Abstract
To escape the immune system, tumor cells may remove surface molecules such as the major histocompatibility complex (MHC) and co-stimulatory molecules, which are essential for recognition by lymphocytes. Down-regulation of the co-stimulatory molecules CD70 (TNFSF7) and CD80 may contribute to tumor cell survival; however, the mechanism of down-regulation of the TNFSF7 gene during tumorigenesis is poorly understood. Here we present evidence indicating that TNFSF7 gene expression is epigenetically down-regulated via DNA hypermethylation within its promoter region during progression in breast cancer cells in the isogenic MCF10 model. Bisulfite sequencing revealed that the CpG pairs at the proximal region of the TNFSF7 promoter are heavily methylated during progression of breast cancer cells but that methylation of the more distal sequences was not changed considerably. Thus, this epigenetic silencing of the TNFSF7 gene via hypermethylation of its proximal region may allow the benign and invasive MCF10 variants to escape immune surveillance.
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References
Baylin, S.B., and Jones, P.A. (2007). Epigenetic determinants of cancer. In Epigenetics, C.D. Allis, T. Jenuwein, and D. Reinberg, eds. (New York, USA: Cold Spring Harbor, Cold Spring Harbor Laboratory Press), pp. 457–476.
Borst, J., Hendriks, J., and Xiao, Y. (2005). CD27 and CD70 in T cell and B cell activation. Curr. Opin. Immunol. 17, 275–281.
Choi, B., Suh, Y., Kim, W.H., Christa, L., Park, J., and Bae, C.D. (2007). Down-regulation of regenerating islet-derived 3 alpha (REG3A) in primary human gastric adenocarcinomas. Exp. Mol. Med. 39, 796–804.
Cormary, C., Gonzalez, R., Faye, J.C., Favre, G., and Tilin-Mariame, A.F. (2004). Induction of T-cell antitumor immunity and protection against tumor growth by secretion of soluble human CD70 molecules. Cancer Gene Ther. 11, 497–507.
Diegmann, J., Junker, K., Loncarevic, I.F., Michel, S., Schimmel, B., and Eggeling, Fv. (2006). Immune escape for renal cell carcinoma: CD70 mediates apoptosis in mymphocytes. Neoplasia 8, 933–938.
Douin-Echinard, V., Bornes, S., Rochaix, P., Tilkin, A.F., Peron, J.M., Bonnet, J., Favre, G., and Coudere, B. (2000). The expression of CD70 and CD80 by gene-modified tumor cells induces an antitumor response depending on the MHC status. Cancer Gene Ther. 7, 1543–1556.
Douin-Echinard, V., Peron, J.M., Lauwers-Cances, V., Favre, G., and Couderc, B. (2003). Involvement of CD70 and CD80 intracytoplasmic domains in the co-stimulatory signal required to provide an antitumor immune response. Int. Immunol. 15, 359–372.
Huang, Y., Tan, M., Gosink, M., Wang, K.K.W., and Sun, Y. (2002). Histone deacetylase 5 is not a p53 target gene, but its overexpression inhibits tumor cell growth and induces apoptosis. Cancer Res. 62, 2913–2922.
Hurst, D.R., Xie, Y., Edmonds, M.D., and Welch, D.R. (2009). Multiple forms of BRMS1 are differentially expressed in the MCF10 isogenic breast cancer progression model. Clin. Exp. Metastasis 26, 89–96.
Kim, J.H., Hwang, E.H., Park, H.J., Paik, Y.K., and Shim, Y.H. (2005). Methylation of CpG islands in the rat 7-dehydrocholesterol reductase promoter suppresses transcriptional activation. Mol. Cells 19, 279–282.
Lu, Q., Wu, A., and Richardson, B.C. (2005). Demethylation of the same promoter sequence increases CD70 expression in Lupus T cells and T cells treated with Lupus-inducing drugs. J. Immunol. 174, 6212–6219.
Marella, N.V., Malyavantham, K.S., Wang, J., Matsui, S., Liang, P., and Berezney, R. (2009). Cytogenetic and cDNA microarray expression analysis of MCF10 human breast cancer progresssion cell lines. Cancer Res. 69, 5946–5953.
Motegi, K., Azuma, M., Tamatani, T., Ashida, Y., and Sato, M. (2005). Expression of aquaporin-5 in and fluid secretion from immortalized human salivary gland ductal cells by treatment with 5-aza-2’-deoxycytidine: a possibility for improvement of xerostomia in patients with Sjogren-fs syndrome. Lab. Invest. 85, 342–353.
Pardoll, D.M. (1998). Cancer vaccines. Nat. Med. 4, 525–531.
Park, W.S., Cho, Y.G., Kim, C.J., Song, J.H., Lee, Y.S., Kim, S.Y., Nam, S.W., Lee, S.H., Yoo, N.J., and Lee, J.Y. (2005). Hypermethylation of the RUNX3 gene in hepatocellular carcinoma. Exp. Mol. Med. 37, 276–281.
Park, H.Y., Jeon, Y.K., Shin, H.J., Kim, I.J., Kang, H.C., Jeong, S.J., Chung, D.H., and Lee, C.W. (2007). Differential promoter methylation may be a key molecular mechanism in regulating BubR1 expression in cancer cells. Exp. Mol. Med. 39, 195–204.
Rhee, D.K., Park, S.H., and Jang, Y.K. (2008). Molecular signatures associated with transformation and progression to breast cancer in the isogenic MCF10 model. Genomics 92, 419–428.
Robertson, K.D. (2005). DNA methylation and human disease. Nat. Rev. Genet. 6, 597–610.
Santner, S.J., Dawson, P.J., Tait, L., Soule, H.D., Eliason, J., Mohamed, A.N., Wolman, S.R., Heppner, G.H., and Miller, F.R. (2001). Malignant MCF10CA1 cell lines derived from premalignant human breast epithelial MCF10AT cells. Breast Cancer Res. Treat. 65, 101–110.
Song, J.H., Choi, C.H., Yeom, H.J., Hwang, S.Y., and Kim, T.S. (2006). Monitoring the gene expression profiles of doxorubicinresistant acute myelocytic leukemia cells by DNA microarray analysis. Life Sci. 79, 193–202.
Worsham, M.J., Pals, G., Schouten, J.P., Miller, F.R., Tiwari, N., van Spaendonk, R., and Wolman, S.R. (2006). High-resolution mapping of molecular events associated with immortalization, transforma-tion, and progression to breast cancer in the MCF10 model. Breast Cancer Res. Treat. 96, 177–186.
Xu, J., Zhou, J.Y., Tainsky, M.A., and Wu, G.S. (2007). Evidence that tumor necrosis factor-related apoptosis-inducing ligand induction by 5-Aza-2’-deoxycytidine sensitizes human breast cancer cells to adriamycin. Cancer Res. 67, 1203–1211.
Zhu, J.Q., Liu, J.H., Liang, X.W., Xu, B.Z., Hou, Y., Zhao, X.X., and Sun, Q.Y. (2008). Heat stress causes aberrant DNA methylation of H19 and Igf-2r on mouse balstocysts. Mol. Cells 25, 211–215.
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Yu, S.E., Park, S.H. & Jang, Y.K. Epigenetic silencing of TNFSF7 (CD70) by DNA methylation during progression to breast cancer. Mol Cells 29, 217–221 (2010). https://doi.org/10.1007/s10059-010-0052-9
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DOI: https://doi.org/10.1007/s10059-010-0052-9