Aberrant Methylation of IL-12Rβ2 Gene in Lung Adenocarcinoma Cells Is Associated with Unfavorable Prognosis

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• 作者：Makoto Suzuki MD (1)
  Toshihiko Iizasa MD (1)
  Takahiro Nakajima MD (1)
  Rieko Kubo PhD (1)
  Akira Iyoda MD (1)
  Kenzo Hiroshima MD (2)
  Yukio Nakatani MD (2)
  Takehiko Fujisawa MD (1)
  
• 关键词：IL ; 12Rβ2 ; Methylation ; Lung cancer ; Prognosis
• 刊名：Annals of Surgical Oncology
• 出版年：2007
• 出版时间：September 2007
• 年：2007
• 卷：14
• 期：9
• 页码：2636-2642
• 全文大小：308KB
• 参考文献：1. Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. / Nat Rev Immunol 2003; 3:133-6. CrossRef
  2. Hill HC, Conway TF Jr, Sabel MS, Jong YS, Mathiowitz E, Bankert RB, Egilmez NK. Cancer immunotherapy with interleukin 12 and granulocyte-macrophage colony-stimulating factor-encapsulated microspheres: coinduction of innate and adaptive antitumor immunity and cure of disseminated disease. / Cancer Res 2002; 62:7254-3.
  3. Qian C, Liu XY, Prieto J. Therapy of cancer by cytokines mediated by gene therapy approach. / Cell Res 2006; 6:182-. CrossRef
  4. Sangro B, Melero I, Qian C, Prieto J. Gene therapy of cancer based on interleukin 12. / Curr Gene Ther 2005; 5:573-1. CrossRef
  5. Presky DH, Yang H, Minetti LJ, Chua AO, Nabavi N, Wu CY, Gately MK, Gubler U. A functional interleukin 12 receptor complex is composed of two beta-type cytokine receptor subunits. / Proc Natl Acad Sci USA 1996; 93:14002-. CrossRef
  6. Yao BB, Niu P, Surowy CS, Faltynek CR. Direct interaction of STAT4 with the IL-12 receptor. / Arch Biochem Biophys 1999; 368:147-5. CrossRef
  7. Airoldi I, Guglielmino R, Carra G, Corcione A, Gerosa F, Taborelli G, Trinchieri G, Pistoia V. The interleukin-12 and interleukin-12 receptor system in normal and transformed human B lymphocytes. / Haematologica 2002; 87:434-2.
  8. Airoldi I, Di Carlo E, Banelli B, Moserle L, Cocco C, Pezzolo A, Sorrentino C, Rossi E, Romani M, Amadori A, Pistoia V. The IL-12Rbeta2 gene functions as a tumor suppressor in human B cell malignancies. / J Clin Invest 2004; 113:1651-. CrossRef
  9. Airoldi I, Cocco C, Di Carlo E, Disaro S, Ognio E, Basso G, Pistoia V. Methylation of the IL-12Rbeta2 gene as novel tumor escape mechanism for pediatric B-acute lymphoblastic leukemia cells. / Cancer Res 2006; 66:3978-0. CrossRef
  10. Airoldi I, Di Carlo E, Cocco C, Sorrentino C, Fais F, Cilli M, D’Antuono T, Colombo MP, Pistoia V. Lack of Il12rb2 signaling predisposes to spontaneous autoimmunity and malignancy. / Blood 2005; 106:3846-3. CrossRef
  11. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. / Nat Rev Genet 2002; 3:415-8. CrossRef
  12. Suzuki M, Shigematsu H, Iizasa T, Hiroshima K, Nakatani Y, Minna JD, Gazdar AF, Fujisawa T. Exclusive mutation in epidermal growth factor receptor gene, HER-2, and KRAS, and synchronous methylation of nonsmall cell lung cancer. / Cancer 2006; 106:2200-. CrossRef
  13. Suzuki M, Toyooka S, Shivapurkar N, Shigematsu H, Miyajima K, Takahashi T, Stastny V, Zern AL, Fujisawa T, Pass HI, Carbone M, Gazdar AF. Aberrant methylation profile of human malignant mesotheliomas and its relationship to SV40 infection. / Oncogene 2005; 24:1302-. CrossRef
  14. Shigematsu H, Suzuki M, Takahashi T, Miyajima K, Toyooka S, Shivapurkar N, Tomlinson GE, Mastrangelo D, Pass HI, Brambilla E, Sathyanarayana UG, Czerniak B, Fujisawa T, Shimizu N, Gazdar AF. Aberrant methylation of HIN-1 (high in normal-1) is a frequent event in many human malignancies. / Int J Cancer 2005; 113:600-. CrossRef
  15. Takahashi T, Suzuki M, Shigematsu H, Shivapurkar N, Echebiri C, Nomura M, Stastny V, Augustus M, Wu CW, Wistuba II, Meltzer SJ, Gazdar AF. Aberrant methylation of Reprimo in human malignancies. / Int J Cancer 2005; 115:503-0. CrossRef
  16. Ragnarsson G, Eiriksdottir G, Johannsdottir JT, Jonasson JG, Egilsson V, Ingvarsson S. Loss of heterozygosity at chromosome 1p in different solid human tumours: association with survival. / Br J Cancer 1999; 79:1468-4. CrossRef
  17. Suzuki M, Shigematsu H, Shames DS, Sunaga N, Takahashi T, Shivapurkar N, Iizasa T, Frenkel EP, Minna JD, Fujisawa T, Gazdar AF. DNA methylation-associated inactivation of TGFbeta-related genes DRM/Gremlin, RUNX3, and HPP1 in human cancers. / Br J Cancer 2005; 93:1029-7. CrossRef
  18. Airoldi I, Gri G, Marshall JD, Corcione A, Facchetti P, Guglielmino R, Trinchieri G, Pistoia V. Expression and function of IL-12 and IL-18 receptors on human tonsillar B cells. / J Immunol 2000; 165:6880-.
  19. Suzuki M, Toyooka S, Miyajima K, Iizasa T, Fujisawa T, Bekele NB, Gazdar AF. Alterations in the mitochondrial displacement loop in lung cancers. / Clin Cancer Res 2003; 9:5636-1.
  20. Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. / Proc Natl Acad Sci USA 1996; 93:9821-. CrossRef
  
• 作者单位：Makoto Suzuki MD (1)
  Toshihiko Iizasa MD (1)
  Takahiro Nakajima MD (1)
  Rieko Kubo PhD (1)
  Akira Iyoda MD (1)
  Kenzo Hiroshima MD (2)
  Yukio Nakatani MD (2)
  Takehiko Fujisawa MD (1)
  
  1. Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
  2. Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan
  

文摘

Background Interleukin-12 receptor β2 (IL-12Rβ2) knock-out mice develop lung adenocarcinoma, and epigenetic silencing by CpG methylation leads to loss of this gene in B-cell malignancies. The aim of this study was to determine whether IL-12Rβ2 methylation is a common feature in human lung cancer. Methods We examined mRNA expression of IL-12Rβ2 in lung cancer cell lines, and normal bronchial, and tracheal epithelial cells using RT-PCR, and we examined the methylation status of IL-12Rβ2 in primary lung cancers. Results Loss of expression was found in 10 of 13 (77%) NSCLC cell lines, and 2 of 5 (40%) SCLC cell lines compared with normal bronchial or tracheal cells. Treatment of 11 expression-negative cell lines with a demethylating agent restored expression in all cases. Aberrant methylation status of IL-12Rβ2 gene was reversely concordant with its mRNA expression. IL-12Rβ2 methylation was detected in 96 of 230 primary NSCLCs (42%) and 3 of 6 primary SCLCs (50%). IL-12Rβ2 methylation correlated with poorer prognosis in lung adenocarcinomas (hazard ratio?=?2.33, P?=?0.0059). Conclusions We conclude that epigenetic silencing of IL-12Rβ2 is a frequent event in lung cancers. Aberrant methylation of this gene seems to be a useful predictor of long-term outcome for adenocarcinoma of the lung.