Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Inhibition of Oncogenes Affects the Expression of NKG2D Ligands in Cancer Cells

k-ras와 c-myc, wnt 억제에 의한 NKG2D 리간드의 발현변화

  • Heo, Woong (Department of Biochemistry, Pusan National University School of Medicine) ;
  • Lee, Young Shin (Department of Biochemistry, Pusan National University School of Medicine) ;
  • Bae, Jaeho (Department of Biochemistry, Pusan National University School of Medicine)
  • 허웅 (부산대학교 의학전문대학원 생화학교실) ;
  • 이영신 (부산대학교 의학전문대학원 생화학교실) ;
  • 배재호 (부산대학교 의학전문대학원 생화학교실)
  • Received : 2013.09.06
  • Accepted : 2013.10.26
  • Published : 2013.10.30
Download PDF
⟨ Previous Next ⟩

Abstract

NK cells are lymphoid immune cells that participate in innate immunity to protect against foreign pathogens and transforming cells. It is known that the activity of NK cells is regulated by a balance between activating and inhibitory signals rather than specific antigens. One important activating signal is mediated by the NKG2D receptor, which recognizes NKG2D ligands on cancer cells. Therefore, tumor cells that express sufficient amounts of NKG2D ligands could be eliminated by NKD2D+ cells, including NK cells. Oncogenes drive tumor cells to apoptosis resistant and uncontrolled proliferation by altered expression of many critical genes. Therefore, the expression of NKG2D ligands may be affected by oncogenes. This study focused on increasing the susceptibility of cancer cells to NK cells by regulating the expression of NKG2D ligands influenced by three oncogenes: k-ras, wnt, and c-myc. We demonstrated that inhibition of k-ras and c-myc increased the expression of NKG2D ligands and enhanced the susceptibility of cancer cells to NK cells. On the contrary, inhibition of the wnt pathway decreased MICA and ULBP1 transcripts. Although the decreased transcription of NKG2D ligands by inhibition of the wnt pathway, surface proteins of NKG2D ligands were not changed, and the susceptibility of HCT-116 cells was unaffected. The results demonstrate that the transcription of NKG2D ligands are regulated deferentially by the k-ras, c-myc, and wnt pathways and that the cytotoxicity of NK cells solely depends on the amount of surface NKG2D ligands.

자연살상세포(NK cells)은 림프구계의 세포로서 외부 침임 병원균을 막고 체내 형질변환세포를 제거하는데 참여하고 있다. 이러한 자연살상세포의 활성은 특정한 항원이 필요 없고 활성화 신호와 억제성 신호의 균형에 의해 조절되고 있다. 자연살상세포의 중요한 활성화 신호 중의 하나는 NKG2D 수용체를 통한 것인데, 이 NKG2D 수용체를 통해 자연살상세포는 암세포에 있는 NKG2D 리간드를 인식할 수 있다. 지금까지 인간에서는 여덟개의 NKG2D 리간드가 밝혀져 있고 이러한 리간드의 발현은 다양한 기전을 엄격하게 조절되고 있다. 암세포는 암유전자(oncogenes)에 의해 세포내 다양한 유전자의 발현이 정상세포와 확연히 달라지는데, 이러한 암유전자에 의해서 NKG2D 리간드의 발현이 영향을 받을 것으로 생각되어 진다. 이 연구는 인간의 암세포에서 가장 자주 발현되는 세가지 암유전자 k-ras와 c-myc, wnt의 억제를 통해 NKG2D 리간드의 발현이 어떻게 변화되는 지를 알아보았다. k-ras와 c-myc의 억제는 NKG2D 리간드의 발현을 효과적을 증가시켰고 암세포가 자연살상세포에 더욱 잘 죽게 변화되었다. 그러나 wnt 억제는 MICA와 ULBP1의 전사를 감소시켰다. wnt 억제에 의한 NKG2D 리간드의 전사억제에도 불구하고 세포막의 단백질 발현은 변하지 않아서 암세포의 자연살상세포에 대한 감수성은 별다른 변화를 보이지 않았다. 따라서 k-ras와 c-myc, wnt 억제는 각각 다른 반응을 보였으며 최종적인 자연살상세포에 대한 감수성은 NKG2D 리간드의 세포표면단백질 발현정도에 의해 결정됨을 알 수 있었다.

Keywords

References

  1. Bae, J. H., Kim, J. Y., Kim, M. J., Chang, S. H., Park, Y. S., Son, C. H., Park, S. J., Chung, J. S., Lee, E. Y., Kim, S. H. and Kang, C. D. 2010. Quercetin enhances susceptibility to NK cell-mediated lysis of tumor cells through induction of NKG2D ligands and suppression of HSP70. J Immunother 33, 391-401. https://doi.org/10.1097/CJI.0b013e3181d32f22
  2. Bae, J. H., Kim, S. J., Kim, M. J., Oh, S. O., Chung, J. S., Kim, S. H. and Kang, C. D. 2012. Susceptibility to natural killer cell-mediated lysis of colon cancer cells is enhanced by treatment with epidermal growth factor receptor inhibitors through UL16-binding protein-1 induction. Cancer Sci 103, 7-16. https://doi.org/10.1111/j.1349-7006.2011.02109.x
  3. Campoli, M. and Ferrone, S. 2008. Tumor escape mechanisms: potential role of soluble HLA antigens and NK cells activating ligands. Tissue Antigens 72, 321-334. https://doi.org/10.1111/j.1399-0039.2008.01106.x
  4. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. and Schreiber, R. D. 2002. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3, 991-998. https://doi.org/10.1038/ni1102-991
  5. Fuertes, M. B., Girart, M. V., Molinero, L. L., Domaica, C. I., Rossi, L. E., Barrio, M. M., Mordoh, J., Rabinovich, G. A. and Zwirner, N. W. 2008. Intracellular retention of the NKG2D ligand MHC class I chain-related gene A in human melanomas confers immune privilege and prevents NK cell-mediated cytotoxicity. J Immunol 180, 4606-4614. https://doi.org/10.4049/jimmunol.180.7.4606
  6. Greenman, C., Stephens, P., Smith, R., Dalgliesh, G. L., Hunter, C., Bignell, G., Davies, H., Teague, J., Butler, A., Stevens, C., Edkins, S., O'Meara, S., Vastrik, I., Schmidt, E. E., Avis, T., Barthorpe, S., Bhamra, G., Buck, G., Choudhury, B., Clements, J., Cole, J., Dicks, E., Forbes, S., Gray, K., Halliday, K., Harrison, R., Hills, K., Hinton, J., Jenkinson, A., Jones, D., Menzies, A., Mironenko, T., Perry, J., Raine, K., Richardson, D., Shepherd, R., Small, A., Tofts, C., Varian, J., Webb, T., West, S., Widaa, S., Yates, A., Cahill, D. P., Louis, D. N., Goldstraw, P., Nicholson, A. G., Brasseur, F., Looijenga, L., Weber, B. L., Chiew, Y. E., DeFazio, A., Greaves, M. F., Green, A. R., Campbell, P., Birney, E., Easton, D. F., Chenevix-Trench, G., Tan, M. H., Khoo, S. K., Teh, B. T., Yuen, S. T., Leung, S. Y., Wooster, R., Futreal, P. A. and Stratton, M. R. 2007. Patterns of somatic mutation in human cancer genomes. Nature 446, 153-158. https://doi.org/10.1038/nature05610
  7. Mazieres, J., He, B., You, L., Xu, Z. and Jablons, D. M. 2005. Wnt signaling in lung cancer. Cancer Lett 222, 1-10. https://doi.org/10.1016/j.canlet.2004.08.040
  8. Minamoto, T., Mai, M. and Ronai, Z. 2000. K-ras mutation: early detection in molecular diagnosis and risk assessment of colorectal, pancreas, and lung cancers--a review. Cancer Detect Prev 24, 1-12.
  9. Molinero, L. L., Domaica, C. I., Fuertes, M. B., Girart, M. V., Rossi, L. E. and Zwirner, N. W. 2006. Intracellular expression of MICA in activated CD4 T lymphocytes and protection from NK cell-mediated MICA-dependent cytotoxicity. Hum Immunol 67, 170-182. https://doi.org/10.1016/j.humimm.2006.02.010
  10. Nesbit, C. E., Tersak, J. M. and Prochownik, E. V. 1999. MYC oncogenes and human neoplastic disease. Oncogene 18, 3004-3016. https://doi.org/10.1038/sj.onc.1202746
  11. Park, S. W., Bae, J. H., Kim, S. D., Son, Y. O., Kim, J. Y., Park, H. J., Lee, C. H., Park, D. Y., Lee, M. K., Chung, B. S., Kim, S. H. and Kang, C. D. 2007. Comparison of level of NKG2D ligands between normal and tumor tissue using multiplex RT-PCR. Cancer Invest 25, 299-307. https://doi.org/10.1080/07357900701208824
  12. Rubinfeld, B., Souza, B., Albert, I., Muller, O., Chamberlain, S. H., Masiarz, F. R., Munemitsu, S. and Polakis, P. 1993. Association of the APC gene product with beta-catenin. Science 262, 1731-1734. https://doi.org/10.1126/science.8259518
  13. Salih, J., Hilpert, J., Placke, T., Grunebach, F., Steinle, A., Salih, H. R. and Krusch, M. 2010. The BCR/ABL-inhibitors imatinib, nilotinib and dasatinib differentially affect NK cell reactivity. Int J Cancer 127, 2119-2128. https://doi.org/10.1002/ijc.25233
  14. Shimizu, H., Julius, M. A., Giarre, M., Zheng, Z., Brown, A. M. and Kitajewski, J. 1997. Transformation by Wnt family proteins correlates with regulation of beta-catenin. Cell Growth Differ 8, 1349-1358.
  15. Smyth, M. J., Hayakawa, Y., Takeda, K. and Yagita, H. 2002. New aspects of natural-killer-cell surveillance and therapy of cancer. Nat Rev Cancer 2, 850-861. https://doi.org/10.1038/nrc928
  16. Takebe, N., Harris, P. J., Warren, R. Q. and Ivy, S. P. 2011. Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat Rev Clin Oncol 8, 97-106. https://doi.org/10.1038/nrclinonc.2010.196
  17. Van Scoyk, M., Randall, J., Sergew, A., Williams, L. M., Tennis, M. and Winn, R. A. 2008. Wnt signaling pathway and lung disease. Transl Res 151, 175-180. https://doi.org/10.1016/j.trsl.2007.12.011
  18. Vita, M. and Henriksson, M. 2006. The Myc oncoprotein as a therapeutic target for human cancer. Semin Cancer Biol 16, 318-330. https://doi.org/10.1016/j.semcancer.2006.07.015