NF-κB and STAT3 signaling pathways collaboratively link infl ammation to cancer
NF-κB and STAT3 signaling pathways collaboratively link infl ammation to cancer
Yihui Fan1(), Renfang Mao2, Jianhua Yang1
1. Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; 2. The Methodist Hospital Research Institute and the Departments of Radiology, the Methodist Hospital,Houston, TX 77030, USA
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 infl ammation 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 infl ammatory 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.
Aaronson, D.S., and Horvath, C.M. (2002). A road map for those who don't know JAK-STAT. Science 296, 1653-1655 . doi: 10.1126/science.1071545
2
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-defi cient T lymphocytes. Int Immunol 10, 1747-1751 . doi: 10.1093/intimm/10.11.1747
3
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 . doi: 10.1586/ern.10.21
4
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 . doi: 10.1016/j.canlet.2007.03.024
5
Balkwill, F., and Mantovani, A. (2001). Infl ammation and cancer: back to Virchow? Lancet 357, 539-545 . doi: 10.1016/S0140-6736(00)04046-0
6
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 . doi: 10.1006/bbrc.1998.8741
7
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 . doi: 10.1038/376167a0
8
Bhoj, V.G., and Chen, Z.J. (2009). Ubiquitylation in innate and adaptive immunity. Nature 458, 430-437 . doi: 10.1038/nature07959
9
Bollrath, J., and Greten, F.R. (2009). IKK/NF-kappaB and STAT3 pathways: central signalling hubs in infl ammation-mediated tumour promotion and metastasis. EMBO Rep 10, 1314-1319 . doi: 10.1038/embor.2009.243
10
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., . (2004). Activation of IKKalpha target genes depends on recognition of specifi c kappaB binding sites by RelB:p52 dimers. Embo J 23, 4202-4210 . doi: 10.1038/sj.emboj.7600391
11
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 . doi: 10.1073/pnas.131568898
12
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 . doi: 10.1084/jem.187.2.185
13
Colotta, F., Allavena, P., Sica, A., Garlanda, C., and Mantovani, A. (2009). Cancer-related infl ammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30, 1073-1081 . doi: 10.1093/carcin/bgp127
14
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 . doi: 10.1101/gad.1662308
15
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 . doi: 10.1038/nrc1782
16
Dunn, G.P., Old, L.J., and Schreiber, R.D. (2004). The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21, 137-148 . doi: 10.1016/j.immuni.2004.07.017
17
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 . doi: 10.1016/S0092-8674(00)81289-1
18
Eferl, R., and Wagner, E.F. (2003). AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3, 859-868 . doi: 10.1038/nrc1209
19
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 . doi: 10.1080/13547500902965047
20
Gao, S.P., Mark, K.G., Leslie, K., Pao, W., Motoi, N., Gerald, W.L., Travis, W.D., Bornmann, W., Veach, D., Clarkson, B., . (2007). Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest 117, 3846-3856 . doi: 10.1172/JCI31871
21
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 . doi: 10.1038/sj.onc.1207410
22
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 . doi: 10.1126/science.1171721
23
Grivennikov, S., Karin, E., Terzic, J., Mucida, D., Yu, G.Y., Vallabhapurapu, S., Scheller, J., Rose-John, S., Cheroutre, H., Eckmann, L., . (2009). IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15, 103-113 . doi: 10.1016/j.ccr.2009.01.001
24
Grivennikov, S., and Karin, M. (2008). Autocrine IL-6 signaling: a key event in tumorigenesis? Cancer Cell 13, 7-9 . doi: 10.1016/j.ccr.2007.12.020
25
Grivennikov, S.I., Greten, F.R., and Karin, M. (2010). Immunity, infl ammation, and cancer. Cell 140, 883-899 . doi: 10.1016/j.cell.2010.01.025
26
Grivennikov, S.I., and Karin, M.Dangerous liaisons: STAT3 and NFkappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev 21, 11-19 . doi: 10.1016/j.cytogfr.2009.11.005
27
Grivennikov, S.I., and Karin, M.Infl ammation and oncogenesis: a vicious connection. Curr Opin Genet Dev 20, 65-71 . doi: 10.1016/j.gde.2009.11.004
28
Grusby, M.J. (1997). Stat4- and Stat6-deficient mice as models for manipulating T helper cell responses. Biochem Soc Trans 25, 359-360 .
29
Hanahan, D., and Weinberg, R.A. (2000). The hallmarks of cancer. Cell 100, 57-70 . doi: 10.1016/S0092-8674(00)81683-9
30
He, G., and Karin, M. (2011). NF-kappaB and STAT3- key players in liver infl ammation and cancer. Cell Res 21, 159-168 . doi: 10.1038/cr.2010.183
31
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 . doi: 10.1074/jbc.M300609200
32
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 . doi: 10.1016/0042-6822(79)90272-1
33
Hoffmann, A., and Baltimore, D. (2006). Circuitry of nuclear factor kappaB signaling. Immunol Rev 210, 171-186 . doi: 10.1111/j.0105-2896.2006.00375.x
34
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 . doi: 10.1101/gad.9.8.984
35
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 .
36
Hursting, S.D., and Berger, N.A. (2010). Energy balance, host-related factors, and cancer progression. J Clin Oncol 28, 4058-4065 . doi: 10.1200/JCO.2010.27.9935
37
Hussain, S.P., and Harris, C.C. (2007). Infl ammation and cancer: an ancient link with novel potentials. Int J Cancer 121, 2373-2380 . doi: 10.1002/ijc.23173
38
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- defi cient mice. Nature 382, 174-177 . doi: 10.1038/382174a0
39
Karin, M. (2006). Nuclear factor-kappaB in cancer development and progression. Nature 441, 431-436 . doi: 10.1038/nature04870
40
Khasawneh, J., Schulz, M.D., Walch, A., Rozman, J., Hrabe de Angelis, M., Klingenspor, M., Buck, A., Schwaiger, M., Saur, D., Schmid, R.M., . (2009). Infl ammation and mitochondrial fatty acid betaoxidation link obesity to early tumor promotion. Proc Natl Acad Sci U S A 106, 3354-3359 . doi: 10.1073/pnas.0802864106
41
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 fi broblasts. Cytokine 29, 159-168 . doi: 10.1016/j.cyto.2004.10.009
42
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 . doi: 10.1101/gad.9.16.1965
43
Kortylewski, M., Kujawski, M., Wang, T., Wei, S., Zhang, S., Pilon- Thomas, S., Niu, G., Kay, H., Mule, J., Kerr, W.G., . (2005). Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 11, 1314-1321 . doi: 10.1038/nm1325
44
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 . doi: 10.1172/JCI35213
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 . doi: 10.1016/j.ccr.2009.02.015
47
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., . (2008). Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 319, 1676-1679 . doi: 10.1126/science.1153629
48
Libikova, H., Pogady, J., Wiedermann, V., and Breier, S. (1975). Search for herpetic antibodies in the cerebrospinal fl uid in senile dementia and mental retardation. Acta Virol 19, 493-495 .
49
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 . doi: 10.1101/gad.11.2.179
50
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 . doi: 10.1172/JCI26322
51
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 . doi: 10.1038/nature05656
52
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 . doi: 10.1158/0008-5472.CAN-06-1457
Marusawa, H., and Chiba, T. (2010). Helicobacter pylori-induced activation- induced cytidine deaminase expression and carcinogenesis. Curr Opin Immunol 22, 442-447 . doi: 10.1016/j.coi.2010.06.001
55
Matsumura, Y., Kobayashi, T., Ichiyama, K., Yoshida, R., Hashimoto, M., Takimoto, T., Tanaka, K., Chinen, T., Shichita, T., Wyss-Coray, T., . (2007). Selective expansion of foxp3-positive regulatory T cells and immunosuppression by suppressors of cytokine signaling 3-defi cient dendritic cells. J Immunol 179, 2170-2179 .
56
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., . (1996). Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specifi city in the JAK-STAT signaling pathway. Cell 84, 431-442 . doi: 10.1016/S0092-8674(00)81288-X
57
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 . doi: 10.1182/blood-2006-07-033662
58
Moore, R.J., Owens, D.M., Stamp, G., Arnott, C., Burke, F., East, N., Holdsworth, H., Turner, L., Rollins, B., Pasparakis, M., . (1999). Mice defi cient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 5, 828-831 . doi: 10.1038/10552
59
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 . doi: 10.1038/nrc2444
60
Naugler, W.E., and Karin, M. (2008). NF-kappaB and cancer-identifying targets and mechanisms. Curr Opin Genet Dev 18, 19-26 . doi: 10.1016/j.gde.2008.01.020
61
Nguyen, D.X., Bos, P.D., and Massague, J. (2009). Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9, 274-284 . doi: 10.1038/nrc2622
62
Nickoloff, B.J., Ben-Neriah, Y., and Pikarsky, E. (2005). Infl ammation and cancer: is the link as simple as we think? J Invest Dermatol 124, x-xiv . doi: 10.1111/j.0022-202X.2005.23724.x
63
Osborn, L., Kunkel, S., and Nabel, G.J. (1989). Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodefi ciency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci U S A 86, 2336-2340 . doi: 10.1073/pnas.86.7.2336
64
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 . doi: 10.3748/wjg.15.1702
65
Park, C., Li, S., Cha, E., and Schindler, C. (2000). Immune response in Stat2 knockout mice. Immunity 13, 795-804 . doi: 10.1016/S1074-7613(00)00077-7
66
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 infl ammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140, 197-208 . doi: 10.1016/j.cell.2009.12.052
67
Parkin, D.M. (2006). The global health burden of infection-associated cancers in the year 2002. Int J Cancer 118, 3030-3044 . doi: 10.1002/ijc.21731
68
Polk, D.B., and Peek, R.M., Jr. Helicobacter pylori: gastric cancer and beyond. (2010). Nat Rev Cancer 10, 403-414 . doi: 10.1038/nrc2857
69
Polyak, K., Haviv, I., and Campbell, I.G. (2009). Co-evolution of tumor cells and their microenvironment. Trends Genet 25, 30-38 . doi: 10.1016/j.tig.2008.10.012
70
Prasad, S., Ravindran, J., and Aggarwal, B.B. (2010). NF-kappaB and cancer: how intimate is this relationship. Mol Cell Biochem 336, 25-37 . doi: 10.1007/s11010-009-0267-2
71
Psyrri, A., and DiMaio, D. (2008). Human papillomavirus in cervical and head-and-neck cancer. Nat Clin Pract Oncol 5, 24-31 . doi: 10.1038/ncponc0984
72
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 . doi: 10.1089/hum.2006.17.280
73
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 . doi: 10.1182/blood-2005-02-0759
74
Sansone, P., Storci, G., Tavolari, S., Guarnieri, T., Giovannini, C., Taffurelli, M., Ceccarelli, C., Santini, D., Paterini, P., Marcu, K.B., . (2007). IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest 117, 3988-4002 . doi: 10.1172/JCI32533
75
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 . doi: 10.1038/sj.emboj.7601539
76
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 . doi: 10.1016/0092-8674(95)90415-8
77
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 . doi: 10.1038/35074122
78
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 . doi: 10.1016/S0065-2776(06)90001-7
79
Srinivasula, S.M., and Ashwell, J.D. (2008). IAPs: what's in a name? Mol Cell 30, 123-135 . doi: 10.1016/j.molcel.2008.03.008
80
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 infl ammation. Cancer Cell 17, 89-97 . doi: 10.1016/j.ccr.2009.12.008
81
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 . doi: 10.1016/S0092-8674(00)81444-0
82
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., . (1996). Requirement for Stat4 in interleukin- 12-mediated responses of natural killer and T cells. Nature 382, 171-174 . doi: 10.1038/382171a0
83
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 . doi: 10.1073/pnas.94.14.7239
84
Vallabhapurapu, S., and Karin, M. (2009). Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 27, 693-733 . doi: 10.1146/annurev.immunol.021908.132641
85
Waldner, M.J., and Neurath, M.F. (2009). Colitis-associated cancer: the role of T cells in tumor development. Semin Immunopathol 31, 249-256 . doi: 10.1007/s00281-009-0161-8
86
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 . doi: 10.1158/0008-5472.CAN-10-0775
87
Weih, F., Carrasco, D., Durham, S.K., Barton, D.S., Rizzo, C.A., Ryseck, R.P., Lira, S.A., and Bravo, R. (1995). Multiorgan infl ammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family. Cell 80, 331-340 . doi: 10.1016/0092-8674(95)90416-6
88
Wu, S., Rhee, K.J., Albesiano, E., Rabizadeh, S., Wu, X., Yen, H.R., Huso, D.L., Brancati, F.L., Wick, E., McAllister, F., . (2009). A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 15, 1016-1022 . doi: 10.1038/nm.2015
89
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 . doi: 10.1101/gad.1553707
90
Yang, J., and Weinberg, R.A. (2008). Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14, 818-829 . doi: 10.1016/j.devcel.2008.05.009
91
Yang, L., Huang, J., Ren, X., Gorska, A.E., Chytil, A., Aakre, M., Carbone, D.P., Matrisian, L.M., Richmond, A., Lin, P.C., . (2008). Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. Cancer Cell 13, 23-35 . doi: 10.1016/j.ccr.2007.12.004
92
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 . doi: 10.1038/nri1995
93
Yu, H., Pardoll, D., and Jove, R. (2009). STATs in cancer infl ammation and immunity: a leading role for STAT3. Nat Rev Cancer 9, 798-809 . doi: 10.1038/nrc2734
94
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 . doi: 10.1042/BJ20020588
95
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 . doi: 10.1007/s11010-010-0652-x
