Skip to main content


Log in

Perinuclear leucine-rich repeats and immunoglobulin-like domain proteins (LRIG1-3) as prognostic indicators in astrocytic tumors

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript


We have previously characterized three human leucine-rich repeats and immunoglobulin-like domains (LRIG) genes and proteins, named LRIG1-3 and proposed that they may act as suppressors of tumor growth. The LRIG1 transmembrane protein antagonizes the activity of epidermal growth factor receptor family receptor tyrosine kinases. In this study, we evaluated the mRNA expression level of LRIG1-3 in human glioma cell lines and control-matched glioma tissues, characterized the sub-cellular localization of an LRIG3–GFP fusion protein, and analyzed the relationship between sub-cellular localization of LRIG1-3 and clinical parameters in 404 astrocytic tumors by immunohistochemistry. LRIG1-3 mRNA was detected in all human glioma cell lines and matched glioma samples, with large differences in the expression levels. Ectopically expressed LRIG3–GFP localized to perinuclear and cytoplasmic compartments, and to the cell surface of transfected glioma cells. Perinuclear staining of LRIG1-3 was associated with low WHO grade and better survival of the patients. Perinuclear staining of LRIG3 was associated with a lower proliferation index and was in addition to tumor grade, an independent prognostic factor. Furthermore, within the groups of grade III and grade IV tumors, perinuclear staining of LRIG3 significantly correlated with better survival. These results indicate that expression and sub-cellular localization of LRIG1-3 might be of importance in the pathogenesis and prognosis of astrocytic tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others


  1. Andersson U, Guo D, Malmer B, Bergenheim AT, Brannstrom T, Hedman H, Henriksson R (2004) Epidermal growth factor receptor family (EGFR, ErbB2-4) in gliomas and meningiomas. Acta Neuropathol 108:135–142

    Article  PubMed  CAS  Google Scholar 

  2. Cook PW, Piepkorn M, Clegg CH, Plowman GD, DeMay JM, Brown JR, Pittelkow MR (1997) Transgenic expression of the human amphiregulin gene induces a psoriasis-like phenotype. J Clin Invest 100:2286–2294

    Article  PubMed  CAS  Google Scholar 

  3. Dosaka N, Fujita M, Tanaka T, Miyachi Y, Imamura S (1989) Analysis of epidermal growth factor receptor gene in psoriasis. J Dermatol 16:184–186

    PubMed  CAS  Google Scholar 

  4. Guo D, Holmlund C, Henriksson R, Hedman H (2004) The LRIG gene family has three vertebrate paralogs widely expressed in human and mouse tissues and a homolog in Ascidiacea. Genomics 84:157–165

    Article  PubMed  CAS  Google Scholar 

  5. Gur G, Rubin C, Katz M, Amit I, Citri A, Nilsson J, Amariglio N, Henriksson R, Rechavi G, Hedman H, Wides R, Yarden Y (2004) LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. Embo J 23:3270–3281

    Article  PubMed  CAS  Google Scholar 

  6. Haapasalo H, Kylaniemi M, Paunul N, Kinnula VL, Soini Y (2003) Expression of antioxidant enzymes in astrocytic brain tumors. Brain Pathol 13:155–164

    Article  PubMed  CAS  Google Scholar 

  7. Hedman H, Nilsson J, Guo D, Henriksson R (2002) Is LRIG1 a tumour suppressor gene at chromosome 3p14.3? Acta Oncol 41:352–354

    Article  PubMed  CAS  Google Scholar 

  8. Holmlund C, Nilsson J, Guo D, Starefeldt A, Golovleva I, Henriksson R, Hedman H (2004) Characterization and tissue-specific expression of human LRIG2. Gene 332:35–43

    Article  PubMed  CAS  Google Scholar 

  9. Ichimura K, Ohgaki H, Kleihues P, Collins VP (2004) Molecular pathogenesis of astrocytic tumours. J Neurooncol 70:137–160

    Article  PubMed  Google Scholar 

  10. Kleihues P, Cavenee WK (2000) WHO Classification of tumours pathology and genetics of tumours of nervous system. IARC Press, Lyon

    Google Scholar 

  11. Knuutila S, Aalto Y, Autio K, Bjorkqvist AM, El-Rifai W, Hemmer S, Huhta T, Kettunen E, Kiuru-Kuhlefelt S, Larramendy ML, Lushnikova T, Monni O, Pere H, Tapper J, Tarkkanen M, Varis A, Wasenius VM, Wolf M, Zhu Y (1999) DNA copy number losses in human neoplasms. Am J Pathol 155:683–694

    PubMed  CAS  Google Scholar 

  12. Laederich MB, Funes-Duran M, Yen L, Ingalla E, Wu X, Carraway KL 3rd, Sweeney C (2004) The leucine-rich repeat protein LRIG1 is a negative regulator of ErbB family receptor tyrosine kinases. J Biol Chem 279:47050–47056

    Article  PubMed  CAS  Google Scholar 

  13. Mischel PS, Shai R, Shi T, Horvath S, Lu KV, Choe G, Seligson D, Kremen TJ, Palotie A, Liau LM, Cloughesy TF, Nelson SF (2003) Identification of molecular subtypes of glioblastoma by gene expression profiling. Oncogene 22:2361–2373

    Article  PubMed  CAS  Google Scholar 

  14. Nash MA, Deavers MT, Freedman RS (2002) The expression of decorin in human ovarian tumors. Clin Cancer Res 8:1754–1760

    PubMed  CAS  Google Scholar 

  15. Nilsson J, Vallbo C, Guo D, Golovleva I, Hallberg B, Henriksson R, Hedman H (2001) Cloning, characterization, and expression of human LIG1. Biochem Biophys Res Commun 284:1155–1161

    Article  PubMed  CAS  Google Scholar 

  16. Nilsson J, Starefeldt A, Henriksson R, Hedman H (2003) LRIG1 protein in human cells and tissues. Cell Tissue Res 312:65–71

    PubMed  CAS  Google Scholar 

  17. Paquet ME, Cohen-Doyle M, Shore GC, Williams DB (2004) Bap29/31 influences the intracellular traffic of MHC class I molecules. J Immunol 172:7548–7555

    PubMed  CAS  Google Scholar 

  18. Ranuncolo SM, Varela M, Morandi A, Lastiri J, Christiansen S, Bal de Kier Joffe E, Pallotta MG, Puricelli L (2004) Prognostic value of Mdm2, p53 and p16 in patients with astrocytomas. J Neurooncol 68:113–121

    Article  PubMed  Google Scholar 

  19. Reifenberger G, Ichimura K, Reifenberger J, Elkahloun AG, Meltzer PS, Collins VP (1996) Refined mapping of 12q13-q15 amplicons in human malignant gliomas suggests CDK4/SAS and MDM2 as independent amplification targets. Cancer Res 56:5141–5145

    PubMed  CAS  Google Scholar 

  20. Ribom D, Andrae J, Frielingsdorf M, Hartman M, Nister M, Smits A (2002) Prognostic value of platelet derived growth factor alpha receptor expression in grade 2 astrocytomas and oligoastrocytomas. J Neurol Neurosurg Psychiatr 72:782–787

    Article  PubMed  CAS  Google Scholar 

  21. Sandilands E, Cans C, Fincham VJ, Brunton VG, Mellor H, Prendergast GC, Norman JC, Superti-Furga G, Frame MC (2004) RhoB and actin polymerization coordinate Src activation with endosome-mediated delivery to the membrane. Dev Cell 7:855–869

    Article  PubMed  CAS  Google Scholar 

  22. Schamel WW, Kuppig S, Becker B, Gimborn K, Hauri HP, Reth M (2003) A high-molecular-weight complex of membrane proteins BAP29/BAP31 is involved in the retention of membrane-bound IgD in the endoplasmic reticulum. Proc Natl Acad Sci USA 100:9861–9866

    Article  PubMed  CAS  Google Scholar 

  23. Suzuki Y, Sato N, Tohyama M, Wanaka A, Takagi T (1996) cDNA cloning of a novel membrane glycoprotein that is expressed specifically in glial cells in the mouse brain. LIG-1, a protein with leucine-rich repeats and immunoglobulin-like domains. J Biol Chem 271:22522–22527

    Article  PubMed  CAS  Google Scholar 

  24. Suzuki Y, Miura H, Tanemura A, Kobayashi K, Kondoh G, Sano S, Ozawa K, Inui S, Nakata A, Takagi T, Tohyama M, Yoshikawa K, Itami S (2002) Targeted disruption of LIG-1 gene results in psoriasiform epidermal hyperplasia. FEBS Lett 521:67–71

    Article  PubMed  CAS  Google Scholar 

  25. Tanemura A, Nagasawa T, Inui S, Itami S (2005) LRIG-1 provides a novel prognostic predictor in squamous cell carcinoma of the skin: immunohistochemical analysis for 38 cases. Dermatol Surg 31:423–430

    Article  PubMed  CAS  Google Scholar 

  26. Thomasson M, Hedman H, Guo D, Ljungberg B, Henriksson R (2003) LRIG1 and epidermal growth factor receptor in renal cell carcinoma: a quantitative RT–PCR and immunohistochemical analysis. Br J Cancer 89:1285–1289

    Article  PubMed  CAS  Google Scholar 

  27. Varela M, Ranuncolo SM, Morand A, Lastiri J, De Kier Joffe EB, Puricelli LI, Pallotta MG (2004) EGF-R and PDGF-R, but not bcl-2, overexpression predict overall survival in patients with low-grade astrocytomas. J Surg Oncol 86:34–40

    Article  PubMed  CAS  Google Scholar 

  28. Wojcik C, Schroeter D, Wilk S, Lamprecht J, Paweletz N (1996) Ubiquitin-mediated proteolysis centers in HeLa cells: indication from studies of an inhibitor of the chymotrypsin-like activity of the proteasome. Eur J Cell Biol 71:311–318

    PubMed  CAS  Google Scholar 

Download references


This study was supported by grants from The National Cancer Foundation and Lion’s Cancer Research Foundation, Umeå University, Sweden. Kerstin Bergh is acknowledged for her excellent assistance with the immunohistochemical staining. We also thank Björn Tavelin for statistical advice.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Roger Henriksson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guo, D., Nilsson, J., Haapasalo, H. et al. Perinuclear leucine-rich repeats and immunoglobulin-like domain proteins (LRIG1-3) as prognostic indicators in astrocytic tumors. Acta Neuropathol 111, 238–246 (2006).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: