Abstract
Interferon alpha (IFN-α) represents an adjuvant therapy of proven effectiveness in increasing disease-free interval and survival in subgroups of melanoma patients. Since high doses of cytokine are required, the treatment is often accompanied by toxic side effects. In addition, naturally occurring insensitivity to IFN-α may hamper its therapeutic efficacy. Clinical, molecular or immunological markers enabling the selection of potential responders have not so far been identified. To explore the molecular basis of IFN-α responsiveness, we analyzed the expression pattern of about 7000 genes in IFN-α-sensitive and IFN-α-resistant cell lines using high-density oligonucleotide arrays. Melanoma cell lines were screened for their sensitivity to proliferation inhibition and HLA class I induction by IFN-α by standard 3H-thymidine incorporation and flow cytometry. Total cellular RNA from four sensitive and two resistant cell lines was extracted, reverse-transcribed and hybridized to high- density oligonucleotide arrays. The comparative analysis of gene expression in either set of cell lines allowed the identification of four genes (RCC1, IFI16, hox2 and hi9) preferentially transcribed in sensitive cells and two (SHB and PKC-0 preferentially expressed in resistant cells.
These data may provide a useful basis for the development of diagnostic tools to select potential IFN-a responders as eligible for treatment, while avoiding unnecessary toxicity to nonresponders.
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References
Acampora D, D’Esposito M, Faiella A, Pannese M, Migliaccio E, Morelli F, Stornaiuolo A, Nigro V, Simeone A, Boncinelli E (1989) The human HOX gene family. Nucleic Acids Res 17:10385–10402.
Agarwala SS, Kirkwood JM (1996) Interferons in melanoma. Curr Opin Oncol 8:167–174.
Barbee JL, Loomis CR, Deutscher SL, Burns DJ (1993) The cDNA sequence encoding human protein kinase C-zeta. Gene 132:305–306.
Bischoff FR, Ponstingl H (1991) Catalysis of guanine nucleotide exchange on Ran by the mitotic regulator RCC1. Nature 354:80–82.
Brannan CI, Dees EC, Ingram RS, Tilghman SM (1990) The product of the H19 gene may function as an RNA. Mol Cell Biol 19:28–36.
Certa U, de Saizieu A, Mous J (2001) Hybridization analysis of labeled RNA by oligonucleotide arrays. Methods Mol Biol 170:141–156.
DeRisi J, Penland L, Brown PO, Bittner ML, Meltzer PS, Ray M, Chen Y, Su YA, Trent JM (1996) Use of a cDNA microarray to analyse gene expression patterns in human cancer. Nat Genet 14:457–460.
Grob JJ, Dreno B, de la Salmoniere P, Delaunay M, Cupissol D, Guillot B, Souteyrand P, Sas- solas B, Cesarini J-P, Lionnet S, Lok C, Chastang C, Bonerandi JJ (1998) Randomised trial of interferon a-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases Lancet 351:1905–1910.
Heller RA, Schena M, Chai A, Shalon D, Bedilion T, Gilmore J, Woolley DE, Davis RW (1997) Discovery and analysis of inflammatory disease-related genes using cDNA micro- arrays. Proc Natl Acad Sci USA 94:2150–2155.
Iyer VR, Eisen MB, Ross DT, Schuler G, Moore T, Lee JCF, Trent JM, Staudt LM, Hudson J, Boguski MS, Lashkari D, Shalon D, Botstein D, Brown PO (1999) The transcriptional program in the response of human fibroblasts to serum. Science 283:83–87.
Kirkwood JM (1998) Adjuvant IFN alpha2 therapy of melanoma. Lancet 351:1901–1903.
Kirkwood JM, Resnick GD, Cole BF (1997) Efficacy, safety, and risk-benefit analysis of adjuvant interferon alfa-2b in melanoma. Semin Oncol 24:16–23.
Lüscher U, Filgueira L, Juretic A, Zuber M, Liischer NJ, Heberer M, Spagnoli GC (1994) The pattern of cytokine gene expression in freshly excised human metastatic melanoma suggests a state of reversible anergy of tumor-infiltrating lymphocytes. Int J Cancer 57:612–619.
Mahadevappa M, Warrington JA (1999) A high-density probe array sample preparation method using 10- to 100-fold fewer cells. Nat Biotechnol 17:1134–1136.
Marton MJ, DeRisi JL, Bennett HA, Iyer VR, Meyer MR, Roberts CJ, Stoughton R, Burchard J, Slade D, Dai H, Bassett DE, Hartwell LH, Brown PO, Friend SH (1998) Drug target validation and identification of secondary drug target effects using DNA microarrays. Nat Med 4:1293–1301.
Pansky A, Hildebrand P, Fasler-Kann E, Baselgia L, Ketterer S, Beglinger C, Heim MH (2000) Defective Jak-STAT signal transduction pathway in melanoma cells resistant to growth inhibition by interferon-a. Int J Cancer 85:720–725.
Pollack JR, Perou CM, Alizadeh AA, Eisen MB, Pergamenschikov A, Williams CF, Jeffrey SS, Botstein D, Brown PO (1999) Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nat Gen 23:41–46.
Ralph SJ, Wines BD, Payne MJ, Grubb D, Hatzinisiriou I, Linnane AW, Devenish RJ (1995) Resistance of melanoma cell lines to interferons correlates with reduction of IFN-in- duced tyrosine phosphorylation. Induction of the anti-viral state by IFN is prevented by tyrosine kinase inhibitors. J Immunol 154:2248–2256.
Schena M, Shalon D, Davis RW, Brown PO (1995) Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270:467–470.
Schena M, Shalon D, Heller R, Chai A, Brown PO, Davis RW (1996) Parallel human genome analysis, microarray-based expression monitoring of 1000 genes. Proc Natl Acad Sci USA 93:10614–10619.
Trapani JA, Dawson M, Apostolidis VA, Browne KA (1994) Genomic organization of IFI16, an interferon-inducible gene whose expression is associated with human myeloid cell differentiation: correlation of predicted protein domains with exon organization. Immuno- genetics 40:415–424.
Vial T, Descotes J (1994) Clinical toxicity of Interferons. Drug Safety 10:115–150.
Welsh M, Mares J, Karlsson T, Lavergne C, Breant B, Claesson-Welsh L (1994) Shb is a ubiquitously expressed Src homology 2 protein. Oncogene 9:19–27.
Wong LH, Krauer KG, Hatzinisiriou I, Estcourt MJ, Hersey P, Tam ND, Edmonson S, Devenish RJ, Ralph SJ (1997) Interferon-resistant human melanoma cells are deficient in ISGF3 components, STAT1, STAT2, and p48-ISGF3gamma. J Biol Chem 272:28779–28785.
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Certa, U., Seiler, M., Padovan, E., Spagnoli, G.C. (2002). Interferon-α Sensitivity in Melanoma Cells: Detection of Potential Response Marker Genes. In: Dummer, R., Nestle, F.O., Burg, G. (eds) Cancers of the Skin. Recent Results in Cancer Research, vol 160. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-59410-6_12
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DOI: https://doi.org/10.1007/978-3-642-59410-6_12
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