Skip to main content

Advertisement

SpringerLink
Log in

LANA-1, Bcl-2, Mcl-1 and HIF-1α protein expression in HIV-associated Kaposi sarcoma

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Human herpesvirus 8 (HHV8) is necessary for Kaposi sarcoma (KS) to develop, but whether the tissue viral load is a marker of KS progression is still unclear. Little is known about the level of expression of apoptosis-regulating proteins and of hypoxia-inducible factors (HIFs) in KS tumour cells relative to HHV8 expression. We therefore investigated the expression of the latency-associated nuclear antigen (LANA-1) of HHV8, Bcl-2, Mcl-1, Bax, Bcl-xL, caspase 3 and HIF-1αin KS tissue specimens at different stages of the disease. The expression of these proteins was evaluated immunohistochemically using tissue microarrays (TMAs) in tissue specimens from 245 HIV-positive patients at different stages of the disease. Both LANA-1 and HIF-1α were expressed in KS biopsies taken at different stages, but their level increased throughout tumour progression. Additionally, the levels of Bcl-2 and Mcl-1 were higher in visceral KS lesions compared to levels observed in cutaneous and mucosal KS. This study demonstrates that late tumour stages of KS in tissues from HIV-positive patients are associated with high levels of LANA-1, HIF-1α and of the anti-apoptotic proteins, Bcl-2 and Mcl-1. Finally, the expression of these proteins can be potentially used as a tissue biomarker in defining patients with a higher risk of disease progression.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

References

  1. Beral V, Peterman TA, Berkelman RL et al (1990) Kaposi’s sarcoma among persons with AIDS: a sexually transmitted infection ? Lancet 335:123–128

    Article  PubMed  CAS  Google Scholar 

  2. Cattelan AM, Calabro ML, De Rossi A et al (2005) Long-term clinical outcome of AIDS-related Kaposi’s sarcoma during highly active antiretroviral therapy. Int J Oncol 27:779–785

    PubMed  CAS  Google Scholar 

  3. Jones JL, Hanson DL, Dworkin MS et al (1999) Effects of antiretroviral therapy on recent trends in selected cancers among HIV-infected persons. J Acquir Immune Defic Syndr 21:S11–S17

    PubMed  CAS  Google Scholar 

  4. Parkin DM, Wabinga H, Nambooze S et al (1999) AIDS-related cancers in Africa: maturation of the epidemic in Uganda. AIDS 13:2563–2570

    Article  PubMed  CAS  Google Scholar 

  5. Bower M, Nelson M, Young AM et al (2005) Immune reconstitution inflammatory syndrome associated with Kaposi’s sarcoma. J Clin Oncol 23:5224–5228

    Article  PubMed  CAS  Google Scholar 

  6. Hofman P, Nelson AM (2006) The pathology induced by highly active antiretroviral therapy against human immunodeficiency virus: an update. Curr Med Chem 13:3121–3132

    Article  PubMed  CAS  Google Scholar 

  7. Chang Y, Cesarman E, Pessin MS et al (1994) Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science 266:1865–1869

    Article  PubMed  CAS  Google Scholar 

  8. Hiatt KM, Nelson AM, Lichy JH et al (2008) Classic Kaposi Sarcoma in the United States over the last two decades: a clinicopathologic and molecular study of 438 non-HIV-related Kaposi Sarcoma patients with comparison to HIV-related Kaposi sarcoma. Mod Pathol 21:572–582

    Article  PubMed  CAS  Google Scholar 

  9. Schalling M, Ekman M, Kaaya EE et al (1995) A role for a new herpes virus (KSHV) in different forms of Kaposi’s sarcoma. Nat Med 1:707–708

    Article  PubMed  CAS  Google Scholar 

  10. Hengge UR, Ruzicka T, Tyring ST et al (2002) Update on Kaposi’s sarcoma and other HHV8 associated diseases. Part 1: epidemiology, environmental predispositions, clinical manifestations, and therapy. Lancet Infect Dis 2:281–292

    Article  PubMed  Google Scholar 

  11. Weiss SW, Goldblum JR (2001) Enzinger and Weiss’s soft tissue tumors, 4th edn. Mosby, St. Louis, pp 917–954

    Google Scholar 

  12. Afessa B, Green W, Chiao J et al (1998) Pulmonary complications of HIV infection: autopsy findings. Chest 113:1225–1229

    Article  PubMed  CAS  Google Scholar 

  13. Hofman P, Saint-Paul MC, Battaglione V et al (1999) Autopsy findings in the acquired immunodeficiency syndrome (AIDS). A report of 395 cases from the south of France. Pathol Res Pract 195:209–217

    PubMed  CAS  Google Scholar 

  14. Klatt EC, Nichols L, Nogushi TT (1994) Evolving trends revealed by autopsies of patients with the acquired immunodeficiency syndrome. 565 autopsies in adults with the acquired immunodeficiency syndrome, Los Angeles, Calif, 1982–1993. Arch Pathol Lab Med 118:884–890

    PubMed  CAS  Google Scholar 

  15. Hengge UR, Ruzicka T, Tyring SK et al (2002) Update on Kaposi’s sarcoma and other HHV8 associated diseases. Part 2: pathogenesis, Castleman’s disease, and pleural effusion lymphoma. Lancet Infect Dis 2:344–352

    Article  PubMed  Google Scholar 

  16. Renne R, Barry C, Dittmer D et al (2001) Modulation of cellular and viral gene expression by the latency-associated nuclear antigen of Kaposi sarcoma-associated herpesvirus. J Virol 75:458–468

    Article  PubMed  CAS  Google Scholar 

  17. Bais C, Santomasso B, Coso O et al (1998) G-protein-coupled receptor of Kaposi sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 391:86–89

    Article  PubMed  CAS  Google Scholar 

  18. Cheng EH, Nicholas J, Bellows DS et al (1997) A Bcl-2 homolog encoded by Kaposi sarcoma-associated virus, human herpesvirus 8, inhibits apoptosis but does not heterodimerize with Bax or Bak. Proc Natl Acad Sci U S A 94:690–694

    Article  PubMed  CAS  Google Scholar 

  19. Kirchoff S, Sebens T, Baumann S et al (2002) Viral IFN-regulatory factors inhibit activation-induced cell death via two positive regulator factor 1-dependent domains in the CD95 ligand promoter. J Immunol 168:1226–1234

    Google Scholar 

  20. Cai Q, Murakami M, Si H et al (2007) A potential a-helix motif in the amino terminus of LANA encoded by Kaposi sarcoma-associated Herpesvirus is critical for nuclear accumulation of HIF-1α in normoxia. J Virol 81:10413–10423

    Article  PubMed  CAS  Google Scholar 

  21. Campbell TB, Borok M, Gwanzura L (2000) Relationship of human herpesvirus 8 peripheral blood virus load and Kaposi sarcoma clinical stage. AIDS 14:2109–2116

    Article  PubMed  CAS  Google Scholar 

  22. Giltane JM, Rimm DL (2004) Technology insight: identification of biomarkers with tissue microarray technology. Nat Clin Pract 1:104–111

    Article  Google Scholar 

  23. Hoos A, Cordon-Cardo C (2001) Tissue microarray profiling of cancer specimens and cell lines opportunities and limitations. Lab Invest 81:1331–1338

    PubMed  CAS  Google Scholar 

  24. Hofman P, Butori C, Havet K et al (2008) Prognostic significance of cortactin levels in head and neck squamous cell carcinoma: comparison with epidermal growth factor receptor status. Br J Cancer 98:956–964

    Article  PubMed  CAS  Google Scholar 

  25. Hofman V, Lassalle S, Selva E et al (2007) Involvement of mast cells in gastritis caused by Helicobacter pylori: a potential role in epithelial cell apoptosis. J Clin Pathol 60:600–607

    Article  PubMed  CAS  Google Scholar 

  26. Cannon MJ, Dollard SC, Black JB (2003) Risk factors for Kaposi sarcoma in men seropositive for both human herpesvirus 8 and human immunodeficiency virus. AIDS 17:215–222

    Article  PubMed  CAS  Google Scholar 

  27. Laney AS, Dollard SC, Jaffe HW et al (2004) Repeated measures study of human herpesvirus 8 (HHV8) DNA and antibodies in men seropositive for both HHV8 and HIV. AIDS 18:1819–1826

    Article  PubMed  CAS  Google Scholar 

  28. Laney AS, Cannon MJ, Jaffe HW et al (2007) Human herpesvirus 8 presence and viral load are associated with the progression of AIDS-associated Kaposi sarcoma. AIDS 21:1541–1545

    Article  PubMed  Google Scholar 

  29. Marcelin AG, Gorin I, Morand P et al (2004) Quantification of Kaposi sarcoma-associated herpesvirus in blood, oral mucosa, and saliva in patients with Kaposi sarcoma. AIDS Res Hum Retroviruses 20:704–708

    Article  PubMed  Google Scholar 

  30. Pak F, Mwakigonja AR, Kokhaei P et al (2007) Kaposi sarcoma herpes virus load in biopsies of cutaneous and oral Kaposi sarcoma lesions. Eur J Cancer 43:1877–1882

    Article  PubMed  CAS  Google Scholar 

  31. Hayward GS (1999) Human herpesvirus 8 latent-state gene expression and apoptosis in Kaposi sarcoma lesions. J Natl Cancer Inst 9:1705–1707

    Article  Google Scholar 

  32. Massambu C, Pyakurel P, Kaaya E et al (2003) Serum HHV8 DNA and Tat antibodies in Kaposi sarcoma patients with and without HIV-1 infection. Anticancer Res 23:2389–2395

    PubMed  CAS  Google Scholar 

  33. Guttman-Yassky E, Abada R, Kra-Oz Z (2007) Relationship between human herpesvirus 8 loads and disease stage in classic Kaposi sarcoma patients. Diagn Microbiol Infect Dis 57:387–392

    Article  PubMed  Google Scholar 

  34. Nsubuga MM, Biggar RJ, Combs S et al (2008) Human herpesvirus 8 load and progression of AIDS-related Kaposi sarcoma lesions. Cancer Lett 263:182–188

    Article  PubMed  CAS  Google Scholar 

  35. Stebbing J, Sanitt A, Nelson M et al (2006) A prognostic index for AIDS-associated Kaposi ‘s sarcoma in the era of highly active antiretroviral therapy. Lancet 367:1495–1502

    Article  PubMed  Google Scholar 

  36. Stuber G, Mattsson K, Flaberg E et al (2007) HHV8 encoded LANA-1 alters the higher organization of the cell nucleus. Mol Cancer 6:28

    Article  PubMed  CAS  Google Scholar 

  37. Pyakurel P, Massambu C, Castaños-Vélez E et al (2004) Human herpesvirus 8/Kaposi sarcoma herpesvirus cell association during evolution of Kaposi sarcoma. J Acquir Immune Defic Syndr 36:678–683

    Article  PubMed  Google Scholar 

  38. Dada MA, Chetty R, Biddolph SC et al (1996) The immunoexpression of bcl-2 and p53 in Kaposi’s sarcoma. Histopathology 29:159

    Article  PubMed  CAS  Google Scholar 

  39. Foreman KE, Wrone-Smith T, Boise LH et al (1996) Kaposi’s sarcoma tumor cells preferentially express Bcl-xL. Am J Pathol 149:795–803

    PubMed  CAS  Google Scholar 

  40. Hodak E, Hammel I, Feinmesser M et al (1999) Differential expression of p53 and Ki-67 proteins in classic and iatrogenic Kaposi’s sarcoma. Am J Dermatopathol 21:138–145

    Article  PubMed  CAS  Google Scholar 

  41. Ramos da Silva S, Bacchi MM, Bacchi CE et al (2007) Human bcl-2 expression, cleaved caspase-3, and KSHV LANA-1 in Kaposi sarcoma lesions. Am J Clin Pathol 128:794–802

    Article  PubMed  CAS  Google Scholar 

  42. Simonart T, Degraef C, Noel JC et al (1998) Overexpression of Bcl-2 in Kaposi’s sarcoma-derived cells. J Invest Dermatol 111:349–353

    Article  PubMed  CAS  Google Scholar 

  43. Widmer I, Wernli M, Bachmann F et al (2002) Differential expression of viral Bcl-2 encoded by Kaposi’s sarcoma-associated herpesvirus and human Bcl-2 in primary effusion lymphoma cells and Kaposi’s sarcoma lesions. J Virol 76:2551–2556

    Article  PubMed  CAS  Google Scholar 

  44. Stürzl M, Hohenadl C, Zietz C et al (1999) Expression of K13/v-FLIP gene of human herpesvirus 8 and apoptosis in Kaposi’s sarcoma spindle cells. J Natl Cancer Inst 91:1725–1733

    Article  PubMed  Google Scholar 

  45. Rezaee SA, Cunningham C, Davison AJ et al (2006) Kaposi’s sarcoma-associated herpesvirus immune modulation: an overview. J Gen Virol 87:1781–1804

    Article  PubMed  CAS  Google Scholar 

  46. Brahimi-Horn MC, Chiche J, Pouysségur J (2007) Hypoxia and cancer. J Mol Med 85:1301–1317

    Article  PubMed  Google Scholar 

  47. Harris AL (2002) Hypoxia-a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47

    Article  PubMed  CAS  Google Scholar 

  48. Hickey MM, Simon MC (2006) Regulation of angiogenesis by hypoxia and hypoxia-inducible factors. Curr Top Dev Biol 76:217–257

    Article  PubMed  CAS  Google Scholar 

  49. Talks KL, Turley H, Gatter KC et al (2000) The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2 alpha in normal tissues, cancers, and tumor-associated macrophages. Am J Pathol 157:411–421

    PubMed  CAS  Google Scholar 

  50. Sermeus A, Cosse JP, Crespin M et al (2008) Hypoxia induces protection against etoposide-induced apoptosis: molecular profiling of changes in gene expression and transcription factor activity. Mol Cancer 7:27

    Article  PubMed  CAS  Google Scholar 

  51. Carroll PA, Kenerson HL, Yeung RS et al (2006) Latent Kaposi’s sarcoma-associated herpesvirus infection of endothelial cells activates hypoxia-induced factors. J Virol 80:10802–10812

    Article  PubMed  CAS  Google Scholar 

  52. Thirunarayanan N, Cifire F, Fichtner I et al (2007) Enhanced tumorigenicity of fibroblasts transformed with human herpesvirus 8 chemokine receptor vGPCR by successive passage in nude and immunocompetent mice. Oncogene 26:5702–5712

    Article  PubMed  CAS  Google Scholar 

  53. Glaunsinger B, Ganem D (2004) Highly selective escape from KSHV-mediated host mRNA shutoff and its implications for viral pathogenesis. J Exp Med 200:391–398

    Article  PubMed  CAS  Google Scholar 

  54. Montaner S, Sodhi A, Servitja JM et al (2004) The small GTPase Rac1 links the Kaposi sarcoma-associated herpesvirus vGPCR to cytokine secretion and paracrine neoplasia. Blood 104:2903–2911

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Christiane Brahimi-Horn for editing the manuscript. This work is supported by the Canceropôle PACA (LPCE Platform).

Conflict of interest statement

No conflict of interest

Author information

Authors and Affiliations

  1. Laboratory of Clinical and Experimental Pathology, Louis Pasteur Hospital, 30 avenue de la voie romaine, Nice, 06002, France

    E Long, M Ilie, V Hofman, K Havet, C Butori & P Hofman

  2. INSERM ERI-21/EA 4319, Nice, France

    V Hofman, C Butori & P Hofman

  3. Human Tissue Biobank Unit/CRB INSERM, Nice, France

    V Hofman, E Selva, C Butori & P Hofman

  4. Department of Dermatology, University of Nice Sophia Antipolis, Nice, 06002, France

    J P Lacour

  5. Armed Forces Institute of Pathology, Washington, DC, 20306-6000, USA

    A M Nelson

  6. Institute for Infectious Pathology, Liestal, Switzerland

    G Cathomas

Authors
  1. E Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Ilie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V Hofman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K Havet
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E Selva
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Butori
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J P Lacour
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A M Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G Cathomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. P Hofman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P Hofman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Long, E., Ilie, M., Hofman, V. et al. LANA-1, Bcl-2, Mcl-1 and HIF-1α protein expression in HIV-associated Kaposi sarcoma. Virchows Arch 455, 159–170 (2009). https://doi.org/10.1007/s00428-009-0791-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-009-0791-1

Keywords

Search

Navigation