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Br J Cancer. May 2001; 84(10): 1372–1376.
PMCID: PMC2363629

The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression

Abstract

Genes of the polycomb group function by silencing homeotic selector genes that regulate embryogenesis. In mice, downregulation of one of the polycomb genes, bmi-1, leads to neurological alterations and severe proliferative defects in lymphoid cells, whilst bmi-1 overexpression, together with upregulation of myc-1, induces lymphoma. An oncogenic function has been further supported in primary fibroblast studies where bmi-1 overexpression induces immortalization due to repression of p16/p19ARF, and where together with H-ras, it readily transforms MEFs. It was the aim of this study to assess the expression of bmi-1 in resectable non-small cell lung cancer (NSCLC) in association with p16 and p14ARF (=human p19ARF). Tumours (48 resectable NSCLC (32 squamous, 9 adeno-, 2 large cell, 4 undifferentiated carcinomas and 1 carcinoid); stage I, 29, II, 7, III, 12; T1, 18, T2, 30; differentiation: G1 12, G2 19, G3 17) were studied by immunohistochemistry for protein expression and by comparative multiplex PCR for gene amplification analysis. In tumour-free, normal lung tissue from patients, weak – moderate bmi-1 staining was seen in some epithelial cells, lymphocytes, glandular cells and in fibroblasts, whereas blood, endothelial, chondrocytes, muscle cells and adipocytes did not exhibit any bmi-1 expression. In tumours, malignant cells were negative/weakly, moderately and strongly positive in 20, 22 and 6 cases, respectively. As assessed by multiplex PCR, bmi-1 gene amplification was not the reason for high-level bmi-1 expression. Tumours with moderate or strong bmi-1 expression were more likely to have low levels of p16 and p14ARF (P = 0.02). Similarly, tumours negative for both, p16 and p14ARF, exhibit moderate–strong bmi-1 staining. 58% of resectable NSCLC exhibit moderate–high levels of bmi-1 protein. The inverse correlation of bmi-1 and the INK4 locus proteins expression (p16/p14ARF) supports a possible role for bmi-1 misregulation in lung carcinogenesis. © 2001 Cancer Research Campaign www.bjcancer.com

Keywords: bmi-1, polycomb group gene, cell cycle, p16, p14ARF, NSCLC

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Selected References

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  • Alkema MJ, Wiegant J, Raap AK, Berns A, van Lohuizen M. Characterization and chromosomal localization of the human proto-oncogene BMI-1. Hum Mol Genet. 1993 Oct;2(10):1597–1603. [PubMed]
  • Alkema MJ, Bronk M, Verhoeven E, Otte A, van 't Veer LJ, Berns A, van Lohuizen M. Identification of Bmi1-interacting proteins as constituents of a multimeric mammalian polycomb complex. Genes Dev. 1997 Jan 15;11(2):226–240. [PubMed]
  • Alkema MJ, Jacobs H, van Lohuizen M, Berns A. Pertubation of B and T cell development and predisposition to lymphomagenesis in Emu Bmi1 transgenic mice require the Bmi1 RING finger. Oncogene. 1997 Aug 18;15(8):899–910. [PubMed]
  • Beà S, Ribas M, Hernández JM, Bosch F, Pinyol M, Hernández L, García JL, Flores T, González M, López-Guillermo A, et al. Increased number of chromosomal imbalances and high-level DNA amplifications in mantle cell lymphoma are associated with blastoid variants. Blood. 1999 Jun 15;93(12):4365–4374. [PubMed]
  • Betticher DC, Heighway J, Hasleton PS, Altermatt HJ, Ryder WD, Cerny T, Thatcher N. Prognostic significance of CCND1 (cyclin D1) overexpression in primary resected non-small-cell lung cancer. Br J Cancer. 1996 Feb;73(3):294–300. [PMC free article] [PubMed]
  • Betticher DC, White GR, Vonlanthen S, Liu X, Kappeler A, Altermatt HJ, Thatcher N, Heighway J. G1 control gene status is frequently altered in resectable non-small cell lung cancer. Int J Cancer. 1997 Oct 21;74(5):556–562. [PubMed]
  • Brunk BP, Martin EC, Adler PN. Drosophila genes Posterior Sex Combs and Suppressor two of zeste encode proteins with homology to the murine bmi-1 oncogene. Nature. 1991 Sep 26;353(6342):351–353. [PubMed]
  • Gould A. Functions of mammalian Polycomb group and trithorax group related genes. Curr Opin Genet Dev. 1997 Aug;7(4):488–494. [PubMed]
  • Haupt Y, Alexander WS, Barri G, Klinken SP, Adams JM. Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice. Cell. 1991 May 31;65(5):753–763. [PubMed]
  • Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature. 1999 Jan 14;397(6715):164–168. [PubMed]
  • Lessard J, Baban S, Sauvageau G. Stage-specific expression of polycomb group genes in human bone marrow cells. Blood. 1998 Feb 15;91(4):1216–1224. [PubMed]
  • Paro R. Propagating memory of transcriptional states. Trends Genet. 1995 Aug;11(8):295–297. [PubMed]
  • Pomerantz J, Schreiber-Agus N, Liégeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, et al. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell. 1998 Mar 20;92(6):713–723. [PubMed]
  • van der Lugt NM, Domen J, Linders K, van Roon M, Robanus-Maandag E, te Riele H, van der Valk M, Deschamps J, Sofroniew M, van Lohuizen M, et al. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev. 1994 Apr 1;8(7):757–769. [PubMed]
  • van Lohuizen M. Functional analysis of mouse Polycomb group genes. Cell Mol Life Sci. 1998 Jan;54(1):71–79. [PubMed]
  • van Lohuizen M, Verbeek S, Scheijen B, Wientjens E, van der Gulden H, Berns A. Identification of cooperating oncogenes in E mu-myc transgenic mice by provirus tagging. Cell. 1991 May 31;65(5):737–752. [PubMed]
  • van Lohuizen M, Frasch M, Wientjens E, Berns A. Sequence similarity between the mammalian bmi-1 proto-oncogene and the Drosophila regulatory genes Psc and Su(z)2. Nature. 1991 Sep 26;353(6342):353–355. [PubMed]
  • Voncken JW, Schweizer D, Aagaard L, Sattler L, Jantsch MF, van Lohuizen M. Chromatin-association of the Polycomb group protein BMI1 is cell cycle-regulated and correlates with its phosphorylation status. J Cell Sci. 1999 Dec;112(Pt 24):4627–4639. [PubMed]
  • Vonlanthen S, Heighway J, Tschan MP, Borner MM, Altermatt HJ, Kappeler A, Tobler A, Fey MF, Thatcher N, Yarbrough WG, et al. Expression of p16INK4a/p16alpha and p19ARF/p16beta is frequently altered in non-small cell lung cancer and correlates with p53 overexpression. Oncogene. 1998 Nov 26;17(21):2779–2785. [PubMed]
  • Weber JD, Taylor LJ, Roussel MF, Sherr CJ, Bar-Sagi D. Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol. 1999 May;1(1):20–26. [PubMed]
  • Whyte P. The retinoblastoma protein and its relatives. Semin Cancer Biol. 1995 Apr;6(2):83–90. [PubMed]
  • Zhang Y, Xiong Y, Yarbrough WG. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell. 1998 Mar 20;92(6):725–734. [PubMed]

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