., Allavena, P., Sica, A., Garlanda, C., and Mantovani, A. (2009). Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30, 1073–1081.
Dan, H.C., Cooper, M.J., Cogswell, P.C., Duncan, J.A., Ting, J.P., and Baldwin, A.S. (2008). Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK. Genes Dev 22, 1490–1500.
de Visser, K.E., Eichten, A., and Coussens, L.M. (2006). Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6, 24–37.
Dunn, G.P., Old, L.J., and Schreiber, R.D. (2004). The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21, 137–148.
Durbin, J.E., Hackenmiller, R., Simon, M.C., and Levy, D.E. (1996). Targeted disruption of the mouse Stat1 gene results in compromised innate immunity to viral disease. Cell 84, 443–450.
Eferl, R., and Wagner, E.F. (2003). AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3, 859–868.
Faux, S.P., Tai, T., Thorne, D., Xu, Y., Breheny, D., and Gaca, M. (2009). The role of oxidative stress in the biological responses of lung epithelial cells to cigarette smoke. Biomarkers 14 Suppl 1, 90–96.
Gao, S.P., Mark, K.G., Leslie, K., Pao, W., Motoi, N., Gerald, W.L., Travis, W.D., Bornmann, W., Veach, D., Clarkson, B., et al. (2007). Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest 117, 3846–3856.
Gilmore, T.D., Kalaitzidis, D., Liang, M.C., and Starczynowski, D.T. (2004). The c-Rel transcription factor and B-cell proliferation: a deal with the devil. Oncogene 23, 2275–2286.
Gough, D.J., Corlett, A., Schlessinger, K., Wegrzyn, J., Larner, A.C., and Levy, D.E. (2009). Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science 324, 1713–1716.
Grivennikov, S., Karin, E., Terzic, J., Mucida, D., Yu, G.Y., Vallabhapurapu, S., Scheller, J., Rose-John, S., Cheroutre, H., Eckmann, L., et al. (2009). IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15, 103–113.
Grivennikov, S., and Karin, M. (2008). Autocrine IL-6 signaling: a key event in tumorigenesis? Cancer Cell 13, 7–9.
Grivennikov, S.I., Greten, F.R., and Karin, M. (2010). Immunity, inflammation, and cancer. Cell 140, 883–899.
Grivennikov, S.I., and Karin, M. Dangerous liaisons: STAT3 and NFkappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev 21, 11–19.
Grivennikov, S.I., and Karin, M. Inflammation and oncogenesis: a vicious connection. Curr Opin Genet Dev 20, 65–71.
Grusby, M.J. (1997). Stat4- and Stat6-deficient mice as models for manipulating T helper cell responses. Biochem Soc Trans 25, 359–360.
Hanahan, D., and Weinberg, R.A. (2000). The hallmarks of cancer. Cell 100, 57–70.
He, G., and Karin, M. (2011). NF-kappaB and STAT3 — key players in liver inflammation and cancer. Cell Res 21, 159–168.
Helbig, G., Christopherson, K.W., 2nd, Bhat-Nakshatri, P., Kumar, S., Kishimoto, H., Miller, K.D., Broxmeyer, H.E., and Nakshatri, H. (2003). NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem 278, 21631–21638.
Hoelzer, J.D., Franklin, R.B., and Bose, H.R., Jr. (1979). Transformation by reticuloendotheliosis virus: development of a focus assay and isolation of a nontransforming virus. Virology 93, 20–30.
Hoffmann, A., and Baltimore, D. (2006). Circuitry of nuclear factor kappaB signaling. Immunol Rev 210, 171–186.
Horvath, C.M., Wen, Z., and Darnell, J.E., Jr. (1995). A STAT protein domain that determines DNA sequence recognition suggests a novel DNA-binding domain. Genes Dev 9, 984–994.
Huber, M.A., Azoitei, N., Baumann, B., Grunert, S., Sommer, A., Pehamberger, H., Kraut, N., Beug, H., and Wirth, T. (2004). NFkappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 114, 569–581.
Hursting, S.D., and Berger, N.A. (2010). Energy balance, host-related factors, and cancer progression. J Clin Oncol 28, 4058–4065.
Hussain, S.P., and Harris, C.C. (2007). Inflammation and cancer: an ancient link with novel potentials. Int J Cancer 121, 2373–2380.
Kaplan, M.H., Sun, Y.L., Hoey, T., and Grusby, M.J. (1996). Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature 382, 174–177.
Karin, M. (2006). Nuclear factor-kappaB in cancer development and progression. Nature 441, 431–436.
Khasawneh, J., Schulz, M.D., Walch, A., Rozman, J., Hrabe de Angelis, M., Klingenspor, M., Buck, A., Schwaiger, M., Saur, D., Schmid, R.M., et al. (2009). Inflammation and mitochondrial fatty acid betaoxidation link obesity to early tumor promotion. Proc Natl Acad Sci U S A 106, 3354–3359.
Kida, Y., Kobayashi, M., Suzuki, T., Takeshita, A., Okamatsu, Y., Hanazawa, S., Yasui, T., and Hasegawa, K. (2005). Interleukin-1 stimulates cytokines, prostaglandin E2 and matrix metalloproteinase-1 production via activation of MAPK/AP-1 and NF-kappaB in human gingival fibroblasts. Cytokine 29, 159–168.
Kontgen, F., Grumont, R.J., Strasser, A., Metcalf, D., Li, R., Tarlinton, D., and Gerondakis, S. (1995). Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression. Genes Dev 9, 1965–1977.
Kortylewski, M., Kujawski, M., Wang, T., Wei, S., Zhang, S., Pilon-Thomas, S., Niu, G., Kay, H., Mule, J., Kerr, W.G., et al. (2005). Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 11, 1314–1321.
Kujawski, M., Kortylewski, M., Lee, H., Herrmann, A., Kay, H., and Yu, H. (2008). Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. J Clin Invest 118, 3367–3377.
Lee, D.F., Kuo, H.P., Chen, C.T., Hsu, J.M., Chou, C.K., Wei, Y., Sun, H.L., Li, L.Y., Ping, B., Huang, W.C., et al. (2007). IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 130, 440–455.
Lee, H., Herrmann, A., Deng, J.H., Kujawski, M., Niu, G., Li, Z., Forman, S., Jove, R., Pardoll, D.M., and Yu, H. (2009). Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. Cancer Cell 15, 283–293.
Lenz, G., Davis, R.E., Ngo, V.N., Lam, L., George, T.C., Wright, G.W., Dave, S.S., Zhao, H., Xu, W., Rosenwald, A., et al. (2008). Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 319, 1676–1679.
Libikova, H., Pogady, J., Wiedermann, V., and Breier, S. (1975). Search for herpetic antibodies in the cerebrospinal fluid in senile dementia and mental retardation. Acta Virol 19, 493–495.
Liu, X., Robinson, G.W., Wagner, K.U., Garrett, L., Wynshaw-Boris, A., and Hennighausen, L. (1997). Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes Dev 11, 179–186.
Luo, J.L., Kamata, H., and Karin, M. (2005). IKK/NF-kappaB signaling: balancing life and death—a new approach to cancer therapy. J Clin Invest 115, 2625–2632.
Luo, J.L., Tan, W., Ricono, J.M., Korchynskyi, O., Zhang, M., Gonias, S.L., Cheresh, D.A., and Karin, M. (2007). Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin. Nature 446, 690–694.
Mann, A.P., Verma, A., Sethi, G., Manavathi, B., Wang, H., Fok, J.Y., Kunnumakkara, A.B., Kumar, R., Aggarwal, B.B., and Mehta, K. (2006). Overexpression of tissue transglutaminase leads to constitutive activation of nuclear factor-kappaB in cancer cells: delineation of a novel pathway. Cancer Res 66, 8788–8795.
Mantovani, A. (2009). Cancer: Inflaming metastasis. Nature 457, 36–37.
Marusawa, H., and Chiba, T. (2010). Helicobacter pylori-induced activation-induced cytidine deaminase expression and carcinogenesis. Curr Opin Immunol 22, 442–447.
Matsumura, Y., Kobayashi, T., Ichiyama, K., Yoshida, R., Hashimoto, M., Takimoto, T., Tanaka, K., Chinen, T., Shichita, T., Wyss-Coray, T., et al. (2007). Selective expansion of foxp3-positive regulatory T cells and immunosuppression by suppressors of cytokine signaling 3-deficient dendritic cells. J Immunol 179, 2170–2179.
Meraz, M.A., White, J.M., Sheehan, K.C., Bach, E.A., Rodig, S.J., Dighe, A.S., Kaplan, D.H., Riley, J.K., Greenlund, A.C., Campbell, D., et al. (1996). Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 84, 431–442.
Miletic, A.V., Graham, D.B., Montgrain, V., Fujikawa, K., Kloeppel, T., Brim, K., Weaver, B., Schreiber, R., Xavier, R., and Swat, W. (2007). Vav proteins control MyD88-dependent oxidative burst. Blood 109, 3360–3368.
Moore, R.J., Owens, D.M., Stamp, G., Arnott, C., Burke, F., East, N., Holdsworth, H., Turner, L., Rollins, B., Pasparakis, M., et al. (1999). Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 5, 828–831.
Murdoch, C., Muthana, M., Coffelt, S.B., and Lewis, C.E. (2008). The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8, 618–631.
Naugler, W.E., and Karin, M. (2008). NF-kappaB and cancer-identifying targets and mechanisms. Curr Opin Genet Dev 18, 19–26.
Nguyen, D.X., Bos, P.D., and Massague, J. (2009). Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9, 274–284.
Nickoloff, B.J., Ben-Neriah, Y., and Pikarsky, E. (2005). Inflammation and cancer: is the link as simple as we think? J Invest Dermatol 124, x–xiv.
Osborn, L., Kunkel, S., and Nabel, G.J. (1989). Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci U S A 86, 2336–2340.
Pan, J.S., Hong, M.Z., and Ren, J.L. (2009). Reactive oxygen species: a double-edged sword in oncogenesis. World J Gastroenterol 15, 1702–1707.
Park, C., Li, S., Cha, E., and Schindler, C. (2000). Immune response in Stat2 knockout mice. Immunity 13, 795–804.
Park, E.J., Lee, J.H., Yu, G.Y., He, G., Ali, S.R., Holzer, R.G., Osterreicher, C.H., Takahashi, H., and Karin, M. (2010). Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140, 197–208.
Parkin, D.M. (2006). The global health burden of infection-associated cancers in the year 2002. Int J Cancer 118, 3030–3044.
Polk, D.B., and Peek, R.M., Jr. Helicobacter pylori: gastric cancer and beyond. (2010). Nat Rev Cancer 10, 403–414.
Polyak, K., Haviv, I., and Campbell, I.G. (2009). Co-evolution of tumor cells and their microenvironment. Trends Genet 25, 30–38.
Prasad, S., Ravindran, J., and Aggarwal, B.B. (2010). NF-kappaB and cancer: how intimate is this relationship. Mol Cell Biochem 336, 25–37.
Psyrri, A., and DiMaio, D. (2008). Human papillomavirus in cervical and head-and-neck cancer. Nat Clin Pract Oncol 5, 24–31.
Qiao, L., Zhang, H., Yu, J., Francisco, R., Dent, P., Ebert, M.P., Rocken, C., and Farrell, G. (2006). Constitutive activation of NF-kappaB in human hepatocellular carcinoma: evidence of a cytoprotective role. Hum Gene Ther 17, 280–290.
Qin, H., Wilson, C.A., Lee, S.J., Zhao, X., and Benveniste, E.N. (2005). LPS induces CD40 gene expression through the activation of NFkappaB and STAT-1alpha in macrophages and microglia. Blood 106, 3114–3122.
Sansone, P., Storci, G., Tavolari, S., Guarnieri, T., Giovannini, C., Taffurelli, M., Ceccarelli, C., Santini, D., Paterini, P., Marcu, K.B., et al. (2007). IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest 117, 3988–4002.
Schmidt, D., Textor, B., Pein, O.T., Licht, A.H., Andrecht, S., Sator-Schmitt, M., Fusenig, N.E., Angel, P., and Schorpp-Kistner, M. (2007). Critical role for NF-kappaB-induced JunB in VEGF regulation and tumor angiogenesis. Embo J 26, 710–719.
Sha, W.C., Liou, H.C., Tuomanen, E.I., and Baltimore, D. (1995). Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses. Cell 80, 321–330.
Shankaran, V., Ikeda, H., Bruce, A.T., White, J.M., Swanson, P.E., Old, L.J., and Schreiber, R.D. (2001). IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111.
Smyth, M.J., Dunn, G.P., and Schreiber, R.D. (2006). Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol 90, 1–50.
Srinivasula, S.M., and Ashwell, J.D. (2008). IAPs: what’s in a name? Mol Cell 30, 123–135.
Staudt, L.M. Oncogenic activation of NF-kappaB. Cold Spring Harb Perspect Biol 2, a000109.
Takahashi, H., Ogata, H., Nishigaki, R., Broide, D.H., and Karin, M. (2010). Tobacco smoke promotes lung tumorigenesis by triggering IKKbeta- and JNK1-dependent inflammation. Cancer Cell 17, 89–97.
Teglund, S., McKay, C., Schuetz, E., van Deursen, J.M., Stravopodis, D., Wang, D., Brown, M., Bodner, S., Grosveld, G., and Ihle, J.N. (1998). Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 93, 841–850.
Thierfelder, W.E., van Deursen, J.M., Yamamoto, K., Tripp, R.A., Sarawar, S.R., Carson, R.T., Sangster, M.Y., Vignali, D.A., Doherty, P.C., Grosveld, G.C., et al. (1996). Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382, 171–174.
Udy, G.B., Towers, R.P., Snell, R.G., Wilkins, R.J., Park, S.H., Ram, P.A., Waxman, D.J., and Davey, H.W. (1997). Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. Proc Natl Acad Sci U S A 94, 7239–7244.
Vallabhapurapu, S., and Karin, M. (2009). Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 27, 693–733.
Waldner, M.J., and Neurath, M.F. (2009). Colitis-associated cancer: the role of T cells in tumor development. Semin Immunopathol 31, 249–256.
Wang, L., Yi, T., Zhang, W., Pardoll, D.M., and Yu, H. (2010). IL-17 enhances tumor development in carcinogen-induced skin cancer. Cancer Res 70, 10112–10120.
Weih, F., Carrasco, D., Durham, S.K., Barton, D.S., Rizzo, C.A., Ryseck, R.P., Lira, S.A., and Bravo, R. (1995). Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell 80, 331–340.
Wu, S., Rhee, K.J., Albesiano, E., Rabizadeh, S., Wu, X., Yen, H.R., Huso, D.L., Brancati, F.L., Wick, E., McAllister, F., et al. (2009). A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 15, 1016–1022.
Yang, J., Liao, X., Agarwal, M.K., Barnes, L., Auron, P.E., and Stark, G.R. (2007). Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Dev 21, 1396–1408.
Yang, J., and Weinberg, R.A. (2008). Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14, 818–829.
Yang, L., Huang, J., Ren, X., Gorska, A.E., Chytil, A., Aakre, M., Carbone, D.P., Matrisian, L.M., Richmond, A., Lin, P.C., et al. (2008). Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13, 23–35.
Yu, H., Kortylewski, M., and Pardoll, D. (2007). Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 7, 41–51.
Yu, H., Pardoll, D., and Jove, R. (2009). STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9, 798–809.
Yu, Z., Zhang, W., and Kone, B.C. (2002). Signal transducers and activators of transcription 3 (STAT3) inhibits transcription of the inducible nitric oxide synthase gene by interacting with nuclear factor kappaB. Biochem J 367, 97–105.
Zargan, J., Sajad, M., Umar, S., Naime, M., Ali, S., and Khan, H.A. (2011). Scorpion (Odontobuthus doriae) venom induces apoptosis and inhibits DNA synthesis in human neuroblastoma cells. Mol Cell Biochem 348, 173–181.
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Fan, Y., Mao, R. & Yang, J. NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell 4, 176–185 (2013). https://doi.org/10.1007/s13238-013-2084-3
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DOI: https://doi.org/10.1007/s13238-013-2084-3