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Loss of oncostatin M receptor β in metastatic melanoma cells

Oncogene volume 26, pages 881–892 (2007)Cite this article

Abstract

Oncostatin M (OSM) is an interleukin-6 (IL-6) type cytokine originally described by its capacity to inhibit melanoma proliferation in vitro. Here, the mechanisms involved in resistance to growth inhibition by OSM were analysed for the first time on a large panel of metastatic melanoma cell lines. OSM resistance did not strictly correlate with IL-6, interferon-γ or tumor necrosis factor-α resistance. Rather, it correlated with a specific loss of the OSM receptor-β (OSMRβ) subunit, in conjunction with a lower level of histone acetylation in the OSMRβ promoter region. Treatment of various OSM-resistant melanoma cells with the histone deacetylase inhibitor Trichostatin A increased activity and histone acetylation of the OSMRβ promoter as well as expression of OSMRβ mRNA and protein, allowing OSM to activate the signal transducer and activator of transcription 3 (STAT3) and to inhibit proliferation. Other defects associated with OSM resistance were identified at the level of OSMRβ transcription or protein expression, as well as downstream of or parallel to STAT3 activation. Altogether, our results suggest a role for OSM in the prevention of melanoma progression and that metastatic melanoma cells could escape this growth control by the epigenetic silencing of OSMRβ.

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References

  • Bani MR, Rak J, Adachi D, Wiltshire R, Trent JM, Kerbel RS et al. (1996). Multiple features of advanced melanoma recapitulated in tumorigenic variants of early stage (radial growth phase) human melanoma cell lines: evidence for a dominant phenotype. Cancer Res 56: 3075–3086.

    CAS  PubMed  Google Scholar 

  • Blanchard F, Chipoy C . (2005). Histone deacetylase inhibitors: new drugs for the treatment of inflammatory diseases? Drug Discov Today 10: 197–204.

    Article  CAS  Google Scholar 

  • Blanchard F, Kinzie E, Wang Y, Duplomb L, Godard A, Held WA et al. (2002). FR901228, an inhibitor of histone deacetylases, increases the cellular responsiveness to IL-6 type cytokines by enhancing the expression of receptor proteins. Oncogene 21: 6264–6277.

    Article  CAS  Google Scholar 

  • Blanchard F, Pitard V, Taupin JL, Raher S, Hallet MM, Moreau JF et al. (1997). Epitope-function relationships of human leukemia inhibitory factor receptors using a novel set of anti-gp190mAB. Int Immunol 9: 1775–1784.

    Article  CAS  Google Scholar 

  • Blanchard F, Tracy E, Smith J, Chattopadhyay S, Wang Y, Held WA et al. (2003). DNA methylation controls the responsiveness of hepatoma cells to leukemia inhibitory factor. Hepatology 38: 1516–1528.

    Article  CAS  Google Scholar 

  • Bohm M, Schulte U, Funk JO, Raghunath M, Behrmann I, Kortylewski M et al. (2001). Interleukin-6-resistant melanoma cells exhibit reduced activation of STAT3 and lack of inhibition of cyclin E-associated kinase activity. J Invest Dermatol 117: 132–140.

    Article  CAS  Google Scholar 

  • Boing I, Stross C, Radtke S, Lippok BE, Heinrich PC, Hermanns HM . (2006). Oncostatin M-induced activation of stress-activated MAP kinases depends on tyrosine 861 in the OSM receptor and requires Jak1 but not Src kinases. Cell Signal 18: 50–61.

    Article  Google Scholar 

  • Boyle GM, Martyn AC, Parsons PG . (2005). Histone deacetylase inhibitors and malignant melanoma. Pig Cell Res 18: 160–166.

    Article  CAS  Google Scholar 

  • Bromberg J, Darnell Jr JE . (2000). The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19: 2468–2473.

    Article  CAS  Google Scholar 

  • Chambers AE, Banerjee S, Chaplin T, Dunne J, Debernardi S, Joel SP et al. (2003). Histone acetylation-mediated regulation of genes in leukaemic cells. Eur J Cancer 39: 1165–1175.

    Article  CAS  Google Scholar 

  • Chipoy C, Berreur M, Couillaud S, Pradal G, Vallette F, Colombeix C et al. (2004). Downregulation of osteoblast markers and induction of the glial fibrillary acidic protein by oncostatin M in osteosarcoma cells require PKCdelta and STAT3. J Bone Miner Res 19: 1850–1861.

    Article  CAS  Google Scholar 

  • Chudnovsky Y, Khavari PA, Adams AE . (2005). Melanoma genetics and the development of rational therapeutics. J Clin Invest 115: 813–824.

    Article  CAS  Google Scholar 

  • Dagoneau N, Scheffer D, Huber C, Al-Gazali LI, Di Rocco M, Godard A et al. (2004). Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve–Wiedemann/Schwartz–Jampel type 2 syndrome. Am J Hum Genet 74: 298–305.

    Article  CAS  Google Scholar 

  • Dreno B, Nguyen JM, Khammari A, Pandolfino MC, Tessier MH, Bercegeay S et al. (2002). Randomized trial of adoptive transfer of melanoma tumor-infiltrating lymphocytes as adjuvant therapy for stage III melanoma. Cancer Immunol Immunother 51: 539–546.

    Article  CAS  Google Scholar 

  • Florenes VA, Lu C, Bhattacharya N, Rak J, Sheehan C, Slingerland JM et al. (1999). Interleukin-6 dependent induction of the cyclin dependent kinase inhibitor p21WAF1/CIP1 is lost during progression of human malignant melanoma. Oncogene 18: 1023–1032.

    Article  CAS  Google Scholar 

  • Gervois N, Heuze F, Diez E, Jotereau F . (1990). Selective expansion of a specific anti-tumor CD8+ cytotoxic T lymphocyte clone in the bulk culture of tumor-infiltrating lymphocytes from a melanoma patient: cytotoxic activity and T cell receptor gene rearrangements. Eur J Immunol 20: 825–831.

    Article  CAS  Google Scholar 

  • Grant SL, Begley CG . (1999). The oncostatin M signalling pathway: reversing the neoplastic phenotype? Mol Med Today 5: 406–412.

    Article  CAS  Google Scholar 

  • Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F . (2003). Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374: 1–20.

    Article  CAS  Google Scholar 

  • Heymann D, Blanchard F, Raher S, De Groote D, Godard A . (1995). Modulation of LIF expression in human melanoma cells by oncostatin M. Immunol Lett 46: 245–251.

    Article  CAS  Google Scholar 

  • Jaenisch R, Bird A . (2003). Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33 (Suppl): 245–254.

    Article  CAS  Google Scholar 

  • Jarry A, Masson D, Cassagnau E, Parois S, Laboisse C, Denis MG . (2004). Real-time allele-specific amplification for sensitive detection of the BRAF mutation V600E. Mol Cell Probes 18: 349–352.

    Article  CAS  Google Scholar 

  • Kim H, Baumann H . (1999). Dual signaling role of the protein tyrosine phosphatase SHP-2 in regulating expression of acute-phase plasma proteins by interleukin-6 cytokine receptors in hepatic cells. Mol Cell Biol 19: 5326–5338.

    Article  CAS  Google Scholar 

  • Klausen P, Pedersen L, Jurlander J, Baumann H . (2000). Oncostatin M and interleukin 6 inhibit cell cycle progression by prevention of p27kip1 degradation in HepG2 cells. Oncogene 19: 3675–3683.

    Article  CAS  Google Scholar 

  • Kortylewski M, Heinrich PC, Mackiewicz A, Schniertshauer U, Klingmuller U, Nakajima K et al. (1999). Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1. Oncogene 18: 3742–3753.

    Article  CAS  Google Scholar 

  • Kortylewski M, Jove R, Yu H . (2005). Targeting STAT3 affects melanoma on multiple fronts. Cancer Metastasis Rev 24: 315–327.

    Article  CAS  Google Scholar 

  • Labarriere N, Pandolfino MC, Gervois N, Khammari A, Tessier MH, Dreno B et al. (2002). Therapeutic efficacy of melanoma-reactive TIL injected in stage III melanoma patients. Cancer Immunol Immunother 51: 532–538.

    Article  CAS  Google Scholar 

  • Lu C, Rak JW, Kobayashi H, Kerbel RS . (1993). Increased resistance to oncostatin M-induced growth inhibition of human melanoma cell lines derived from advanced-stage lesions. Cancer Res 53: 2708–2711.

    CAS  PubMed  Google Scholar 

  • Marks PA, Richon VM, Miller T, Kelly WK . (2004). Histone deacetylase inhibitors. Adv Cancer Res 91: 137–168.

    Article  CAS  Google Scholar 

  • Mosley B, De Imus C, Friend D, Boiani N, Thoma B, Park LS et al. (1996). Dual oncostatin M (OSM) receptors. Cloning and characterization of an alternative signaling subunit conferring OSM-specific receptor activation. J Biol Chem 271: 32635–32643.

    Article  CAS  Google Scholar 

  • Mule JJ, McIntosh JK, Jablons DM, Rosenberg SA . (1990). Antitumor activity of recombinant interleukin 6 in mice. J Exp Med 171: 629–636.

    Article  CAS  Google Scholar 

  • Nawrocki S, Murawa P, Malicki J, Kapcinska M, Gryska K, Izycki D et al. (2000). Genetically modified tumour vaccines (GMTV) in melanoma clinical trials. Immunol Lett 74: 81–86.

    Article  CAS  Google Scholar 

  • Niu G, Bowman T, Huang M, Shivers S, Reintgen D, Daud A et al. (2002). Roles of activated Src and Stat3 signaling in melanoma tumor cell growth. Oncogene 21: 7001–7010.

    Article  CAS  Google Scholar 

  • Ozbek S, Peters M, Breuhahn K, Mann A, Blessing M, Fischer M et al. (2001). The designer cytokine hyper-IL-6 mediates growth inhibition and GM-CSF-dependent rejection of B16 melanoma cells. Oncogene 20: 972–979.

    Article  CAS  Google Scholar 

  • Pansky A, Hildebrand P, Fasler-Kan E, Baselgia L, Ketterer S, Beglinger C et al. (2000). Defective Jak-STAT signal transduction pathway in melanoma cells resistant to growth inhibition by interferon-alpha. Int J Cancer 85: 720–725.

    Article  CAS  Google Scholar 

  • Pfaffl MW . (2001). A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29: e45.

    Article  CAS  Google Scholar 

  • Pfaffl MW, Tichopad A, Prgomet C, Neuvians TP . (2004). Determination of stable housekeeping genes, differentially regulated target genes and sample integrity: BestKeeper – Excel-based tool using pair-wise correlations. Biotechnol Lett 26: 509–515.

    Article  CAS  Google Scholar 

  • Radtke S, Hermanns HM, Haan C, Schmitz-Van De Leur H, Gascan H, Heinrich PC et al. (2002). Novel role of Janus kinase 1 in the regulation of oncostatin M receptor surface expression. J Biol Chem 277: 11297–11305.

    Article  CAS  Google Scholar 

  • Sandor V, Bakke S, Robey RW, Kang MH, Blagosklonny MV, Bender J et al. (2002). Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms. Clin Cancer Res 8: 718–728.

    CAS  PubMed  Google Scholar 

  • Tanaka M, Miyajima A . (2003). Oncostatin M, a multifunctional cytokine. Rev Physiol Biochem Pharmacol 149: 39–52.

    Article  CAS  Google Scholar 

  • Wong LH, Krauer KG, Hatzinisiriou I, Estcourt MJ, Hersey P, Tam ND et al. (1997). Interferon-resistant human melanoma cells are deficient in ISGF3 components, STAT1, STAT2, and p48-ISGF3gamma. J Biol Chem 272: 28779–28785.

    Article  CAS  Google Scholar 

  • Yannelli JR, Wroblewski JM . (2004). On the road to a tumor cell vaccine: 20 years of cellular immunotherapy. Vaccine 23: 97–113.

    Article  CAS  Google Scholar 

  • Yoshida M, Furumai R, Nishiyama M, Komatsu Y, Nishino N, Horinouchi S . (2001). Histone deacetylase as a new target for cancer chemotherapy. Cancer Chemother Pharmacol 48 (Suppl 1): S20–26.

    Article  CAS  Google Scholar 

  • Yuan ZL, Guan YJ, Chatterjee D, Chin YE . (2005). Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307: 269–273.

    Article  CAS  Google Scholar 

  • Zarling JM, Shoyab M, Marquardt H, Hanson MB, Lioubin MN, Todaro GJ . (1986). Oncostatin M: a growth regulator produced by differentiated histiocytic lymphoma cells. Proc Natl Acad Sci USA 83: 9739–9743.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr M Denis (Inserm U539, Nantes, France) for performing the B-Raf mutation analysis. This work was supported by Association pour la Recherche sur le Cancer (F Blanchard), the Ligue contre le Cancer and the Institut National de la Santé et de la Recherche Médicale.

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Author notes

  1. F Blanchard

    Present address: INSERM, ERI7, 1 rue Gaston Veil, 44035, Nantes, cedex 1, France

Authors and Affiliations

  1. INSERM, U601, Groupe de Recherche Cytokines et Récepteurs, Institut de Biologie, Nantes, France

    A Lacreusette, M-C Pandolfino, Y Jacques, A Godard & F Blanchard

  2. Université de Nantes, UFR Médecine, IFR26, Institut de Biologie, Nantes, France

    A Lacreusette, M-C Pandolfino, Y Jacques, A Godard & F Blanchard

  3. PIMESP, Nantes, France

    J-M Nguyen

  4. Unit of Skin Cancer, CHU de Nantes, Nantes, France

    A Khammari & B Dreno

  5. Laboratoire de Biochimie, CHU de Nantes, Nantes, France

    A Godard

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  1. A Lacreusette
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Correspondence to A Godard or F Blanchard.

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

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Lacreusette, A., Nguyen, JM., Pandolfino, MC. et al. Loss of oncostatin M receptor β in metastatic melanoma cells. Oncogene 26, 881–892 (2007). https://doi.org/10.1038/sj.onc.1209844

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  • DOI: https://doi.org/10.1038/sj.onc.1209844

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