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:

ILEI requires oncogenic Ras for the epithelial to mesenchymal transition of hepatocytes and liver carcinoma progression

Oncogene volume 28, pages 638–650 (2009)Cite this article

Abstract

In human hepatocellular carcinoma (HCC), epithelial to mesenchymal transition (EMT) correlates with aggressiveness of tumors and poor survival. We employed a model of EMT based on immortalized p19ARF null hepatocytes (MIM), which display tumor growth upon expression of oncogenic Ras and undergo EMT through the synergism of Ras and transforming growth factor (TGF)-β. Here, we show that the interleukin-related protein interleukin-like EMT inducer (ILEI), a novel EMT-, tumor- and metastasis-inducing protein, cooperates with oncogenic Ras to cause TGF-β-independent EMT. Ras-transformed MIM hepatocytes overexpressing ILEI showed cytoplasmic E-cadherin, loss of ZO-1 and induction of α-smooth muscle actin as well as platelet-derived growth factor (PDGF)/PDGF-R isoforms. As shown by dominant-negative PDGF-R expression in these cells, ILEI-induced PDGF signaling was required for enhanced cell migration, nuclear accumulation of β-catenin, nuclear pY-Stat3 and accelerated growth of lung metastases. In MIM hepatocytes expressing the Ras mutant V12-C40, ILEI collaborated with PI3K signaling resulting in tumor formation without EMT. Clinically, human HCC samples showed granular or cytoplasmic localization of ILEI correlating with well and poorly differentiated tumors, respectively. In conclusion, these data indicate that ILEI requires cooperation with oncogenic Ras to govern hepatocellular EMT through mechanisms involving PDGF-R/β-catenin and PDGF-R/Stat3 signaling.

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

References

  • Breuhahn K, Longerich T, Schirmacher P . (2006). Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene 25: 3787–3800.

    Article  CAS  PubMed  Google Scholar 

  • Bruix J, Boix L, Sala M, Llovet JM . (2004). Focus on hepatocellular carcinoma. Cancer Cell 5: 215–219.

    Article  CAS  PubMed  Google Scholar 

  • Calvisi DF, Ladu S, Gorden A, Farina M, Conner EA, Lee JS et al. (2006). Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 130: 1117–1128.

    Article  CAS  PubMed  Google Scholar 

  • Campbell JS, Hughes SD, Gilbertson DG, Palmer TE, Holdren MS, Haran AC et al. (2005). Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc Natl Acad Sci USA 102: 3389–3394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Campbell JS, Johnson MM, Bauer RL, Hudkins KL, Gilbertson DG, Riehle KJ et al. (2007). Targeting stromal cells for the treatment of platelet-derived growth factor C-induced hepatocellular carcinogenesis. Differentiation 75: 843–852.

    Article  CAS  PubMed  Google Scholar 

  • Edmondson HA, Steiner PE . (1954). Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies. Cancer 7: 462–503.

    Article  CAS  PubMed  Google Scholar 

  • Eger A, Aigner K, Sonderegger S, Dampier B, Oehler S, Schreiber M et al. (2005). DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene 24: 2375–2385.

    Article  CAS  PubMed  Google Scholar 

  • El-Serag HB, Rudolph KL . (2007). Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132: 2557–2776.

    Article  CAS  PubMed  Google Scholar 

  • Fischer AN, Fuchs E, Mikula M, Huber H, Beug H, Mikulits W . (2007). PDGF essentially links TGF-beta signaling to nuclear beta-catenin accumulation in hepatocellular carcinoma progression. Oncogene 26: 3395–3405.

    Article  CAS  PubMed  Google Scholar 

  • Fischer AN, Herrera B, Mikula M, Proell V, Fuchs E, Gotzmann J et al. (2005). Integration of Ras subeffector signaling in TGF-{beta} mediated late stage hepatocarcinogenesis. Carcinogenesis 26: 931–942.

    Article  CAS  PubMed  Google Scholar 

  • Garcia R, Bowman TL, Niu G, Yu H, Minton S, Muro-Cacho CA et al. (2001). Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene 20: 2499–2513.

    Article  CAS  PubMed  Google Scholar 

  • Giannelli G, Bergamini C, Fransvea E, Sgarra C, Antonaci S . (2005). Laminin-5 with transforming growth factor-beta1 induces epithelial to mesenchymal transition in hepatocellular carcinoma. Gastroenterology 129: 1375–1383.

    Article  CAS  PubMed  Google Scholar 

  • Giebel B, Wodarz A . (2006). Tumor suppressors: control of signaling by endocytosis. Curr Biol 16: R91–R92.

    Article  CAS  PubMed  Google Scholar 

  • Gotzmann J, Fischer AN, Zojer M, Mikula M, Proell V, Huber H et al. (2006). A crucial function of PDGF in TGF-beta-mediated cancer progression of hepatocytes. Oncogene 25: 3170–3185.

    Article  CAS  PubMed  Google Scholar 

  • Gotzmann J, Huber H, Thallinger C, Wolschek M, Jansen B, Schulte-Hermann R et al. (2002). Hepatocytes convert to a fibroblastoid phenotype through the cooperation of TGF-beta1 and Ha-Ras: steps towards invasiveness. J Cell Sci 115: 1189–1202.

    CAS  PubMed  Google Scholar 

  • Grunert S, Jechlinger M, Beug H . (2003). Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol 4: 657–665.

    Article  PubMed  Google Scholar 

  • Herath NI, Leggett BA, MacDonald GA . (2006). Review of genetic and epigenetic alterations in hepatocarcinogenesis. J Gastroenterol Hepatol 21: 15–21.

    Article  CAS  PubMed  Google Scholar 

  • Huber MA, Kraut N, Beug H . (2005). Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol 17: 548–558.

    Article  CAS  PubMed  Google Scholar 

  • Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED et al. (2007). Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. J Cell Physiol 213: 374–383.

    Article  CAS  PubMed  Google Scholar 

  • Jechlinger M, Sommer A, Moriggl R, Seither P, Kraut N, Capodiecci P et al. (2006). Autocrine PDGFR signaling promotes mammary cancer metastasis. J Clin Invest 116: 1561–1570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kensler TW, Qian GS, Chen JG, Groopman JD . (2003). Translational strategies for cancer prevention in liver. Nat Rev Cancer 3: 321–329.

    Article  CAS  PubMed  Google Scholar 

  • Kondoh N, Wakatsuki T, Hada A, Shuda M, Tanaka K, Arai M et al. (2001). Genetic and epigenetic events in human hepatocarcinogenesis. Int J Oncol 18: 1271–1278.

    CAS  PubMed  Google Scholar 

  • Lacher MD, Tiirikainen MI, Saunier EF, Christian C, Anders M, Oft M et al. (2006). Transforming growth factor-beta receptor inhibition enhances adenoviral infectability of carcinoma cells via up-regulation of Coxsackie and Adenovirus Receptor in conjunction with reversal of epithelial-mesenchymal transition. Cancer Res 66: 1648–1657.

    Article  CAS  PubMed  Google Scholar 

  • Lee HC, Kim M, Wands JR . (2006a). Wnt/Frizzled signaling in hepatocellular carcinoma. Front Biosci 11: 1901–1915.

    Article  CAS  PubMed  Google Scholar 

  • Lee TK, Man K, Poon RT, Lo CM, Yuen AP, Ng IO et al. (2006b). Signal transducers and activators of transcription 5b activation enhances hepatocellular carcinoma aggressiveness through induction of epithelial-mesenchymal transition. Cancer Res 66: 9948–9956.

    Article  CAS  PubMed  Google Scholar 

  • Macheiner D, Heller G, Kappel S, Bichler C, Stattner S, Ziegler B et al. (2006). NORE1B, a candidate tumor suppressor, is epigenetically silenced in human hepatocellular carcinoma. J Hepatol 45: 81–89.

    Article  CAS  PubMed  Google Scholar 

  • Mikula M, Fuchs E, Huber H, Beug H, Schulte-Hermann R, Mikulits W . (2004). Immortalized p19ARF null hepatocytes restore liver injury and generate hepatic progenitors after transplantation. Hepatology 39: 628–634.

    Article  CAS  PubMed  Google Scholar 

  • Ogata H, Chinen T, Yoshida T, Kinjyo I, Takaesu G, Shiraishi H et al. (2006a). Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-beta1 production. Oncogene 25: 2520–2530.

    Article  CAS  PubMed  Google Scholar 

  • Ogata H, Kobayashi T, Chinen T, Takaki H, Sanada T, Minoda Y et al. (2006b). Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis. Gastroenterology 131: 179–193.

    Article  CAS  PubMed  Google Scholar 

  • Pardali K, Moustakas A . (2007). Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta 1775: 21–62.

    CAS  PubMed  Google Scholar 

  • Pietras K, Sjoblom T, Rubin K, Heldin CH, Ostman A . (2003). PDGF receptors as cancer drug targets. Cancer Cell 3: 439–443.

    Article  CAS  PubMed  Google Scholar 

  • Rossmanith W, Schulte-Hermann R . (2001). Biology of transforming growth factor beta in hepatocarcinogenesis. Microsc Res Tech 52: 430–436.

    Article  CAS  PubMed  Google Scholar 

  • Silva CM . (2004). Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis. Oncogene 23: 8017–8023.

    Article  CAS  PubMed  Google Scholar 

  • Tannapfel A, Busse C, Weinans L, Benicke M, Katalinic A, Geissler F et al. (2001). INK4a-ARF alterations and p53 mutations in hepatocellular carcinomas. Oncogene 20: 7104–7109.

    Article  CAS  PubMed  Google Scholar 

  • Thiery JP, Sleeman JP . (2006). Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7: 131–142.

    Article  CAS  PubMed  Google Scholar 

  • Thorgeirsson SS, Grisham JW . (2002). Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 31: 339–346.

    Article  CAS  PubMed  Google Scholar 

  • Waerner T, Alacakaptan M, Tamir I, Oberauer R, Gal A, Brabletz T et al. (2006). ILEI: a cytokine essential for EMT, tumor formation, and late events in metastasis in epithelial cells. Cancer Cell 10: 227–239.

    Article  CAS  PubMed  Google Scholar 

  • Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C et al. (2004). Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117: 927–939.

    Article  CAS  PubMed  Google Scholar 

  • Yang SF, Wang SN, Wu CF, Yeh YT, Chai CY, Chunag SC et al. (2007). Altered p-STAT3 (tyr705) expression is associated with histological grading and intratumour microvessel density in hepatocellular carcinoma. J Clin Pathol 60: 642–648.

    Article  CAS  PubMed  Google Scholar 

  • Yoshikawa H, Matsubara K, Qian GS, Jackson P, Groopman JD, Manning JE et al. (2001). SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet 28: 29–35.

    CAS  PubMed  Google Scholar 

  • Zhou L, Rui JA, Wang SB, Chen SG, Qu Q, Chi TY et al. (2007). Outcomes and prognostic factors of cirrhotic patients with hepatocellular carcinoma after radical major hepatectomy. World J Surg 31: 1782–1787.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank ORIDIS Biomed for providing HCC tissue arrays and immunohistochemical staining. This work was supported by grants from the Austrian Science Fund, FWF, Grant number SFB F28 and P19598-B13.

Author information

Authors and Affiliations

  1. Division: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Borschke-Gasse 8a, Vienna, Austria

    C Lahsnig, G Zulehner, D Schneller, F van Zijl, H Huber & W Mikulits

  2. Research Institute of Molecular Pathology, Dr Bohr-Gasse 7, Vienna, Austria

    M Mikula, M Petz, A Csiszar & H Beug

Authors
  1. C Lahsnig
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Mikula
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Petz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G Zulehner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Schneller
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. F van Zijl
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H Huber
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Csiszar
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. H Beug
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. W Mikulits
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to W Mikulits.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lahsnig, C., Mikula, M., Petz, M. et al. ILEI requires oncogenic Ras for the epithelial to mesenchymal transition of hepatocytes and liver carcinoma progression. Oncogene 28, 638–650 (2009). https://doi.org/10.1038/onc.2008.418

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2008.418

Keywords

This article is cited by

Search

Advanced search

Quick links