Cryptotanshinone, a novel tumor angiogenesis inhibitor, destabilizes tumor necrosis factor-α mRNA via decreasing nuclear–cytoplasmic translocation of RNA-binding protein HuR
Zhijie Zhu
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorYang Zhao
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorJunbo Li
Model Animal Research Center of Nanjing University, Nanjing, 210061 China
Search for more papers by this authorLi Tao
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorPeiliang Shi
Model Animal Research Center of Nanjing University, Nanjing, 210061 China
Search for more papers by this authorZhonghong Wei
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorXiaobo Sheng
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorDandan Shen
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorZhaoguo Liu
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorLiang Zhou
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorChao Tian
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorFangtian Fan
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorCunsi Shen
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorPingting Zhu
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorAiyun Wang
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorWenxing Chen
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorQingshun Zhao
Model Animal Research Center of Nanjing University, Nanjing, 210061 China
Search for more papers by this authorCorresponding Author
Yin Lu
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Correspondence to: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Search for more papers by this authorZhijie Zhu
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorYang Zhao
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorJunbo Li
Model Animal Research Center of Nanjing University, Nanjing, 210061 China
Search for more papers by this authorLi Tao
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorPeiliang Shi
Model Animal Research Center of Nanjing University, Nanjing, 210061 China
Search for more papers by this authorZhonghong Wei
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorXiaobo Sheng
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorDandan Shen
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorZhaoguo Liu
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorLiang Zhou
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorChao Tian
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorFangtian Fan
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorCunsi Shen
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorPingting Zhu
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorAiyun Wang
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorWenxing Chen
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Search for more papers by this authorQingshun Zhao
Model Animal Research Center of Nanjing University, Nanjing, 210061 China
Search for more papers by this authorCorresponding Author
Yin Lu
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, 210023 China
Correspondence to: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine; Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Search for more papers by this authorAbstract
Cryptotanshinone (CT), one major lipophilic component isolated from Salvia miltiorrhiza Bunge, has shown to possess chemopreventive properties against various types of cancer cells. In this study, CT was shown to be a potent anti-angiogenic agent in zebrafish, and mouse models and could limit tumor growth by inhibiting tumor angiogenesis. We further found that CT could inhibit the proliferation, migration, angiogenic sprouting, and tube formation of HUVECs. In addition, we demonstrated that CT could lower the level of TNF-α due to the destabilization of TNF-α mRNA, which associated with regulating 3′-untranslated region (3′-UTR) of TNF-α and preventing the translocation of RNA binding protein, HuR, from the nucleus to the cytoplasm. Moreover, the underlying mechanism responsible for the regulation in angiogenesis by CT was partially related to the suppression of NF-κB, and STAT3 activity. Based on the abilities of CT in targeting tumor cells, inhibiting angiogenesis, and destroying tumor vasculature, CT is worthy of further investigation for preventive, and therapeutic purposes in cancer. © 2015 Wiley Periodicals, Inc.
Supporting Information
Additional supporting information may be found in the online version of this article at the publisher's web-site.
| Filename | Description |
|---|---|
| mc22383-sup-0001-SupFig-S1.tif783.2 KB |
Figure S1. Chemical structure of Cryptotanshinone. |
| mc22383-sup-0002-SupFig-S2.tif5.3 MB |
Figure S2. CT inhibited LPS-induced angiogenesis in zebrafish embryos. |
| mc22383-sup-0003-SupFig-S3.tif4.4 MB |
Figure S3. Effect of CT on proliferation of HUVECs (DNA synthesis). |
| mc22383-sup-0004-SupFig-S4.tif3.3 MB |
Figure S4. CT inhibited migration ability of HUVECs. |
| mc22383-sup-0005-SupFig-S5.tif8.4 MB |
Figure S5. Effects of CT on protein expressions of Notch signaling, VEGF and TLR4 in HUVECs. |
| mc22383-sup-0006-SupFig-S6.tif4.9 MB |
Figure S6. Neutralization of TNF-α resulted in the inhibition of tube formation and wound healing. |
| mc22383-sup-0007-SupFig-S7.tif2.3 MB |
Figure S7. LPS time-dependently induced NF-κB but not STAT3 transcriptional activity. |
| mc22383-sup-0008-SupFig-S8.tif7.2 MB |
Figure S8. Effects of CT on other signaling pathways. |
| mc22383-sup-0009-SupFig-S9.tif2.8 MB |
Figure S9. Schematic diagram of CT on angiogenesis. |
| mc22383-sup-0010-SupData-S1.doc55 KB | Supporting Information. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1 Ribatti D, Vacca A, Nico B, Prestâ M, Roncali L. Angiogenesis: Basic and clinical aspects. Ital J Anat Embryol 2002; 108: 1–24.
- 2 Folkman J. Role of angiogenesis in tumor growth and metastasis. Elsevier 2002; 15–18.
- 3 Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2002; 2: 727–739.
- 4 Folkman J. Angiogenesis. Annu Rev Med 2006; 57: 1–18.
- 5 Balkwill F. Tumour necrosis factor and cancer. Nat Rev Cancer 2009; 9: 361–371.
- 6 Vanderslice P, Munsch CL, Rachal E, et al. Angiogenesis induced by tumor necrosis factor-agr; is mediated by α4 integrins. Angiogenesis 1998; 2: 265–275.
- 7 Rajasingh J, Bord E, Luedemann C, et al. IL-10-induced TNF-alpha mRNA destabilization is mediated via IL-10 suppression of p38 MAP kinase activation and inhibition of HuR expression. FASEB J 2006; 20: 2112–2114.
- 8 Chen X, Shu Y, Li W, Yin Y. TNF-alpha-induced metastasis gene changes in MCF-7 cells. J Nanjing Med Univ 2008; 22: 366–371.
- 9 Mochizuki Y, Nakanishi H, Kodera Y, et al. TNF-α promotes progression of peritoneal metastasis as demonstrated using a green fluorescence protein (GFP)-tagged human gastric cancer cell line. Clin Exp Metastasis 2004; 21: 39–47.
- 10 Anderson P. Post-transcriptional regulation of tumour necrosis factor alpha production. Ann Rheum Dis 2000; 59: i3–i5.
- 11 Taylor PC. Developing anti-TNF and biologic agents. Rheumatology 2011; 50: 1351–1353.
- 12 Li X, Lian L-H, Bai T, et al. Cryptotanshinone inhibits LPS-induced proinflammatory mediators via TLR4 and TAK1 signaling pathway. Int Immunopharmacol 2011; 11: 1871–1876.
- 13 Lee D-S, Lee S-H, Noh J-G, Hong S-D. Antibacterial activities of cryptotanshinone and dihydrotanshinone I from a medicinal herb, Salvia miltiorrhiza Bunge. Biosci Biotechnol Biochem 1999; 63: 2236–2239.
- 14 Park E-J, Zhao Y-Z, Kim Y-C, Sohn DH. Preventive effects of a purified extract isolated from Salvia miltiorrhiza enriched with tanshinone I, tanshinone IIA and cryptotanshinone on hepatocyte injury in vitro and in vivo. Food Chem Toxicol 2009; 47: 2742–2748.
- 15 Jin D-Z, Yin L-L, Ji X-Q, Zhu X-Z. Cryptotanshinone inhibits cyclooxygenase-2 enzyme activity but not its expression. Eur J Pharmacol 2006; 549: 166–172.
- 16 Chen W, Luo Y, Liu L, et al. Cryptotanshinone inhibits cancer cell proliferation by suppressing mammalian target of rapamycin-mediated cyclin d1 expression and Rb phosphorylation. Cancer Prev Res 2010; 3: 1015–1025.
- 17 Chen L, Zheng S-z, Sun Z-g, et al. Cryptotanshinone has diverse effects on cell cycle events in melanoma cell lines with different metastatic capacity. Cancer Chemother Pharmacol 2011; 68: 17–27.
- 18 Shin D-S, Kim H-N, Shin KD, et al. Cryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells. Cancer Res 2009; 69: 193–202.
- 19 Ge Y, Cheng R, Zhou Y, et al. Cryptotanshinone induces cell cycle arrest and apoptosis of multidrug resistant human chronic myeloid leukemia cells by inhibiting the activity of eukaryotic initiation factor 4E. Mol Cell Biochem 2012; 368: 17–25.
- 20 Park I-J, Yang WK, Nam S-H, et al. Cryptotanshinone induces G1 cell cycle arrest and autophagic cell death by activating the AMP-activated protein kinase signal pathway in HepG2 hepatoma. Apoptosis 2013; 1–14.
- 21 Bian W, Xu Y, Wang L, Chen F. The antiangiogenesis effect of cryptotanshinone on chick embryo chorioallantoic membrane. J Chin Microcirc 2007; 12: 23–26.
- 22 Hur JM, Shim JS, Jung HJ, Kwon HJ. Cryptotanshinone but not tanshinone IIA inhibits angiogenesis in vitro. Exp Mol Med 2005; 37: 133–137.
- 23 Westerfield M. The zebrafish book: A guide for the laboratory use of zebrafish (Brachydanio rerio): University of Oregon. Eugene, OR: Press; 1993.
- 24 Prewett M, Huber J, Li Y, et al. Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors. Cancer Res 1999; 59: 5209–5218.
- 25 Rouhi P, Jensen LD, Cao Z, et al. Hypoxia-induced metastasis model in embryonic zebrafish. Nat Prot 2010; 5: 1911–1918.
- 26 Lee SLC, Rouhi P, Jensen LD, et al. Hypoxia-induced pathological angiogenesis mediates tumor cell dissemination, invasion, and metastasis in a zebrafish tumor model. Proc Natl Acad Sci 2009; 106: 19485–19490.
- 27 Ponce ML. Tube formation: An in vitro matrigel angiogenesis assay. Methods Mol Biol 2009; 467: 183–188.
- 28 Mitola S, Ravelli C, Moroni E, et al. Gremlin is a novel agonist of the major proangiogenic receptor VEG FR2. Blood 2010; 116: 3677–3680.
- 29 Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell 2011; 146: 873–887.
- 30 Kerbel RS. Tumor angiogenesis. N Engl J Med 2008; 358: 2039–2049.
- 31 Colucci S, Brunetti G, Cantatore F, et al. Lymphocytes and synovial fluid fibroblasts support osteoclastogenesis through RANKL, TNFα, and IL-7 in an in vitro model derived from human psoriatic arthritis. J Pathol 2007; 212: 47–55.
- 32 Deleault KM, Skinner SJ, Brooks SA. Tristetraprolin regulates TNF TNF-α mRNA stability via a proteasome dependent mechanism involving the combined action of the ERK and p38 pathways. Mol Immunol 2008; 45: 13–24.
- 33 Dean JL, Wait R, Mahtani KR, Sully G, Clark AR, Saklatvala J. The 3′ untranslated region of tumor necrosis factor alpha mRNA is a target of the mRNA-stabilizing factor HuR. Mol Cell Biol 2001; 21: 721–730.
- 34 Chae M-J, Sung HY, Kim E-H, et al. Chemical inhibitors destabilize HuR binding to the AU-rich element of TNF-α mRNA. Exp Mol Med 2009; 41: 824–831.
- 35 Chen Z, Han ZC. STAT3: A critical transcription activator in angiogenesis. Med Res Rev 2008; 28: 185–200.
- 36 Noort A-R, van Zoest KP, Koolwijk P, Tak P-P, Tas SW. NF-kappaB inducing kinase (NIK) is a key regulator of inflammation-induced angiogenesis. J Transl Med 2012; 10: O1.
- 37 de Jong PR, Schadenberg AW, van den Broek T, et al. STAT3 regulates monocyte TNF-alpha production in systemic inflammation caused by cardiac surgery with cardiopulmonary bypass. PLoS ONE 2012; 7: e35070.
- 38 Napetschnig J, Wu H. Molecular basis of NF-kappaB signaling. Annu Rev Biophys 2013; 42: 443–468.
- 39 Grivennikov SI, Karin M. Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev 2010; 21: 11–19.
- 40 Chen X, Guo J, Bao J, Lu J, Wang Y. The Anticancer Properties of Salvia Miltiorrhiza Bunge (Danshen): A Systematic Review. Med Res Rev 2014; 34: 768–794.
- 41 Tian X-H, Wu JH. Tanshinone derivatives: CNY a patent review (January 2006-September 2012). Expert Opin Ther Patents 2013; 23: 19–29.
- 42 Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011; 144: 646–674.
- 43 Mazibrada J, Rittà M, Mondini M, et al. Interaction between inflammation and angiogenesis during different stages of cervical carcinogenesis. Gynecol Oncol 2008; 108: 112–120.
- 44 Scaldaferri F, Vetrano S, Sans M, et al. VEGF-A links angiogenesis and inflammation in inflammatory bowel disease pathogenesis. Gastroenterology 2009; 136: 585–595. e585.
- 45 Hippenstiel S, Soeth S, Kellas B, et al. Rho proteins and the p38-MAPK pathway are important mediators for LPS-induced interleukin-8 expression in human endothelial cells. Blood 2000; 95: 3044–3051.
- 46 Harmey JH, Bucana CD, Lu W, et al. Lipopolysaccharide-induced metastatic growth is associated with increased angiogenesis, vascular permeability and tumor cell invasion. Int J Cancer 2002; 101: 415–422.
- 47 Carney EF. Therapy: TNF inhibition suppresses angiogenic mechanisms implicated in RA. Nat Rev Rheumatol 2012; 8: 307–307.
- 48 Lantz R, Chen G, Solyom A, Jolad S, Timmermann B. The effect of turmeric extracts on inflammatory mediator production. Phytomedicine 2005; 12: 445–452.
- 49 Okunieff P, Xu J, Hu D, et al. Curcumin protects against radiation-induced acute and chronic cutaneous toxicity in mice and decreases mRNA expression of inflammatory and fibrogenic cytokines. Int J Radiat Oncol* Biol* Phys 2006; 65: 890–898.
- 50 Benedito R, Roca C, Sörensen I, et al. The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 2009; 137: 1124–1135.
- 51 Suchting S, Eichmann A. Jagged gives endothelial tip cells an edge. Cell 2009; 137: 988–990.
- 52 Stoecklin G, Lu M, Rattenbacher B, Moroni C. A constitutive decay element promotes tumor necrosis factor alpha mRNA degradation via an AU-rich element-independent pathway. Mol Cell Biol 2003; 23: 3506–3515.
- 53 Aurora AB, Biyashev D, Mirochnik Y, et al. NF-κB balances vascular regression and angiogenesis via chromatin remodeling and NFAT displacement. Blood 2010; 116: 475–484.
- 54 Fan Y, Mao R, Yang J. NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell 2013; 4: 176–185.
- 55 Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009; 9: 798–809.
- 56 Grivennikov SI, Greten FR, arin K. M. Immunity, inflammation, and cancer. Cell 2010; 140: 883–899.
