Home LiteratureArticle Details
PMID: 20307196 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

p16 Modulates VEGF expression via its interaction with HIF-1alpha in breast cancer cells.

Cancer investigation ·Vol. 28 ·No. 6 ·2010-07-00 ·Pages 588-97

Zhang J, Lu A, Li L, Yue J, Lu Y

Abstract

The degree of tumor progression (such as growth, angiogenesis, and metastasis) directly correlates with the expression of vascular endothelial growth factor (VEGF), but inversely correlates with the expression of tumor-suppressor gene p16, therefore we examined whether the restoration of p16 in breast cancer cells would modulate VEGF expression. Adenoviral-mediated p16 expression downregulated VEGF gene expression in breast cancer cells, and inhibited breast cancer cell-induced angiogenesis by a dorsal air sac model in mice. Moreover, p16 appears to form a complex with HIF-1a, the transcription factor for the VEGF gene promoter. Taken together, the binding between p16 and HIF-1a protein may alter HIF-1a's ability to transactivate VEGF expression.

MeSH Terms
Adenoviridae/genetics Animals Binding Sites Breast Neoplasms/blood supply,genetics,metabolism,pathology Cell Line, Tumor Cyclin-Dependent Kinase Inhibitor p16/genetics,metabolism Down-Regulation Female Gene Expression Regulation, Neoplastic Genetic Vectors Humans Hypoxia-Inducible Factor 1, alpha Subunit/genetics,metabolism Mice Mice, Nude Neovascularization, Pathologic/genetics,metabolism,prevention & control Promoter Regions, Genetic Transcriptional Activation Transfection Vascular Endothelial Growth Factor A/genetics,metabolism
Chemicals
Cyclin-Dependent Kinase Inhibitor p16 HIF1A protein, human Hypoxia-Inducible Factor 1, alpha Subunit VEGFA protein, human Vascular Endothelial Growth Factor A
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Zhang Jun
Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
Lu Andrew
Li Liyuan
Yue Junming
Lu Yi
References (42)
42 references, click to expand
  1. Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma.
    J Natl Cancer Inst. 1997 Jan 15;89(2):139-47 PMID: 8998183
  2. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.
    Cell. 1996 Aug 9;86(3):353-64 PMID: 8756718
  3. Induction of vascular endothelial tubular morphogenesis by human glioma cells. A model system for tumor angiogenesis.
    J Clin Invest. 1993 Jul;92(1):54-61 PMID: 7686924
  4. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid.
    Science. 1983 Feb 25;219(4587):983-5 PMID: 6823562
  5. p16INK4A as a human tumor suppressor.
    Biochim Biophys Acta. 1996 Mar 18;1242(3):165-9 PMID: 8603068
  6. Acute hypoxia enhances spontaneous lymph node metastasis in an orthotopic murine model of human cervical carcinoma.
    Cancer Res. 2004 Mar 15;64(6):2054-61 PMID: 15026343
  7. Hypoxia and hypoxia-inducible factor-1 expression enhance osteolytic bone metastases of breast cancer.
    Cancer Res. 2007 May 1;67(9):4157-63 PMID: 17483326
  8. Adenovirus-mediated wild-type p53 gene transfer down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human colon cancer.
    Cancer Res. 1998 Jun 1;58(11):2288-92 PMID: 9622060
  9. Induction of cyclin-dependent kinase inhibitors and G(1) prolongation by the chemopreventive agent N-acetylcysteine.
    Carcinogenesis. 1999 Sep;20(9):1869-72 PMID: 10469636
  10. Targeting HIF-1 for cancer therapy.
    Nat Rev Cancer. 2003 Oct;3(10):721-32 PMID: 13130303
  11. Delivery of adenoviral vectors to the prostate for gene therapy.
    Cancer Gene Ther. 1999 Jan-Feb;6(1):64-72 PMID: 10078965
  12. The transcription factors HIF-1 and HNF-4 and the coactivator p300 are involved in insulin-regulated glucokinase gene expression via the phosphatidylinositol 3-kinase/protein kinase B pathway.
    J Biol Chem. 2004 Jan 23;279(4):2623-31 PMID: 14612449
  13. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.
    Mol Cell Biol. 1996 Sep;16(9):4604-13 PMID: 8756616
  14. What, if anything, is an angiogenic factor?
    Cancer Metastasis Rev. 1996 Jun;15(2):149-51 PMID: 8842485
  15. Hypoxia, gene expression, and metastasis.
    Cancer Metastasis Rev. 2007 Jun;26(2):333-9 PMID: 17458506
  16. Vascular endothelial growth factor (VEGF) and its receptors.
    FASEB J. 1999 Jan;13(1):9-22 PMID: 9872925
  17. RB2/p130 gene-enhanced expression down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in vivo.
    Cancer Res. 2001 Jan 15;61(2):462-8 PMID: 11212232
  18. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells.
    Biochem Biophys Res Commun. 1989 Jun 15;161(2):851-8 PMID: 2735925
  19. YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1.
    J Natl Cancer Inst. 2003 Apr 2;95(7):516-25 PMID: 12671019
  20. Angiogenic growth factors in preinvasive breast disease.
    Clin Cancer Res. 1999 Oct;5(10):2867-76 PMID: 10537355
  21. Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function.
    Cancer Res. 1999 Apr 1;59(7):1592-8 PMID: 10197634
  22. Manipulation of adenovirus vectors.
    Methods Mol Biol. 1991;7:109-28 PMID: 21416352
  23. Vascular endothelial growth factor (VEGF) in human breast cancer: correlation with disease-free survival.
    Int J Cancer. 1997 Aug 22;74(4):455-8 PMID: 9291439
  24. Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis.
    Curr Top Microbiol Immunol. 1999;237:97-132 PMID: 9893348
  25. Hypoxia-driven selection of the metastatic phenotype.
    Cancer Metastasis Rev. 2007 Jun;26(2):319-31 PMID: 17458507
  26. The p14ARF tumor suppressor protein facilitates nucleolar sequestration of hypoxia-inducible factor-1alpha (HIF-1alpha ) and inhibits HIF-1-mediated transcription.
    J Biol Chem. 2001 Jul 27;276(30):28421-9 PMID: 11382768
  27. Hydroxylation of HIF-1: oxygen sensing at the molecular level.
    Physiology (Bethesda). 2004 Aug;19:176-82 PMID: 15304631
  28. Frequency of homozygous deletion at p16/CDKN2 in primary human tumours.
    Nat Genet. 1995 Oct;11(2):210-2 PMID: 7550353
  29. Expression of vascular endothelial growth factor, its receptor, and other angiogenic factors in human breast cancer.
    Cancer Res. 1996 May 1;56(9):2013-6 PMID: 8616842
  30. Quantitative relationships of intravascular tumor cells, tumor vessels, and pulmonary metastases following tumor implantation.
    Cancer Res. 1974 May;34(5):997-1004 PMID: 4841969
  31. Angiostatin induces and sustains dormancy of human primary tumors in mice.
    Nat Med. 1996 Jun;2(6):689-92 PMID: 8640562
  32. Association of p53, p16, and vascular endothelial growth factor protein expressions with the prognosis and metastasis of gallbladder cancer.
    J Am Coll Surg. 2001 Oct;193(4):380-3 PMID: 11584965
  33. The hypoxic tumour microenvironment and metastatic progression.
    Clin Exp Metastasis. 2003;20(3):237-50 PMID: 12741682
  34. Expression of vascular endothelial growth factor induces an invasive phenotype in human squamous cell carcinomas.
    Am J Pathol. 2000 Jan;156(1):159-67 PMID: 10623663
  35. Adenoviral vector containing wild-type p16 suppresses prostate cancer growth and prolongs survival by inducing cell senescence.
    Cancer Gene Ther. 2000 Mar;7(3):360-72 PMID: 10766342
  36. 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF.
    Cancer Cell. 2003 Apr;3(4):363-75 PMID: 12726862
  37. Restoration of wild-type p16 down-regulates vascular endothelial growth factor expression and inhibits angiogenesis in human gliomas.
    Cancer Res. 1999 Aug 1;59(15):3783-9 PMID: 10446996
  38. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects.
    J Natl Cancer Inst. 2001 Feb 21;93(4):266-76 PMID: 11181773
  39. Hypoxia-inducible factor-1alpha is a key regulator of metastasis in a transgenic model of cancer initiation and progression.
    Cancer Res. 2007 Jan 15;67(2):563-72 PMID: 17234764
  40. Site-directed mutagenesis studies of the hypoxia-inducible factor-1alpha DNA-binding domain.
    Biochim Biophys Acta. 2002 Oct 11;1578(1-3):73-83 PMID: 12393189
  41. Benign-to-malignant B16 melanoma progression induced in two stages in vitro by exposure to hypoxia.
    J Natl Cancer Inst. 1994 Mar 2;86(5):361-7 PMID: 8308928
  42. The role of hypoxia-inducible factors in cancer.
    Cell Mol Life Sci. 2007 Aug;64(16):2170-80 PMID: 17514355
Article Info
Journal
Cancer investigation
Abbr.
Cancer Invest
ISSN
1532-4192
DOI
10.3109/07357900903286941
Published
2010-07-00
Pages
588-97
Language
English
Region
England
NLM ID
8307154
PMCID
PMC2881182
Subset
IM
Grants
NCI NIH HHS · R01 CA107162 · United States
NCI NIH HHS · R01 CA107162-03 · United States
NCI NIH HHS · R01 CA107162-04 · United States
NCI NIH HHS · CA107162 · United States
External Links
PubMed source DOI: 10.3109/07357900903286941 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2