Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Loss of AP-2α results in deregulation of E-cadherin and MMP-9 and an increase in tumorigenicity of colon cancer cells in vivo

Oncogene volume 26, pages 4049–4058 (2007)Cite this article

Abstract

Activator protein-2 (AP-2) is a transcription factor that regulates proliferation and differentiation in mammalian cells and has been implicated in the acquisition of the metastatic phenotype in several types of cancer. Herein, we examine the role of AP-2α in colon cancer progression. We provide evidence for the lack of AP-2α expression in the late stages of colon cancer cells. Re-expression of the AP-2α gene in the AP-2α-negative SW480 colon cancer cells suppressed their tumorigenicity following orthotopic injection into the cecal wall of nude mice. The inhibition of tumor growth could be attributed to the increased expression of E-cadherin and decreased expression and activity of matrix-metalloproteinase-9 (MMP-9) in the transfected cells, as well as a substantial loss of their in vitro invasive properties. Conversely, targeting constitutive expression of AP-2α in AP-2-positive KM12C colon cancer cells with small interfering RNA resulted in an increase in their invasive potential, downregulation of E-cadherin and increased expression of MMP-9. In SW480 cells, re-expression of AP-2α resulted in a fourfold increase in the activity of E-cadherin promoter, and a 5–14-fold decrease in the activity of MMP-9 promoter, indicating transcriptional regulation of these genes by AP-2α. Chromatin immunoprecipitation assay showed that re-expressed AP-2α directly binds to the promoter of E-cadherin, where it has been previously reported to act as a transcriptional activator. Furthermore, chromatin immunoprecipitation assay revealed AP-2α binding to the MMP-9 promoter, which ensued by decreased binding of transcription factor Sp-1 and changes in the recruitment of transcription factors to a distal AP-1 element, thus, contributing to the overall downregulation of MMP-9 promoter activity. Collectively, our data provide evidence that AP-2α acts as a tumor suppressor gene in colon cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

Abbreviations

AP-2α:

activator protein-2α

EMSA:

electrophoretic mobility shift assay

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

MMP-9:

metalloproteinase-9

ChIP:

chromatin immunoprecipitation

References

  • Bar-Eli M . (2001). Gene regulation in melanoma progression by the AP-2 transcription factor. Pigment Cell Res 14: 78–85.

    Article  CAS  PubMed  Google Scholar 

  • Batsche E, Muchardt C, Behrens J, Hurst HC, Cremisi C . (1998). RB and c-Myc activate expression of the E-cadherin gene in epithelial cells through interaction with transcription factor AP-2. Mol Cell Biol 18: 3647–3658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boedefeld II WM, Bland KI, Heslin MJ . (2003). Recent insights into angiogenesis, apoptosis, invasion, and metastasis in colorectal carcinoma. Ann Surg Oncol 10: 839–851.

    Article  PubMed  Google Scholar 

  • Bosher JM, Totty NF, Hsuan JJ, Williams T, Hurst HC . (1996). A family of AP-2 proteins regulates c-erbB-2 expression in mammary carcinoma. Oncogene 13: 1701–1707.

    CAS  PubMed  Google Scholar 

  • Comijin J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E et al. (2001). The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell 7: 1267–1278.

    Article  Google Scholar 

  • Gershenwald JE, Summer W, Calderon T, Wang Z, Huang S, Bar-Eli M . (2001). Dominant-negative transcription factor AP-2 augments SB-2 melanoma tumor growth in vivo. Oncogene 20: 3363–3375.

    Article  CAS  PubMed  Google Scholar 

  • Gum R, Lengyel E, Juarez J, Chen JH, Sato H, Seiki M et al. (1996). Stimulation of 92-kDa gelatinase B promoter activity by ras is mitogen-activated protein kinase kinase 1-independent and requires multiple transcription factor binding sites including closely spaced PEA3/ets and AP-1 sequences. J Biol Chem 271: 10672–10680.

    Article  CAS  PubMed  Google Scholar 

  • Hilger-Eversheim K, Moser M, Schorle H, Buettner R . (2000). Regulatory roles of AP-2 transcription factors in vertebrate development, apoptosis and cell-cycle control. Gene 260: 1–12.

    Article  CAS  PubMed  Google Scholar 

  • Ho AT, Voura EB, Soloway PD, Watson KL, Khokha R . (2001). MMP inhibitors augment fibroblast adhesion through stabilization of focal adhesion contacts and up-regulation of cadherin function. J Biol Chem 276: 40215–40224.

    Article  CAS  PubMed  Google Scholar 

  • Huang S, Jean D, Luca M, Tainsky MA, Bar-Eli M . (1998). Loss of AP-2 results in downregulation of c-KIT and enhancement of melanoma tumorigenicity and metastasis. EMBO J 17: 4358–4369.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang S, Mills L, Mian B, Tellez C, McCarty M, Yang XD et al. (2002). Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am J Pathol 161: 125–134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jean D, Gershenwald JE, Huang S, Luca M, Hudson MJ, Tainsky MA et al. (1988). Loss of AP-2 results in up-regulation of MCAM/MUC18 and an increase in tumor growth and metastasis of human melanoma cells. J Biol Chem 273: 16501–16508.

    Article  Google Scholar 

  • Karjalainen JM, Kellokoski JK, Eskelinen MJ, Alhava EM, Kosma VM . (1998). Downregulation of transcription factor AP-2 predicts poor survival in stage I cutaneous malignant melanoma. J Clin Oncol 16: 3584–3591.

    Article  CAS  PubMed  Google Scholar 

  • Melnikova VO, Mourad-Zeidan AA, Lev DC, Bar-Eli M . (2006). Platelet-activating factor mediates MMP-2 expression and activation via phosphorylation of cAMP-response element-binding protein and contributes to melanoma metastasis. J Biol Chem 281: 2911–2922.

    Article  CAS  PubMed  Google Scholar 

  • Mitchell PJ, Timmons PM, Hebert JM, Rigby PW, Tjian R . (1991). Transcription factor AP-2 is expressed in neural crest cell lineages during mouse embryogenesis. Genes Dev 5: 105–119.

    Article  CAS  PubMed  Google Scholar 

  • Morikawa K, Walker SM, Nokajima M, Pathak S, Jessup JM, Fidler IJ . (1998). In vivo selection of highly metastatic cells from surgical specimens of different primary human colon carcinomas implanted into nude mice. Cancer Res 48: 6863–6871.

    Google Scholar 

  • Moser M, Imhof A, Pscherer A, Bauer R, Amselgruber W, Sinowatz F et al. (1995). Cloning and characterization of a second AP-2 transcription factor: AP-2 beta. Development 121: 2779–2788.

    CAS  PubMed  Google Scholar 

  • Pellikainen J, Naukkarinen A, Ropponen K, Rummukainen J, Kataja V, Kellokoski J et al. (2004). Expression of HER2 and its association with AP-2 in breast cancer. Eur J Cancer 40: 1485–1495.

    Article  CAS  PubMed  Google Scholar 

  • Pellikainen MJ, Pekola TT, Ropponen KM, Kataja VV, Kellokoski JK, Eskelinen MJ et al. (2003). p21WAF1 expression in invasive breast cancer and its association with p53, AP-2, cell proliferation, and prognosis. J Clin Pathol 56: 214–220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ropponen KM, Kellokoski JK, Lipponen PK, Pietilainen T, Eskelinen MJ, Alhava EM et al. (1999). p21/WAF1 expression in human colorectal carcinoma: association with p53, transcription factor AP-2 and prognosis. Br J Cancer 81: 133–140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ropponen KM, Kellokoski JK, Pirinen RT, Moisio KI, Eskelinen MJ, Alhava EM et al. (2001). Expression of transcription factor AP-2 in colorectal adenomas and adenocarcinomas; comparison of immunohistochemistry and in situ hybridisation. J Clin Pathol 54: 533–538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rozen P . (2004). Cancer of the gastrointestinal tract: early detection or early prevention? Eur J Cancer Prev 13: 71–75.

    Article  CAS  PubMed  Google Scholar 

  • Ruiz M, Pettaway C, Song R, Stoeltzing O, Ellis L, Bar-Eli M . (2004). Activator protein 2alpha inhibits tumorigenicity and represses vascular endothelial growth factor transcription in prostate cancer cells. Cancer Res 4: 631–638.

    Article  Google Scholar 

  • Sato H, Seiki M . (1993). Regulatory mechanism of 92 kDa type IV collagenase gene expression which is associated with invasiveness of tumor cells. Oncogene 8: 395–405.

    CAS  PubMed  Google Scholar 

  • Sumigama S, Ito T, Kajiyama H, Shibata K, Tamakoshi K, Kikkawa F et al. (2004). Suppression of invasion and peritoneal carcinomatosis of ovarian cancer cells by overexpression of AP-2alpha. Oncogene 23: 5496–5504.

    Article  CAS  PubMed  Google Scholar 

  • Tellez C, Bar-Eli M . (2003). Role and regulation of the thrombin receptor (PAR-1) in human melanoma. Oncogene 22: 3130–3137.

    Article  CAS  PubMed  Google Scholar 

  • Tellez C, McCarty M, Ruiz M, Bar-Eli M . (2003). Loss of activator protein-2alpha results in overexpression of protease-activated receptor-1 and correlates with the malignant phenotype of human melanoma. J Biol Chem 21: 46632–46642.

    Article  Google Scholar 

  • Tummala R, Romano RA, Fuchs E, Sinha S . (2003). Molecular cloning and characterization of AP-2 epsilon, a fifth member of the AP-2 family. Gene 321: 93–102.

    Article  CAS  PubMed  Google Scholar 

  • Vainio H, Miller AB . (2003). Primary and secondary prevention in colorectal cancer. Acta Oncol 42: 809–815.

    Article  PubMed  Google Scholar 

  • Wajapeyee N, Somasundaram K . (2003). Cell cycle arrest and apoptosis induction by activator protein 2α (AP-2α) and the role of p53 and p21WAF1/CIP1 in AP-2a-mediated growth inhibition. J Biol Chem 52: 52093–52101.

    Article  Google Scholar 

  • West-Mays JA, Sivak JM, Papagiotas SS, Kim J, Nottoli T, Williams T et al. (2003). Positive influence of AP-2alpha transcription factor on cadherin gene expression and differentiation of the ocular surface. Differentiation 71: 206–216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Williams T, Admon A, Luscher B, Tjian R . (1988). Cloning and expression of AP-2, a cell-type-specific transcription factor that activates inducible enhancer elements. Genes Dev 2: 1557–1569.

    Article  CAS  PubMed  Google Scholar 

  • Yan C, Wang H, Aggarwal BB, Boyd DD . (2004). A novel homologous recombination system to study 92 kDa type IV collagenase transcription demonstrates that the NF-kappaB motif drives the transition from a repressed to an activated state of gene expression. FASEB J 18: 540–551.

    Article  CAS  PubMed  Google Scholar 

  • Zeng YX, Somasundaram K, El-Deiry WS . (1997). AP2 inhibits cancer cell growth and activates p21WAF1/CIP1 expression. Nat Genet 15: 78–82.

    Article  CAS  PubMed  Google Scholar 

  • Zhao F, Satoda M, Licht JD, Hayashizaki Y, Gelb BD . (2001). Cloning and characterization of a novel mouse AP-2 transcription factor, AP-2delta, with unique DNA binding and transactivation properties. J Biol Chem 276: 40755–40760.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by National Institutes of Health grant CA-76098.

Author information

Author notes

  1. B Schwartz and V O Melnikova: These authors contributed equally to this work.

  2. B Schwartz: B Schwartz was on a sabbatical leave from The Institute of Biochemistry, The Hebrew University of Jerusalem, Rehovot 76100, Israel.

Authors and Affiliations

  1. Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    B Schwartz, V O Melnikova, C Tellez, A Mourad-Zeidan, K Blehm, Y-J Zhao, M McCarty, L Adam & M Bar-Eli

Authors
  1. B Schwartz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V O Melnikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Tellez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Mourad-Zeidan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Blehm
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y-J Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M McCarty
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L Adam
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Bar-Eli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Bar-Eli.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schwartz, B., Melnikova, V., Tellez, C. et al. Loss of AP-2α results in deregulation of E-cadherin and MMP-9 and an increase in tumorigenicity of colon cancer cells in vivo. Oncogene 26, 4049–4058 (2007). https://doi.org/10.1038/sj.onc.1210193

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210193

Keywords

This article is cited by

Search

Advanced search

Quick links