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.

  • Original Article
  • Published:

The immediate early gene Ier2 promotes tumor cell motility and metastasis, and predicts poor survival of colorectal cancer patients

Oncogene volume 31, pages 3796–3806 (2012)Cite this article

Subjects

Abstract

Here, we report unbiased screens for genes expressed in metastatic tumor cells that are associated with cell motility. These screens identified Ier2, an immediate early gene of unknown function, as potentially having a role in tumor cell motility and metastasis. Knockdown of Ier2 in 3T3 fibroblasts inhibited their motility upon relief of contact inhibition in monolayer wounding assays. Furthermore, ectopic Ier2 expression promoted the motility and invasiveness of poorly metastatic 1AS pancreatic tumor cells in vitro. Relief of contact inhibition was associated with translocation of the Ier2 protein from the cytoplasm to the nucleus in both 3T3 fibroblasts and 1AS tumor cells. Importantly, ectopic Ier2 expression in 1AS cells stimulated metastasis formation when cells were implanted into experimental animals. Furthermore, we found elevated Ier2 expression in a wide variety of human tumor types. This correlated with poor metastasis-free and overall survival in patients with colorectal adenocarcinomas. Together, these data reveal Ier2 as a new player in the regulation of tumor progression and metastasis, and suggest that Ier2 may be useful prognostically and therapeutically in the management of 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

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  • Aggarwal BB . (2004). Nuclear factor-kappaB: the enemy within. Cancer Cell 6: 203–208.

    Article  CAS  Google Scholar 

  • Baumann P, Cremers N, Kroese F, Orend G, Chiquet-Ehrismann R, Uede T et al. (2005). CD24 expression causes the acquisition of multiple cellular properties associated with tumor growth and metastasis. Cancer Res 65: 10783–10793.

    Article  CAS  Google Scholar 

  • Bradley LM . (2003). Migration and T-lymphocyte effector function. Curr Opin Immunol 15: 343–348.

    Article  CAS  Google Scholar 

  • Charles CH, Simske JS, O'Brien TP, Lau LF . (1990). Pip92: a short-lived, growth factor-inducible protein in BALB/c 3T3 and PC12 cells. Mol Cell Biol 10: 6769–6774.

    Article  CAS  Google Scholar 

  • Chen L, Ma S, Li B, Fink T, Zachar V, Takahashi M et al. (2003). Transcriptional activation of immediate-early gene ETR101 by human T-cell leukaemia virus type I Tax. J Gen Virol 84: 3203–3214.

    Article  CAS  Google Scholar 

  • Chiou CC, Chan CC, Sheu DL, Chen KT, Li YS, Chan EC . (2001). Helicobacter pylori infection induced alteration of gene expression in human gastric cells. Gut 48: 598–604.

    Article  CAS  Google Scholar 

  • Chung KC, Gomes I, Wang D, Lau LF, Rosner MR . (1998). Raf and fibroblast growth factor phosphorylate Elk1 and activate the serum response element of the immediate early gene pip92 by mitogen-activated protein kinase-independent as well as -dependent signaling pathways. Mol Cell Biol 18: 2272–2281.

    Article  CAS  Google Scholar 

  • Chung KC, Kim SM, Rhang S, Lau LF, Gomes I, Ahn YS . (2000a). Expression of immediate early gene pip92 during anisomycin-induced cell death is mediated by the JNK- and p38-dependent activation of Elk1. Eur J Biochem 267: 4676–4684.

    Article  CAS  Google Scholar 

  • Chung KC, Shin SW, Yoo M, Lee MY, Lee HW, Choe BK et al. (2000b). A systemic administration of NMDA induces immediate early gene pip92 in the hippocampus. J Neurochem 75: 9–17.

    Article  CAS  Google Scholar 

  • Coleclough C, Kuhn L, Lefkovits I . (1990). Regulation of mRNA abundance in activated T lymphocytes: identification of mRNA species affected by the inhibition of protein synthesis. Proc Natl Acad Sci USA 87: 1753–1757.

    Article  CAS  Google Scholar 

  • Eschelbach A, Hunziker A, Klimaschewski L . (1998). Differential display PCR reveals induction of immediate early genes by vasoactive intestinal peptide in PC12 cells. Ann N Y Acad Sci 865: 181–188.

    Article  CAS  Google Scholar 

  • Fambrough D, McClure K, Kazlauskas A, Lander ES . (1999). Diverse signaling pathways activated by growth factor receptors induce broadly overlapping, rather than independent, sets of genes. Cell 97: 727–741.

    Article  CAS  Google Scholar 

  • French PJ, Swagemakers SM, Nagel JH, Kouwenhoven MC, Brouwer E, van der Spek P et al. (2005). Gene expression profiles associated with treatment response in oligodendrogliomas. Cancer Res 65: 11335–11344.

    Article  CAS  Google Scholar 

  • Gutmann DH, Hedrick NM, Li J, Nagarajan R, Perry A, Watson MA . (2002). Comparative gene expression profile analysis of neurofibromatosis 1-associated and sporadic pilocytic astrocytomas. Cancer Res 62: 2085–2091.

    CAS  PubMed  Google Scholar 

  • Harlow E, Lane D . (1988). Antibodies: a Laboratory Manual. Cold Spring Harbor Press: Cold Spring Harbor.

    Google Scholar 

  • Herrlich P, Zoller M, Pals ST, Ponta H . (1993). CD44 splice variants: metastases meet lymphocytes. Immunol Today 14: 395–399.

    Article  CAS  Google Scholar 

  • Hippo Y, Taniguchi H, Tsutsumi S, Machida N, Chong JM, Fukayama M et al. (2002). Global gene expression analysis of gastric cancer by oligonucleotide microarrays. Cancer Res 62: 233–240.

    CAS  PubMed  Google Scholar 

  • Hofmann M, Fieber C, Assmann V, Gottlicher M, Sleeman J, Plug R et al. (1998). Identification of IHABP, a 95 kDa intracellular hyaluronate binding protein. J Cell Sci 111 ( Pt 12): 1673–1684.

    CAS  Google Scholar 

  • Hong SK, Dawid IB . (2009). FGF-dependent left-right asymmetry patterning in zebrafish is mediated by Ier2 and Fibp1. Proc Natl Acad Sci USA 106: 2230–2235.

    Article  CAS  Google Scholar 

  • Keeton AB, Amsler MO, Venable DY, Messina JL . (2002). Insulin signal transduction pathways and insulin-induced gene expression. J Biol Chem 277: 48565–48573.

    Article  CAS  Google Scholar 

  • Lau LF, Nathans D . (1985). Identification of a set of genes expressed during the G0/G1 transition of cultured mouse cells. EMBO J 4: 3145–3151.

    Article  CAS  Google Scholar 

  • Li W, Fan J, Chen M, Guan S, Sawcer D, Bokoch GM et al. (2004). Mechanism of human dermal fibroblast migration driven by type I collagen and platelet-derived growth factor-BB. Mol Biol Cell 15: 294–309.

    Article  CAS  Google Scholar 

  • Mengwasser J, Piau A, Schlag P, Sleeman JP . (2004). Differential immunization identifies PHB1/PHB2 as blood-borne tumor antigens. Oncogene 23: 7430–7435.

    Article  CAS  Google Scholar 

  • Milde-Langosch K . (2005). The Fos family of transcription factors and their role in tumourigenesis. Eur J Cancer 41: 2449–2461.

    Article  CAS  Google Scholar 

  • Nestl A, Von Stein OD, Zatloukal K, Thies WG, Herrlich P, Hofmann M et al. (2001). Gene expression patterns associated with the metastatic phenotype in rodent and human tumors. Cancer Res 61: 1569–1577.

    CAS  Google Scholar 

  • Niebuhr K, Lingnau A, Frank R, Wehland J . (1998). Rapid procedures for preparing monoclonal antibodies and identifying their epitopes. In: Celis J (ed). Cell biology: a laboratory handbook, 2nd edn. Academic Press: San Diego, pp 398–403.

  • Rollins BJ, Stiles CD . (1989). Serum-inducible genes. Adv Cancer Res 53: 1–32.

    Article  CAS  Google Scholar 

  • Schneider A, Fischer A, Weber D, von Ahsen O, Scheek S, Kruger C et al. (2004). Restriction-mediated differential display (RMDD) identifies pip92 as a pro-apoptotic gene product induced during focal cerebral ischemia. J Cereb Blood Flow Metab 24: 224–236.

    Article  CAS  Google Scholar 

  • Scott JL, Dunn SM, Zeng T, Baker E, Sutherland GR, Burns GF . (1994). Phorbol ester-induced transcription of an immediate-early response gene by human T cells is inhibited by co-treatment with calcium ionophore. J Cell Biochem 54: 135–144.

    Article  CAS  Google Scholar 

  • Shimizu N, Ohta M, Fujiwara C, Sagara J, Mochizuki N, Oda T et al. (1991). Expression of a novel immediate early gene during 12-O-tetradecanoylphorbol-13-acetate-induced macrophagic differentiation of HL-60 cells. J Biol Chem 266: 12157–12161.

    CAS  PubMed  Google Scholar 

  • Skotheim RI, Lind GE, Monni O, Nesland JM, Abeler VM, Fossa SD et al. (2005). Differentiation of human embryonal carcinomas in vitro and in vivo reveals expression profiles relevant to normal development. Cancer Res 65: 5588–5598.

    Article  CAS  Google Scholar 

  • Sleeman JP, Nazarenko I, Thiele W . (2011). Do all roads lead to Rome? Routes to metastasis development. Int J Cancer 128: 2511–2526.

    Article  CAS  Google Scholar 

  • Smith DB, Johnson KS . (1988). Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase. Gene 67: 31–40.

    Article  CAS  Google Scholar 

  • Stein U, Jurchott K, Schlafke M, Hohenberger P . (2002). Expression of multidrug resistance genes MVP, MDR1, and MRP1 determined sequentially before, during, and after hyperthermic isolated limb perfusion of soft tissue sarcoma and melanoma patients. J Clin Oncol 20: 3282–3292.

    Article  CAS  Google Scholar 

  • Takaya T, Kasatani K, Noguchi S, Nikawa J . (2009). Functional analyses of immediate early gene ETR101 expressed in yeast. Biosci Biotechnol Biochem 73: 1653–1660.

    Article  CAS  Google Scholar 

  • Wallbaum S, Grau N, Schmid A, Frick K, Neeb A, Sleeman JP . (2009). Cell cycle quiescence can suppress transcription from an ecdysone receptor-based inducible promoter in mammalian cells. Biotechniques 46: 433–440.

    Article  CAS  Google Scholar 

  • Yu YP, Landsittel D, Jing L, Nelson J, Ren B, Liu L et al. (2004). Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. J Clin Oncol 22: 2790–2799.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are very grateful to Norma Howells, Selma Huber and Manuela Sauer for their assistance with the animal experiments, to Anja Steffen for expert technical support and to Wilko Thiele for critical reading of this manuscript. The contribution of Franziska Arlt and Markus Niederstrasser is also gratefully acknowledged. This work was supported by grants to JPS and US from the BMBF NGFN2 CancerNet Programme and to JPS from the European Union (FP6 STREP project BRECOSM, contract no. LSHC-CT-2004-503224 and FP7 Collaborative Project TuMIC, contract no. HEALTH-F2-2008-201662).

Author information

Author notes

  1. A Neeb, S Wallbaum and N Novac: These authors contributed equally to this work.

Authors and Affiliations

  1. Karlsruhe Institute of Technology, Institut für Toxikologie und Genetik, Karlsruhe, Germany

    A Neeb, S Wallbaum, N Novac, S Dukovic-Schulze, I Scholl, C Schreiber, J Moll & J P Sleeman

  2. Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

    S Dukovic-Schulze, C Schreiber & J P Sleeman

  3. Charité Comprehensive Cancer Center, Invalidenstraße 80, Berlin, Germany,

    P Schlag

  4. Experimental and Clinical Research Center, Charité University Medicine Berlin at the Max-Delbrück-Center for Molecular Medicine, Berlin, Germany

    U Stein

Authors
  1. A Neeb
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Wallbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N Novac
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Dukovic-Schulze
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. I Scholl
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Schreiber
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. P Schlag
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J Moll
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. U Stein
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J P Sleeman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J P Sleeman.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Neeb, A., Wallbaum, S., Novac, N. et al. The immediate early gene Ier2 promotes tumor cell motility and metastasis, and predicts poor survival of colorectal cancer patients. Oncogene 31, 3796–3806 (2012). https://doi.org/10.1038/onc.2011.535

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.535

Keywords

This article is cited by

Search

Advanced search

Quick links