DOI QR코드

DOI QR Code

The Regulation of FOXP3 Expression by the Treatment of TGF-${\beta}$ and the Modification of DNA Methylation in Lung Cancer Cell Lines

  • Um, Sang-Won (Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Lee, Sang-Hee (Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Kim, Ho-Joong (Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Kwon, O-Jung (Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Kim, Hang-Rae (Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine) ;
  • Kang, Jae-Seung (Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine) ;
  • Lee, Wang-Jae (Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine)
  • Received : 2010.10.11
  • Accepted : 2010.12.07
  • Published : 2011.03.30

Abstract

Background: Transcription factor FOXP3 characterizes the thymically derived regulatory T cells. FOXP3 is expressed by cancer cell itself and FOXP3 expression was induced by TGF-${\beta}$ treatment in pancreatic cancer cell line. However, the expression of FOXP3 expression is not well known in patients with lung cancer. This study was conducted to investigate the expression of FOXP3 in patients with lung cancer and to investigate the regulation of FOXP3 expression by the treatment of TGF-${\beta}$ and DNA methyltransferase inhibitor in lung cancer cell lines. Methods: FOXP3 expression in the tissue of patients with resected non-small cell lung cancer (NSCLC) was evaluated by immunohistochemistry. The regulation of FOXP3 expression was investigated by Western blot and RT-PCR after lung cancer cell lines were stimulated with TGF-${\beta}1$ and TGF-${\beta}2$. The regulation of FOXP3 expression was also investigated by RT-PCR and flow cytometry after lung cancer cell lines were treated with DNA methyltransferase inhibitor (5-AZA-dC). Results: FOXP3 expression was confirmed in 27% of patients with NSCLC. In NCI-H460 cell line, TGF-${\beta}2$ decreased FOXP3 mRNA and protein expressions. In A549 cell line, both TGF-${\beta}1$ and TGF-${\beta}2$ decreased FOXP3 mRNA and protein expressions. 5-AZA-dC increased FOXP3 mRNA expression in NCI-H460 and A549 cell lines. Moreover, 5-AZA-dC increased intracellular FOXP3 protein expression in A549 cell lines. Conclusion: It was shown that FOXP3 is expressed by cancer cell itself in patients with NSCLC. Treatment of TGF-${\beta}2$ and DNA methyltransferase inhibitor seems to be associated with the regulation of FOXP3 expression in lung cancer cell lines.

Keywords

References

  1. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 2005;22:329-41. https://doi.org/10.1016/j.immuni.2005.01.016
  2. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057-61. https://doi.org/10.1126/science.1079490
  3. Zuo T, Wang L, Morrison C, Chang X, Zhang H, Li W, et al. FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene. Cell 2007;129:1275-86. https://doi.org/10.1016/j.cell.2007.04.034
  4. Hinz S, Pagerols-Raluy L, Oberg HH, Ammerpohl O, Grussel S, Sipos B, et al. Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer. Cancer Res 2007;67:8344-50. https://doi.org/10.1158/0008-5472.CAN-06-3304
  5. Merlo A, Casalini P, Carcangiu ML, Malventano C, Triulzi T, Menard S, et al. FOXP3 expression and overall survival in breast cancer. J Clin Oncol 2009;27:1746-52. https://doi.org/10.1200/JCO.2008.17.9036
  6. Zuo T, Liu R, Zhang H, Chang X, Liu Y, Wang L, et al. FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2. J Clin Invest 2007;117:3765-73.
  7. Wang L, Liu R, Li W, Chen C, Katoh H, Chen GY, et al. Somatic single hits inactivate the X-linked tumor suppressor FOXP3 in the prostate. Cancer Cell 2009;16:336-46. https://doi.org/10.1016/j.ccr.2009.08.016
  8. Ebert LM, Tan BS, Browning J, Svobodova S, Russell SE, Kirkpatrick N, et al. The regulatory T cell-associated transcription factor FoxP3 is expressed by tumor cells. Cancer Res 2008;68:3001-9. https://doi.org/10.1158/0008-5472.CAN-07-5664
  9. Karanikas V, Speletas M, Zamanakou M, Kalala F, Loules G, Kerenidi T, et al. Foxp3 expression in human cancer cells. J Transl Med 2008;6:19. https://doi.org/10.1186/1479-5876-6-19
  10. Kim HP, Leonard WJ. CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J Exp Med 2007;204:1543-51. https://doi.org/10.1084/jem.20070109
  11. Cui DD, Huang Y, Mao SH, Chen SC, Qiu M, Ji LL, et al. Synergistic antitumor effect of TRAIL and adriamycin on the human breast cancer cell line MCF-7. Braz J Med Biol Res 2009;42:854-62. https://doi.org/10.1590/S0100-879X2009000900013
  12. Kretzschmar M, Doody J, Timokhina I, Massague J. A mechanism of repression of TGFbeta/Smad signaling by oncogenic Ras. Genes Dev 1999;13:804-16. https://doi.org/10.1101/gad.13.7.804
  13. Massague J, Gomis RR. The logic of TGFbeta signaling. FEBS Lett 2006;580:2811-20. https://doi.org/10.1016/j.febslet.2006.04.033
  14. Park C, Kim WS, Choi Y, Kim H, Park K. Effects of transforming growth factor beta (TGF-beta) receptor on lung carcinogenesis. Lung Cancer 2002;38:143-7. https://doi.org/10.1016/S0169-5002(02)00182-4

Cited by

  1. Regulatory T cells and potential inmmunotherapeutic targets in lung cancer vol.34, pp.2, 2011, https://doi.org/10.1007/s10555-015-9566-0