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Interferon alpha 2a downregulates VEGF expression through PI3 kinase and MAP kinase signaling pathways

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Abstract

An earlier report demonstrated that interferon alpha (IFN-α) inhibited tumor growth and recurrence in an MHCC97 xenograft model in nude mice by suppressing tumor angiogenesis rather than by inhibiting tumor cell proliferation. However, the underlying molecular mechanism was not fully elucidated. In this study, we demonstrated that IFN-α 2a could downregulate VEGF expression both in mRNA and in protein levels, as well as downregulating HIF-1α mRNA expression in MHCC97 cells in vitro. A cDNA micro array analysis followed by Northern and Western blot analysis revealed that PI3 kinase and MAP kinase signaling pathways might be inhibited by IFN-α 2a. Blocking the function of IFN-α receptor with a specific peptide could eliminate the inhibitory effects of IFN-α 2a on VEGF expression. In addition, wortmannin and PD098059, respective inhibitors of the PI3 kinase and the MAP kinase signaling pathways, when used independently or in combination, could also downregulate the VEGF synthesis and secretion in a similar pattern of IFN-α 2a. These observations may lead to the conclusion that IFN-α 2a could suppress VEGF synthesis and secretion by downregulating HIF-1α expression, via inhibition of the PI3 kinase and/or the MAP kinase signaling pathways.

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Abbreviations

HCC:

Hepatocellular carcinoma

IFN-α 2a:

Interferon α 2a

MAPK:

Mitogen-activated protein kinase

PI3 K:

Phosphatidylinosital 3 kinase

VEGF:

Vascular endothelial growth factor

bFGF:

Basic fibroblast growth factor

PDECGF:

Platelet-derived endothelial cell growth factor

HIFα:

Hypoxia-inducible factor α

CHED:

Human Cdc-2 related protein kinase.

References

  • Ahmad SA, Liu W, Jung YD, Fan F, Reinmuth N, Bucana CD, Ellis LM (2001) Differential expression of angiopoietin-1 and angiopoietin-2 in colon carcinoma. A possible mechanism for the initiation of angiogenesis. Cancer 92:1138–1143

    Article  CAS  PubMed  Google Scholar 

  • Akeno N, Robins J, Zhang M, Czyzyk-Krzeska MF, Clemens TL (2002) Induction of vascular endothelial growth factor by IGF-I in osteoblast-like cells is mediated by the PI3 K signaling pathway through the hypoxia-inducible factor-2alpha. Endocrinology 143:420–425

    Article  CAS  PubMed  Google Scholar 

  • Bagheri-Yarmand R, Vadlamudi RK, Wang RA, Mendelsohn J, Kumar R (2000) Vascular endothelial growth factor up-regulation via p21-activated kinase-1 signaling regulates heregulin-beta1-mediated angiogenesis. J Biol Chem 275:39451–39457

    Article  CAS  PubMed  Google Scholar 

  • Benjamin LE, Keshet E (1997) Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal. Proc Natl Acad Sci USA 94:8761–8766

    Article  CAS  PubMed  Google Scholar 

  • Berra E, Pages G, Pouyssegur J (2000) MAP kinases and hypoxia in the control of VEGF expression. Cancer Metastasis Rev 19:139–145

    Article  CAS  PubMed  Google Scholar 

  • Blancher C, Moore JW, Talks KL, Houlbrook S, Harris AL (2000) Relationship of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression to vascular endothelial growth factor induction and hypoxia survival in human breast cancer cell lines. Cancer Res 60:7106–7113

    CAS  PubMed  Google Scholar 

  • Blancher C, Moore JW, Robertson N, Harris AL (2001) Effects of ras and von Hippel-Lindau (VHL) gene mutations on hypoxia-inducible factor (HIF)-1 alpha, HIF-2 alpha, and vascular endothelial growth factor expression and their regulation by the phosphatidylinositol 3’-kinase/Akt signaling pathway. Cancer Res 61:7349–7355

    CAS  PubMed  Google Scholar 

  • Brassard DL, English JM, Malkowski M, Kirschmeier P, Nagabhushan TL, Bishop WR (2002) Inhibitors of farnesyl protein transferase and MEK1,2 induce apoptosis in fibroblasts transformed with farnesylated but not geranylgeranylated H-Ras. Exp Cell Res 273:138–146

    Article  CAS  PubMed  Google Scholar 

  • Brat DJ, Van Meir EG (2001) Glomeruloid microvascular proliferation orchestrated by VPF/VEGF: a new world of angiogenesis research. Am J Pathol 158:789–796

    CAS  PubMed  Google Scholar 

  • Breier G, Blum S, Peli J, Groot M, Wild C, Risau W, Reichmann E (2002) Transforming growth factor-beta and Ras regulate the VEGF/VEGF-receptor system during tumor angiogenesis. Int J Cancer 97:142–148

    Article  CAS  PubMed  Google Scholar 

  • Burke B, Tang N, Corke KP, Tazzyman D, Ameri K, Wells M, Lewis CE (2002) Expression of HIF-1alpha by human macrophages: implications for the use of macrophages in hypoxia-regulated cancer gene therapy. J Pathol 196:204–212

    Article  CAS  PubMed  Google Scholar 

  • Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257

    Article  Google Scholar 

  • Clarke K, Smith K, Gullick WJ, Harris AL (2001) Mutant epidermal growth factor receptor enhances induction of vascular endothelial growth factor by hypoxia and insulin-like growth factor-1 via a PI3 kinase dependent pathway. Br J Cancer 84:1322–1329

    Article  CAS  PubMed  Google Scholar 

  • Currie MJ, Gunningham SP, Han C, Scott PA, Robinson BA, Harris AL, Fox SB (2001) Angiopoietin-1 is inversely related to thymidine phosphorylase expression in human breast cancer, indicating a role in vascular remodeling. Clin Cancer Res 7:918–927

    CAS  PubMed  Google Scholar 

  • Denis GV, Vaziri C, Guo N, Faller DV (2000) RING3 kinase transactivates promoters of cell cycle regulatory genes through E2F. Cell Growth Differ 11:417–424

    CAS  PubMed  Google Scholar 

  • Dinney CP, Bielenberg DR, Perrotte P, Reich R, Eve BY, Bucana CD, Fidler IJ (1998) Inhibition of basic fibroblast growth factor expression, angiogenesis, and growth of human bladder carcinoma in mice by systemic interferon-alpha administration. Cancer Res 58:808–814

    CAS  PubMed  Google Scholar 

  • Dong G, Chen Z, Li ZY, Yeh NT, Bancroft CC, Van Waes C (2001) Hepatocyte growth factor/scatter factor-induced activation of MEK and PI3 K signal pathways contributes to expression of proangiogenic cytokines interleukin-8 and vascular endothelial growth factor in head and neck squamous cell carcinoma. Cancer Res 61:5911–5918

    CAS  PubMed  Google Scholar 

  • Folkman J (1972) Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg 175:409–416

    CAS  PubMed  Google Scholar 

  • Folkman J, Ingber D (1992) Inhibition of angiogenesis. Semin Cancer Biol 3:89–96

    CAS  PubMed  Google Scholar 

  • Folkman J, Browder T, Palmblad J (2001) Angiogenesis research: guidelines for translation to clinical application. Thromb Haemost 86:23–33

    CAS  PubMed  Google Scholar 

  • Fredriksson JM, Lindquist JM, Bronnikov GE, Nedergaard J (2000) Norepinephrine induces vascular endothelial growth factor gene expression in brown adipocytes through a beta-adrenoreceptor/cAMP/protein kinase A pathway involving Src but independently of Erk1/2. J Biol Chem 275:13802–13811

    Article  CAS  PubMed  Google Scholar 

  • Holash J, Wiegand SJ, Yancopoulos GD (1999) New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene 18:5356–5362

    Article  CAS  PubMed  Google Scholar 

  • Ishizaki H, Miyoshi J, Kamiya H, Togawa A, Tanaka M, Sasaki T, Endo K, Mizoguchi A, Ozawa S, Takai Y (2000). Role of rab GDP dissociation inhibitor alpha in regulating plasticity of hippocampal neurotransmission. Proc Natl Acad Sci USA 97:11587–11592

    Article  CAS  PubMed  Google Scholar 

  • Jain RK, Safabakhsh N, Sckell A, Chen Y, Jiang P, Benjamin L, Yuan F, Keshet E (1998) Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor. Proc Natl Acad Sci USA 95:10820–10825

    Article  CAS  PubMed  Google Scholar 

  • Jiang BH, Zheng JZ, Aoki M, Vogt PK (2000) Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells. Proc Natl Acad Sci USA 97:1749–1753

    Article  CAS  PubMed  Google Scholar 

  • Johnson JD, Edman JC, Rutter WJ (1993) A receptor tyrosine kinase found in breast carcinoma cells has an extracellular discoidin I-like domain. Proc Natl Acad Sci USA 90:5677–5681

    CAS  PubMed  Google Scholar 

  • Kim SJ, Uehara H, Karashima T, Mccarty M, Shih N, Fidler IJ (2001) Expression of interleukin-8 correlates with angiogenesis, tumorigenicity, and metastasis of human prostate cancer cells implanted orthotopically in nude mice. Neoplasia 3:33–42

    Article  CAS  PubMed  Google Scholar 

  • Kozawa O, Kawamura H, Hatakeyama D, Matsuno H, Uematsu T (2000) Endothelin-1 induces vascular endothelial growth factor synthesis in osteoblasts: involvement of p38 mitogen-activated protein kinase. Cell Signal 12:375–380

    Article  CAS  PubMed  Google Scholar 

  • Kusters B, de Waal RM, Wesseling P, Verrijp K, Maass C, Heerschap A, Barentsz JO, Sweep F, Ruiter DJ, Leenders WP (2003) Differential effects of vascular endothelial growth factor A isoforms in a mouse brain metastasis model of human melanoma. Cancer Res 63:5408–5413

    PubMed  Google Scholar 

  • Li Y, Tang ZY, Ye SL, Liu YK, Chen J, Xue Q, Chen J, Gao DM, Bao WH (2001) Establishment of cell clones with different metastatic potential from the metastatic hepatocellular carcinoma cell line MHCC97. World J Gastroenterol 7:630–636

    CAS  PubMed  Google Scholar 

  • Li Y, Tang ZY, Ye SL, Liu BB, Liu YK, Chen J, Xue Q (2003) Establishment of a hepatocellular carcinoma cell line with unique metastatic characteristics through in vivo selection and screening for metastasis-related genes through cDNA microarray. J Cancer Res Clin Oncol 129:43–51

    Article  CAS  PubMed  Google Scholar 

  • Liao Y, Tang ZY, Ye SL, Liu KD, Sun FX, Huang Z (2000) Modulation of apoptosis, tumorigenesity and metastatic potential with antisense H-ras oligodeoxynucleotides in a high metastatic tumor model of hepatoma: LCI-D20. Hepatogastroenterology 47:365–370

    Google Scholar 

  • Lippman SM, Parkinson DR, Itri LM, Weber RS, Schantz SP, Ota DM, Schusterman MA, Krakoff IH, Gutterman JU, Hong WK (1992) 13-cis-retinoic acid and interferon alpha-2a: effective combination therapy for advanced squamous cell carcinoma of the skin. J Natl Cancer Inst 84:235–241

    CAS  PubMed  Google Scholar 

  • Maier JA, Morelli D, Lazzerini D, Menard S, Colnaghi MI, Balsari A (1999) Inhibition of fibronectin-activated migration of microvascular endothelial cells by interleukin-1alpha, tumour necrosis factor alpha and interferon gamma. Cytokine 11:134–139

    Article  CAS  PubMed  Google Scholar 

  • Makino Y, Cao R, Svensson K, Bertilsson G, Asman M, Tanaka H, Cao Y, Berkenstam A, Poellinger L (2001) Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 414:550–554

    Article  CAS  PubMed  Google Scholar 

  • Mazure NM, Chen EY, Laderoute KR, Giaccia AJ (1997) Induction of vascular endothelial growth factor by hypoxia is modulated by a phosphatidylinositol 3-kinase/Akt signaling pathway in Ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element. Blood 90:3322–3331

    CAS  PubMed  Google Scholar 

  • Minischetti M, Vacca A, Ribatti D, Iurlaro M, Ria R, Pellegrino A, Gasparini G, Dammacco AF (2000) TNP-470 and recombinant human interferon-alpha2a inhibit angiogenesis synergistically. Br J Haematol 109:829–837

    Article  CAS  PubMed  Google Scholar 

  • Miyoshi C, Ohshima N (2001) Vascular endothelial growth factor (VEGF) expression regulates angiogenesis accompanying tumor growth in a peritoneal disseminated tumor model. In Vivo 15:233–238

    CAS  PubMed  Google Scholar 

  • Mizutani Y, Okada Y, Yoshida O (1997) Expression of platelet-derived endothelial cell growth factor in bladder carcinoma. Cancer 79:1190–1194

    Article  CAS  PubMed  Google Scholar 

  • Molostvov G, Morris A, Rose P, Basu S (2001) Interaction of cytokines and growth factor in the regulation of verotoxin-induced apoptosis in cultured human endothelial cells. Br J Haematol 113:891–897

    Article  CAS  PubMed  Google Scholar 

  • Okabayashi Y, Sugimoto Y, Totty NF, Hsuan J, Kido Y, Sakaguchi K, Gout I, Waterfield MD, Kasuga M (1996) Interaction of Shc with adaptor protein adaptins. J Biol Chem 271:5265–5269

    Article  CAS  PubMed  Google Scholar 

  • Pages G, Milanini J, Richard DE, Berra E, Gothie E, Vinals F, Pouyssegur J (2000) Signaling angiogenesis via p42/p44 MAP kinase cascade. Ann NY Acad Sci 902:187–200

    CAS  PubMed  Google Scholar 

  • Pai R, Szabo IL, Soreghan BA, Atay S, Kawanaka H, Tarnawski AS (2001) PGE(2) stimulates VEGF expression in endothelial cells via ERK2/JNK1 signaling pathways. Biochem Biophys Res Commun 286:923–928

    Article  CAS  PubMed  Google Scholar 

  • Possati L, Rocchetti R, Talevi S, Beatrici V, Margiotta C, Ferrante L, Calza R, Sagrini D, Ferri A (2000) The role of peroxisome proliferator-activated receptor gamma in bladder cancer in relation to angiogenesis and progression. Gen Pharmacol 35:269–275

    CAS  PubMed  Google Scholar 

  • Prigent M, Barlat I, Langen H, Dargemont C (2000) IkappaBalpha and IkappaBalpha /NF-kappa B complexes are retained in the cytoplasm through interaction with a novel partner, RasGAP SH3-binding protein 2. J Biol Chem 275:36441–36449

    Article  CAS  PubMed  Google Scholar 

  • Ravindranath N, Wion D, Brachet P, Djakiew D (2001) Epidermal growth factor modulates the expression of vascular endothelial growth factor in the human prostate. J Androl 22:432–443

    CAS  PubMed  Google Scholar 

  • Riedel F, Gotte K, Bergler W, Rojas W, Hormann K (2000) Expression of basic fibroblast growth factor protein and its downregulation by interferons in head and neck cancer. Head Neck 22:183–189

    Article  CAS  PubMed  Google Scholar 

  • Salven P, Anttonen K, Repo H, Joensuu H, Orpana A (2001) Endotoxins induce and interferon alpha suppresses vascular endothelial growth factor (VEGF) production in human peripheral blood mononuclear cells. FASEB J 15:1318–1320

    CAS  PubMed  Google Scholar 

  • Schena M, Shalon D, Davis RW, Brown PO (1995) Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270:467–470

    CAS  PubMed  Google Scholar 

  • Sidky YA, Borden EC (1987) Inhibition of angiogenesis by interferons: effects on tumor- and lymphocyte-induced vascular responses. Cancer Res 47:5155–5161

    CAS  PubMed  Google Scholar 

  • Slaton JW, Perrotte P, Inoue K, Dinney CP, Fidler IJ (1999) Interferon-alpha-mediated downregulation of angiogenesis-related genes and therapy of bladder cancer are dependent on optimization of biological dose and schedule. Clin Cancer Res 5:2726–2734

    CAS  PubMed  Google Scholar 

  • Stewart RJ, Panigrahy D, Flynn E, Folkman J (2001) Vascular endothelial growth factor expression and tumor angiogenesis are regulated by androgens in hormone responsive human prostate carcinoma: evidence for androgen dependent destabilization of vascular endothelial growth factor transcripts. J Urol 165:688–693

    Article  CAS  PubMed  Google Scholar 

  • Sun FX, Tang ZY, Liu KD, Ye SL, Xue Q, Gao DM, Ma ZC (1996) Establishment of a metastatic model of human hepatocellular carcinoma in nude mice via orthotopic implantation of histologically intact tissue. Int J Cancer 66:239–243

    Article  CAS  PubMed  Google Scholar 

  • Tang XX, Biegel JA, Nycum LM, Yoshioka A, Brodeur GM, Pleasure DE, Ikegaki N (1995) cDNA cloning, molecular characterization, and chromosomal localization of NET(EPHT2), a human EPH-related receptor protein-tyrosine kinase gene preferentially expressed in brain. Genomics 29:426–437

    Article  CAS  PubMed  Google Scholar 

  • Tian J, Tang ZY, Ye SL, Lin ZY, Chen J, Xue Q (1999) New human hepatocellular carcinoma (HCC) cell line with highly metastatic potential (MHCC97) and its expressions of the factors associated with metastasis. Br J Cancer 81:814–821

    Article  CAS  PubMed  Google Scholar 

  • Torcia M, Lucibello M, De Chiara G, Labardi D, Nencioni L, Bonini P, Garaci E, Cozzolino F (1999) Interferon-alpha-induced inhibition of B16 melanoma cell proliferation: interference with the bFGF autocrine growth circuit. Biochem Biophys Res Commun 262:838–844

    Article  CAS  PubMed  Google Scholar 

  • Treins C, Giorgetti-Peraldi S, Murdaca J, Van Obberghen E (2001) Regulation of vascular endothelial growth factor expression by advanced glycation end products. J Biol Chem 276:43836–43841

    Article  CAS  PubMed  Google Scholar 

  • Tsuzuki Y, Fukumura D, Oosthuyse B, Koike C, Carmeliet P, Jain RK (2000) Vascular endothelial growth factor (VEGF) modulation by targeting hypoxia-inducible factor-1alpha-->hypoxia response element-->VEGF cascade differentially regulates vascular response and growth rate in tumors. Cancer Res 60:6248–6252

    CAS  PubMed  Google Scholar 

  • Verheul HM, Pinedo HM (2000) The Role of vascular endothelial growth factor (VEGF) in tumor angiogenesis and early clinical development of VEGF-receptor kinase inhibitors. Clin Breast Cancer 1 [Suppl 1]:S80–84

  • Wang L, Tang ZY, Qin LX, Qin LX, Wu XF, Sun HC, Xue Q, Ye SL (2000) High-dose and long-term therapy with interferon-alfa inhibits tumor growth and recurrence in nude mice bearing human hepatocellular carcinoma xenografts with high metastatic potential. Hepatology 32:43–48

    Article  CAS  PubMed  Google Scholar 

  • Wei LH, Kuo ML, Chen CA, Cheng WF, Cheng SP, Hsieh FJ, Hsieh CY (2001) Interleukin-6 in cervical cancer: the relationship with vascular endothelial growth factor. Gynecol Oncol 82:49–56

    Article  CAS  PubMed  Google Scholar 

  • Xiong S, Grijalva R, Zhang L, Nguyen NT, Pisters PW, Pollock RE, Yu D (2001) Up-regulation of vascular endothelial growth factor in breast cancer cells by the heregulin-beta1-activated p38 signaling pathway enhances endothelial cell migration. Cancer Res 61:1727–1732

    CAS  PubMed  Google Scholar 

  • Xu Y, Yu Q (2001) Angiopoietin-1, unlike angiopoietin-2, is incorporated into the extracellular matrix via its linker peptide region. J Biol Chem 276:34990–34998

    Article  CAS  PubMed  Google Scholar 

  • Yamaoka J, Kabashima K, Kawanishi M, Toda K, Miyachi Y (2002) Cytotoxicity of IFN-gamma and TNF-alpha for vascular endothelial cell is mediated by nitric oxide. Biochem Biophys Res Commun 291:780–786

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Gaspard JP, Chung DC (2001) Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia. Cancer Res 61:6050–6054

    CAS  PubMed  Google Scholar 

  • Zhang L, Conejo-Garcia JR, Yang N, Huang W, Mohamed-Hadley A, Yao W, Benencia F, Coukos G (2002) Different effects of glucose starvation on expression and stability of VEGF mRNA isoforms in murine ovarian cancer cells. Biochem Biophys Res Commun 292:860–868

    Article  CAS  PubMed  Google Scholar 

  • Zhou J, Tang ZY, Fan J, Wu ZQ, Li XM, Liu YK, Liu F, Sun HC, Ye SL (2000) Expression of platelet-derived endothelial cell growth factor and vascular endothelial growth factor in hepatocellular carcinoma and portal vein tumor thrombus. J Cancer Res Clin Oncol 126:57–61

    Article  CAS  PubMed  Google Scholar 

  • Zhou J, Tang ZY, Fan J, Wu ZQ, Ji Y, Xiao YS, Shi YH, Li XM, Sun QM, Liu YK, Ye SL (2003) Capecitabine inhibits postoperative recurrence and metastasis after liver cancer resection in nude mice with relation to the expression of platelet-derived endothelial cell growth factor. Clin Cancer Res 9:6030–6037

    CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Shanghai Biostar Genechip for cDNA micro array service

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Authors and Affiliations

  1. Liver Cancer Institute and Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, 200032, Shanghai, P.R.China

    Wei-Zhong Wu, Hui-Chuan Sun, Yue-Fang Shen, Jie Chen, Lu Wang, Zhao-You Tang & Kang-Da Liu

  2. Institute of Medical Radiation Biology, University of Duisburg-Essen Medical School, Essen, Germany

    Wei-Zhong Wu & George Iliakis

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  1. Wei-Zhong Wu
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  2. Hui-Chuan Sun
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  3. Yue-Fang Shen
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  4. Jie Chen
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  5. Lu Wang
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  6. Zhao-You Tang
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  7. George Iliakis
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  8. Kang-Da Liu
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Correspondence to Kang-Da Liu.

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Supported by the Key Projects for the Clinical Medicine from the Ministry of Public Health of P.R. China (2002–2005): the novel predictive markers and preventive strategies for the recurrence of liver cancer after surgery

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Wu, WZ., Sun, HC., Shen, YF. et al. Interferon alpha 2a downregulates VEGF expression through PI3 kinase and MAP kinase signaling pathways. J Cancer Res Clin Oncol 131, 169–178 (2005). https://doi.org/10.1007/s00432-004-0615-2

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  • DOI: https://doi.org/10.1007/s00432-004-0615-2

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