The importance of alpha/beta (α/β) interferon receptors and signaling pathways for the treatment of cervical intraepithelial neoplasias
1Oncology Research Institute, IPON, Federal University of Triangulo Mineiro (UFTM), Uberaba, MG
2Discipline of Immunology, Oncology Research Institute (IPON), Federal University of Triângulo Mineiro (UFTM), Uberaba, MG
3Discipline of Gynecology and Obstetrics, Oncology Research Institute (IPON), Federal University of Triângulo Mineiro (UFTM), Uberaba, MG (Brazil)
DOI: 10.12892/ejgo24612014 Vol.35,Issue 4,July 2014 pp.368-372
Published: 10 July 2014
*Corresponding Author(s): E.F.C. Murta E-mail: firstname.lastname@example.org
Introduction: Immunotherapies have been effective in treating various forms of cancer, including cervical intraepithelial neoplasias (CINs) predominantly caused by human papilloma virus (HPV). Development: To establish persistent infections in stratified epithelia, HPV induces proliferative lesions. Viral gene products are able to change gene expression and cellular proteins. Interferons (IFNs) are inducible glycoproteins that have immunomodulatory, antiviral, antiproliferative, and antiangiogenic effects. In particular, interferon-alpha (IFN-α) has been shown to inhibit the development and progression of cervical cancer. In this review, actions of interferons α/beta (α/β), including their receptors and signaling pathways, are described, as well as their clinical importance in the immune response against cervical lesions. Conclusion: The interaction of IFN-α/β with its receptor results in a series of phosphorylation events. These mechanisms can be ineffective in IFN response, then it can also compromise the therapeutic effects of immunotherapy.
Type I Interferons; Interferon receptors; Cervical neoplasia.
L. Montes,C.M.R. Andrade,M.A. Michelin,E.F.C. Murta. The importance of alpha/beta (α/β) interferon receptors and signaling pathways for the treatment of cervical intraepithelial neoplasias. European Journal of Gynaecological Oncology. 2014. 35(4);368-372.
 Schiffman M.H., Bauer H.M., Hoover R.N., Glass A.G., Cadell D. M., Rush B.B., et al.: “Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia”. J. Natl. Cancer Inst., 1993; 85, 958.
 Shingleton H.M., Richart R.M., Wiener J., Spiro D.: “Human cervical intraepithelial neoplasia: fine structure of dysplasia and carcinoma in situ”. Cancer Res., 1968, 28, 695.
 Hong S., Mehta K.P., Laimins L.A.: “Suppression of STAT-1 expression by human papillomaviruses is necessary for differentiation-dependent genome amplification and plasmid maintenance”. J. Virol., 2011, 85, 9486.
 Goubau D., Romieu-Mourez R., Solis M., Hernandez E., Mesplènde T., Lin R., et al.:“Transcriptional re-programming of primary macrophages reveals distinct apoptotic and anti-tumoral functions of IRF-3 and IRF-7”. Eur. J. Immunol. ,2009, 39, 527.
 Boccardo E., Lepique A.P., Villa L.L.: “The role of inflammation in HPV carcinogenesis”. Carcinogenesis, 2010, 31, 1905.
 Levy D.E., Darnell J.E.: “Interferon-dependent transcriptional activation: signal transduction without second messenger involvement?” New Biol., 1990, 2, 923.
 Darnell J.E.: “STATs and gene regulation”. Science, 1997, 277, 1630.
 Darnell J.E. Jr., Kerr I.M., Stark G.R.: “Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins”. Science, 1994, 264, 1415.
 Horvath C.M., Darnell J.E. Jr.: “The antiviral state induced by alpha interferon and gamma interferon requires transcriptionally active stat1 protein”. J. Virol., 1996, 70, 647.
 Novick D., Cohen B., Rubinstein M.: “The human interferon alpha/beta receptor: characterization and molecular cloning”. Cell. 1994, 77, 391.
 Kim S.H., Cohen B., Novick D., Rubinstein M.: “Mammalian type I interferon receptors consists of two subunits: IFNaR1 and IFNaR2”. Gene, 1997, 196, 279.
 Ghislain J., Sussman G., Goelz S., Ling L.E., Fish E.N.: “Configuration of the interferon-α/β receptor complex determines the context of the biological response”. J. Biol. Chem., 1995, 270, 21785.
 Moraga I., Harari D., Schreiber G., Uzé G., Pellegrini S.: “Receptor density is key to the alpha2/beta interferon differential activities”. Mol. Cell. Biol., 2009, 17, 4778.
 Liu J., Plotnikov A., Banerjee A., Suresh Kumar K.G., Ragimbeau J., Marijanovic Z., et al.:“Ligand-independent pathway that controls stability of interferon alpha receptor”. Biochem. Biophys. Res. Commun., 2008, 367, 388.
 Ramos M.C., Mardegan M.C., Peghini B.C., Adad S.J., Michelin M. A., Murta E.F.C.: “Expression of cytokines in cervical stroma in patients with high-grade cervical intraepithelial neoplasia after treatment with intralesional interferon alpha-2b”. Eur. J. Gynaecol. Oncol., 2010, 31, 522.
 Mardegan M.C., Ramos M.C., Adad S.J., Michelin M.A., Shimba D., Murta E.F.: “Immunological evaluation of vaginal secretion in patients with high-grade cervical intraepithelial neoplasia treated with intralesional interferon alpha-2b”. Eur. J. Gynaecol. Oncol., 2011, 32, 297.
 Tirone N.R., Peghini B.C., Barcelos A.C.M., Murta E.F.C., Michelin M.A.: “Local expression of interferon-alpha and interferon receptors in cervical intraepithelial neoplasia”. Cancer Immunol. Immunother., 2009, 58, 2003.
 Ota H., Nagano H., Sakon M., Eguchi H., Kondo M., Yamamoto T., et al.: “Treatment of hepatocellular carcinoma with major portal vein thrombosis by combined therapy with subcutaneous interferon-alpha and intra-arterial 5-fluorouracil; role of type 1 interferon receptor expression”. Br. J. Cancer, 2005, 93, 557.
 Vitale G., van Eijck C.H., van Koetsveld Ing. P.M., Erdmann J.I., Speel E.J., Van Wansem Ing. K., et al.:“Type Iinterferons in the treatment of pancreatic cancer. Mechanisms of action and role of related receptors”. Ann. Surg., 2007, 246, 259.
 Chang Y.E., Laimins L.A.: “Microarray analysis identifies interferon-inducible genes and Stat-1 as major transcriptional targets of human papillomavirus type 31”. J. Virol., 2000, 74, 4174.
 Hiscott J.: “Triggering the innate antiviral response through IRF-3 activation”. J. Biol. Chem., 2007, 282, 15325.
 Alarcón-Riquelme M.: “Nucleic acid by-products and chronic inflammation”. Nat Genet., 2006, 38, 866.
 Murata M., Nabeshima S., Kikuchi K., Yamaji K., Furusyo N., Hayashi J.: “A comparison of the antitumor effects of interferon-α and β on human hepatocellular carcinoma cell lines”. Cytokine, 2006, 33, 121.
 Murta E.F.C., Tavares-Murta B.M.: “Successful pregnancy after vaginal cancer treated with interferon”. Tumori, 2004, 90, 247.
 Kim K.Y., Blatt L., Taylor M.W.: “The effects of interferon on the expression of human papillomavirus oncogenes”. J. Gen. Virol., 2000, 81, 695.
 Woodworth C.D., Simpson S.: “Comparative lymphokine secretion by cultured normal human cervical keratinocytes, papillomavirus-immortalized, and carcinoma cell lines”. Am. J. Pathol., 1993, 142,1544.
 Prchal-Murphy M., Semper C., Lassnig C., Wallner B., Gausterer C., Teppner-Klymiuk I., et al.: “TYK2 kinase activity is required for functional type I interferon responses in vivo”. Plos. One, 2012, 7, 1.
 Bromberg J.F., Horvath C.M., Wen Z., Schreiber R.D., Darnell J.E. Jr.: “Transcriptionally active STAT1 is required for the antiproliferative effects of both interferon-α and interferon-γ”. Proc. Natl. Acad. Sci. U S A, 1996, 93, 7673.
 Uzé G., Lutfalla G., Bandu M.T., Proudhon D., Mogensen K.E.: “Behaviour of a cloned murine interferon alpha/beta receptor expressed in homospecific or heterospecific background”. Proc. Natl. Acad. Sci. U S A, 1992, 89, 4774.
 He X., Chang Y., Jiang H., Tang F., Meng F., Xie Q., et al.: “Persistent effect of IFNAR-1 genetic polymorphism on the long-term pathogenesis of chronic HBV infection”. Viral. Immunol., 2010, 23, 251.
 Hsieh C.S., Macatonia S.E., Tripp C.S., Wolf S.F., O’garra A., Murphy K.M.: “Development of TH1 CD4+ T cells through IL-12 produced by Listeria induced macrophages”. Science, 1993, 260, 547.
 Müller U., Steinhoff U., Reis L.F.L., Hemmi S., Paviovic J., Zinkernagel R.M., et al.: “Functional role of type I and type II interferons in antiviral defense”. Science, 1994, 264, 1918.
 Kotenko S.V., Gallagher G., Baurin V.V., Lewis-Antes A., Shen M., Shah N.K., et al.:“IFN-λs mediate antiviral protection through a distinct class II cytokine receptor complex”. Nat. Immunol., 2003, 4, 69.
 Aaronson D.S., Horvath C.M.: “A road map for those who don’t know JAK-STAT”. Science, 2002, 296, 1653.
Vol., Issue , Invalid dateTable of contents
Science Citation Index Expanded (SciSearch) Created as SCI in 1964, Science Citation Index Expanded now indexes over 9,500 of the world’s most impactful journals across 178 scientific disciplines. More than 53 million records and 1.18 billion cited references date back from 1900 to present.
Biological Abstracts Easily discover critical journal coverage of the life sciences with Biological Abstracts, produced by the Web of Science Group, with topics ranging from botany to microbiology to pharmacology. Including BIOSIS indexing and MeSH terms, specialized indexing in Biological Abstracts helps you to discover more accurate, context-sensitive results.
Google Scholar Google Scholar is a freely accessible web search engine that indexes the full text or metadata of scholarly literature across an array of publishing formats and disciplines.
JournalSeek Genamics JournalSeek is the largest completely categorized database of freely available journal information available on the internet. The database presently contains 39226 titles. Journal information includes the description (aims and scope), journal abbreviation, journal homepage link, subject category and ISSN.
Current Contents - Clinical Medicine Current Contents - Clinical Medicine provides easy access to complete tables of contents, abstracts, bibliographic information and all other significant items in recently published issues from over 1,000 leading journals in clinical medicine.
BIOSIS Previews BIOSIS Previews is an English-language, bibliographic database service, with abstracts and citation indexing. It is part of Clarivate Analytics Web of Science suite. BIOSIS Previews indexes data from 1926 to the present.
Journal Citation Reports/Science Edition Journal Citation Reports/Science Edition aims to evaluate a journal’s value from multiple perspectives including the journal impact factor, descriptive data about a journal’s open access content as well as contributing authors, and provide readers a transparent and publisher-neutral data & statistics information about the journal.